Grb2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Upon receptor activation Grb2 is recruited to the plasma membrane (e.g. to phospho-LAT microdomains, activated RTKs) where it nucleates SOS/RAS signaling; a core site of action. Reason: Plasma membrane is where Grb2 assembles active signaling complexes; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0007165 signal transduction	IBA GO_REF:0000033	MODIFY	Summary: The bare 'signal transduction' is too broad for Grb2; its actual role is coupling RTKs to RAS, so the specific 'Ras protein signal transduction' (or MAPK cascade) child is more informative. Reason: Too general; replace with Ras protein signal transduction. Proposed replacements: Ras protein signal transduction Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005654 nucleoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Consistent with Grb2's reported nuclear pool involved in DNA-damage/replication-stress functions; a secondary localization, retained as non-core. Reason: Nuclear-pool localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor. Reason: Broader/less specific than cytosol; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0001784 phosphotyrosine residue binding	IBA GO_REF:0000033	ACCEPT	Summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors. Reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH2 domain specificity (definitions): Grb2’s SH2 domain recognizes phosphotyrosine (pY) motifs with characteristic preferences such as pYxNx and the Shc-derived pYVNV motif.
GO:0005154 epidermal growth factor receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function. Reason: Direct SH2 binding to activated EGFR; canonical core interaction. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md EGFR: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.
GO:0008180 COP9 signalosome	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function. Reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0043408 regulation of MAPK cascade	IBA GO_REF:0000033	ACCEPT	Summary: By coupling RTKs to SOS/RAS, Grb2 activates the RAF->MEK->ERK MAPK cascade; regulation of this cascade is a direct, core consequence of its adaptor activity. Reason: Grb2 directly drives the RAS->RAF->MEK->ERK cascade; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Grb2 has a nuclear pool linked to DNA repair (RAD51/MRE11) and miRNA biogenesis (AGO2/DICER1); a real secondary localization distinct from its core cytosolic/membrane signaling role. Reason: Nuclear localization for moonlighting roles; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor. Reason: Broader/less specific than cytosol; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005768 endosome	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Grb2 participates in receptor endocytic trafficking (with Cbl/dynamin) and is found on endosomes; a secondary localization tied to receptor internalization rather than core RAS activation. Reason: Endocytic-trafficking localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Endocytic trafficking example: Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0005794 Golgi apparatus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Golgi localization is reported (e.g. via PRNP interaction) but is a minor/secondary site relative to cytosol and plasma membrane; retained as non-core localization. Reason: Minor secondary localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0007265 Ras protein signal transduction	IEA GO_REF:0000117	ACCEPT	Summary: Grb2 transmits signals from activated receptors to RAS by recruiting SOS, converting RAS-GDP to RAS-GTP; this RAS-activating role is the central biological process Grb2 mediates. Reason: RAS activation via SOS is the central process; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0019904 protein domain specific binding	IEA GO_REF:0000117	ACCEPT	Summary: Reflects Grb2's SH3-mediated recognition of proline-rich (PxxP/RxxP) domains in partners such as SOS1, Gab2 and Dab2; an informative description of its modular-domain binding mode. Reason: SH3-domain-specific binding to proline-rich motifs is a core Grb2 mechanism. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH3 domain specificity (definitions): SH3 domains bind proline-rich sequences, typically PxxP-type motifs.
GO:0048009 insulin-like growth factor receptor signaling pathway	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Grb2 couples IGF1R (via SHC/IRS) to RAS/MAPK; one specific RTK pathway instance of its general adaptor role, retained as non-core. Reason: Specific IGF1R pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005515 protein binding	IPI PMID:10077576 Characterization of Sam68-like mammalian proteins SLM-1 and ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:10373493 Analysis of tyrosine phosphorylation-dependent interactions ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:10521483 Identification of Tek/Tie2 binding partners. Binding to a mu...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:10748054 CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:10871282 Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biologica...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11259577 Association of insulin receptor substrate 1 (IRS-1) y895 wit...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11445578 ERK regulates the hepatocyte growth factor-mediated interact...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11551227 Mouse alpha1-syntrophin binding to Grb2: further evidence of...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11551923 CD22 regulates B cell receptor-mediated signals via two doma...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11684012 Site-specific incorporation of a phosphotyrosine mimetic rev...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:15102471 Bioinformatics and cellular signaling.	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:15301538 Prion protein interaction with the C-terminal SH3 domain of ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:15953601 Erythropoietin receptor Y479 couples to ERK1/2 activation vi...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:17673906 TGF-beta activates Erk MAP kinase signalling through direct ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:18273058 ShcA signalling is essential for tumour progression in mouse...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:19914172 KIF26A is an unconventional kinesin and regulates GDNF-Ret s...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:21487392 LKB1 regulates TCR-mediated PLCγ1 activation and thymocyte p...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:22561606 Tespa1 is involved in late thymocyte development through the...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:23452850 Interaction domains of Sos1/Grb2 are finely tuned for cooper...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:24584089 Quantitative proteomics analysis of signalosome dynamics in ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:7518772 Phosphorylation of receptor protein-tyrosine phosphatase alp...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:7529871 Interaction of Shc with Grb2 regulates association of Grb2 w...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:7535773 Growth hormone-promoted tyrosyl phosphorylation of SHC prote...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:8479540 The SH2 and SH3 domains of mammalian Grb2 couple the EGF rec...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:9182757 A lipid-anchored Grb2-binding protein that links FGF-recepto...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:9569023 Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2.	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0001784 phosphotyrosine residue binding	IEA GO_REF:0000107	ACCEPT	Summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors. Reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH2 domain specificity (definitions): Grb2’s SH2 domain recognizes phosphotyrosine (pY) motifs with characteristic preferences such as pYxNx and the Shc-derived pYVNV motif.
GO:0005091 guanyl-nucleotide exchange factor adaptor activity	IEA GO_REF:0000120	ACCEPT	Summary: Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF. Reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005154 epidermal growth factor receptor binding	IEA GO_REF:0000107	ACCEPT	Summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function. Reason: Direct SH2 binding to activated EGFR; canonical core interaction. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md EGFR: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.
GO:0005168 neurotrophin TRKA receptor binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2 binds ligand-activated NTRK1/TrkA to relay neurotrophin signals to RAS/MAPK; a specific RTK interaction instance of its core adaptor role, non-core. Reason: Specific TrkA/NTRK1 interaction; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005829 cytosol	IEA GO_REF:0000120	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0007173 epidermal growth factor receptor signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: Grb2 is an obligate node in EGFR signaling, coupling activated EGFR to SOS/RAS/ERK; one of the best-established Grb2 pathway roles and a core process. Reason: Grb2 is a central, well-evidenced EGFR-pathway node. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Concrete phosphosite examples** (illustrative, mechanistically useful for annotation):
GO:0008180 COP9 signalosome	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function. Reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0008286 insulin receptor signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core. Reason: Specific insulin/IRS pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0017124 SH3 domain binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Describes Grb2 being bound by, or binding via, SH3 domains; partly redundant with the more informative SH3/proline-rich adaptor terms, so retained but as non-core. Reason: Redundant with informative SH3 adaptor terms; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH3 domain specificity (definitions): SH3 domains bind proline-rich sequences, typically PxxP-type motifs.
GO:0019901 protein kinase binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Grb2 binds tyrosine kinases (e.g. via SH2 to phospho-RTKs), but 'protein kinase binding' is a generic, uninformative MF subsumed by the specific phosphotyrosine/adaptor terms. Reason: Generic kinase binding; superseded by specific adaptor MFs. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0030674 protein-macromolecule adaptor activity	IEA GO_REF:0000107	ACCEPT	Summary: More specific adaptor MF describing Grb2 physically linking two proteins (e.g. phospho-receptor to SOS); appropriate for the SH2/SH3 bridging activity. Retain as core. Reason: Specific adaptor MF matching Grb2's bridging role. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0031623 receptor internalization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2 cooperates with Cbl/dynamin in ubiquitin-dependent EGFR internalization; a downstream trafficking process linked to but distinct from its core RAS-activating adaptor role. Reason: Receptor-endocytosis role; downstream, non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Endocytic trafficking example: Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0042110 T cell activation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Via phospho-LAT recruitment Grb2 helps organize TCR signaling and T-cell activation; a lineage-specific downstream process, not the abstracted core adaptor function. Reason: Downstream immune process; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md In T cells, tyrosine-phosphorylated LAT recruits Grb2-family adaptors and SOS to the plasma membrane (notably glycolipid-enriched microdomains), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
GO:0042267 natural killer cell mediated cytotoxicity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: In NK cells Grb2 acts in DAP10/NKG2D and CD226 signaling (with Vav1/PI3K) affecting cytotoxicity; a lineage-specific downstream immune process, non-core. Reason: NK-cell-specific downstream immune role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 haploid insufficiency in mice selectively weakened TCR-induced JNK and p38 signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
GO:0042770 signal transduction in response to DNA damage	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2's nuclear DNA-damage signaling (fork protection, RAD51/MRE11 handling, RBBP6 ubiquitination at damage sites) is a moonlighting process distinct from its core RTK adaptor function. Reason: Nuclear DNA-damage signaling moonlighting role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0042802 identical protein binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Grb2 can homodimerize via SH2 domain-swapping, but 'identical protein binding' is a generic MF not informative of its adaptor function; dimerization is better noted as a regulatory layer. Reason: Generic self-binding term; not core adaptor function. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md WT GRB2 purification yielded ~80% monomer / 20% dimer by SEC; a hinge mutant V122P/V123P produced ~80% dimer / 20% monomer; an N188D/N214D mutant showed ~40% dimer / 60% monomer.
GO:0043560 insulin receptor substrate binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2 binds tyrosine-phosphorylated IRS proteins (IRS1/IRS4) via its SH2 domain, connecting insulin/IGF signaling to RAS; a specific real partner interaction, non-core. Reason: Specific IRS partner interaction; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0045953 negative regulation of natural killer cell mediated cytotoxicity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2 also participates in inhibitory NK signaling (e.g. via TIGIT, suppressing PI3K/MAPK); a specialized regulatory immune role downstream of its adaptor function, non-core. Reason: Inhibitory NK-signaling role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 haploid insufficiency in mice selectively weakened TCR-induced JNK and p38 signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
GO:0046875 ephrin receptor binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2 binds Eph receptors (e.g. EphB1) to activate MAPK/ERK and promote chemotaxis; a specific real receptor interaction that is one instance of its general RTK-adaptor role. Reason: Specific Eph-receptor interaction; non-core instance. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0070436 Grb2-EGFR complex	IEA GO_REF:0000107	ACCEPT	Summary: Grb2 physically forms a complex with activated EGFR; this cellular-component term captures the assembled signaling complex at the heart of EGFR->RAS coupling. Retain as core. Reason: Defined Grb2:EGFR complex; directly supported and core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md EGFR: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.
GO:0071479 cellular response to ionizing radiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Grb2 has a nuclear DNA-damage/replication-stress role (protecting stalled forks, modulating RAD51/MRE11); a distinct moonlighting process separate from its core RTK adaptor function. Reason: Nuclear DNA-damage moonlighting role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:2000379 positive regulation of reactive oxygen species metabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Reported ROS-metabolism regulation is a downstream/indirect consequence of Grb2-dependent signaling; retained as a non-core pleiotropic process. Reason: Indirect downstream ROS effect; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0032991 protein-containing complex	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: An extremely generic CC term; every protein in a complex would qualify. Uninformative relative to the specific Grb2-EGFR complex and signaling-complex annotations. Reason: Trivially generic complex term; over-annotated. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005737 cytoplasm	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor. Reason: Broader/less specific than cytosol; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0001784 phosphotyrosine residue binding	ISO GO_REF:0000096	ACCEPT	Summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors. Reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH2 domain specificity (definitions): Grb2’s SH2 domain recognizes phosphotyrosine (pY) motifs with characteristic preferences such as pYxNx and the Shc-derived pYVNV motif.
GO:0001784 phosphotyrosine residue binding	ISO GO_REF:0000119	ACCEPT	Summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors. Reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH2 domain specificity (definitions): Grb2’s SH2 domain recognizes phosphotyrosine (pY) motifs with characteristic preferences such as pYxNx and the Shc-derived pYVNV motif.
GO:0005091 guanyl-nucleotide exchange factor adaptor activity	ISO GO_REF:0000119	ACCEPT	Summary: Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF. Reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005154 epidermal growth factor receptor binding	ISO GO_REF:0000096	ACCEPT	Summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function. Reason: Direct SH2 binding to activated EGFR; canonical core interaction. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md EGFR: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.
GO:0005154 epidermal growth factor receptor binding	ISO GO_REF:0000119	ACCEPT	Summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function. Reason: Direct SH2 binding to activated EGFR; canonical core interaction. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md EGFR: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.
GO:0005168 neurotrophin TRKA receptor binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 binds ligand-activated NTRK1/TrkA to relay neurotrophin signals to RAS/MAPK; a specific RTK interaction instance of its core adaptor role, non-core. Reason: Specific TrkA/NTRK1 interaction; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005634 nucleus	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 has a nuclear pool linked to DNA repair (RAD51/MRE11) and miRNA biogenesis (AGO2/DICER1); a real secondary localization distinct from its core cytosolic/membrane signaling role. Reason: Nuclear localization for moonlighting roles; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005768 endosome	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 participates in receptor endocytic trafficking (with Cbl/dynamin) and is found on endosomes; a secondary localization tied to receptor internalization rather than core RAS activation. Reason: Endocytic-trafficking localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Endocytic trafficking example: Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0005813 centrosome	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: A reported secondary subcellular localization (ISO); not a primary site of Grb2's adaptor signaling activity, so retained as non-core localization. Reason: Secondary localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	ISO GO_REF:0000119	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0007173 epidermal growth factor receptor signaling pathway	ISO GO_REF:0000119	ACCEPT	Summary: Grb2 is an obligate node in EGFR signaling, coupling activated EGFR to SOS/RAS/ERK; one of the best-established Grb2 pathway roles and a core process. Reason: Grb2 is a central, well-evidenced EGFR-pathway node. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Concrete phosphosite examples** (illustrative, mechanistically useful for annotation):
GO:0008180 COP9 signalosome	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function. Reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0008286 insulin receptor signaling pathway	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core. Reason: Specific insulin/IRS pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0017124 SH3 domain binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Describes Grb2 being bound by, or binding via, SH3 domains; partly redundant with the more informative SH3/proline-rich adaptor terms, so retained but as non-core. Reason: Redundant with informative SH3 adaptor terms; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH3 domain specificity (definitions): SH3 domains bind proline-rich sequences, typically PxxP-type motifs.
GO:0019899 enzyme binding	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: Grb2 does bind enzymes (SOS, PTPN11, kinases), but 'enzyme binding' is a generic non-informative MF better captured by the specific adaptor/phosphotyrosine-binding terms. Reason: Generic enzyme binding; superseded by specific adaptor MFs. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0019901 protein kinase binding	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Grb2 binds tyrosine kinases (e.g. via SH2 to phospho-RTKs), but 'protein kinase binding' is a generic, uninformative MF subsumed by the specific phosphotyrosine/adaptor terms. Reason: Generic kinase binding; superseded by specific adaptor MFs. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0019904 protein domain specific binding	ISO GO_REF:0000096	ACCEPT	Summary: Reflects Grb2's SH3-mediated recognition of proline-rich (PxxP/RxxP) domains in partners such as SOS1, Gab2 and Dab2; an informative description of its modular-domain binding mode. Reason: SH3-domain-specific binding to proline-rich motifs is a core Grb2 mechanism. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH3 domain specificity (definitions): SH3 domains bind proline-rich sequences, typically PxxP-type motifs.
GO:0030036 actin cytoskeleton organization	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Through partners (e.g. WASP/WAVE pathways, RAB13/RHOA recruitment), Grb2 can influence actin dynamics; a downstream/pleiotropic effect, not the core RAS-coupling function. Reason: Downstream cytoskeletal effect; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0030674 protein-macromolecule adaptor activity	ISO GO_REF:0000119	ACCEPT	Summary: More specific adaptor MF describing Grb2 physically linking two proteins (e.g. phospho-receptor to SOS); appropriate for the SH2/SH3 bridging activity. Retain as core. Reason: Specific adaptor MF matching Grb2's bridging role. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0031295 T cell costimulation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 contributes to costimulatory (e.g. CD28) signaling during T-cell activation; a specialized downstream immune role secondary to its core adaptor activity. Reason: Specialized costimulatory role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md In T cells, tyrosine-phosphorylated LAT recruits Grb2-family adaptors and SOS to the plasma membrane (notably glycolipid-enriched microdomains), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
GO:0031623 receptor internalization	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 cooperates with Cbl/dynamin in ubiquitin-dependent EGFR internalization; a downstream trafficking process linked to but distinct from its core RAS-activating adaptor role. Reason: Receptor-endocytosis role; downstream, non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Endocytic trafficking example: Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0042110 T cell activation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Via phospho-LAT recruitment Grb2 helps organize TCR signaling and T-cell activation; a lineage-specific downstream process, not the abstracted core adaptor function. Reason: Downstream immune process; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md In T cells, tyrosine-phosphorylated LAT recruits Grb2-family adaptors and SOS to the plasma membrane (notably glycolipid-enriched microdomains), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
GO:0042267 natural killer cell mediated cytotoxicity	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: In NK cells Grb2 acts in DAP10/NKG2D and CD226 signaling (with Vav1/PI3K) affecting cytotoxicity; a lineage-specific downstream immune process, non-core. Reason: NK-cell-specific downstream immune role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 haploid insufficiency in mice selectively weakened TCR-induced JNK and p38 signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
GO:0042770 signal transduction in response to DNA damage	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2's nuclear DNA-damage signaling (fork protection, RAD51/MRE11 handling, RBBP6 ubiquitination at damage sites) is a moonlighting process distinct from its core RTK adaptor function. Reason: Nuclear DNA-damage signaling moonlighting role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0042802 identical protein binding	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Grb2 can homodimerize via SH2 domain-swapping, but 'identical protein binding' is a generic MF not informative of its adaptor function; dimerization is better noted as a regulatory layer. Reason: Generic self-binding term; not core adaptor function. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md WT GRB2 purification yielded ~80% monomer / 20% dimer by SEC; a hinge mutant V122P/V123P produced ~80% dimer / 20% monomer; an N188D/N214D mutant showed ~40% dimer / 60% monomer.
GO:0043560 insulin receptor substrate binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: Grb2 binds tyrosine-phosphorylated IRS proteins (IRS1/IRS4) via its SH2 domain, connecting insulin/IGF signaling to RAS; a specific real partner interaction, non-core. Reason: Specific IRS partner interaction; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0043560 insulin receptor substrate binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 binds tyrosine-phosphorylated IRS proteins (IRS1/IRS4) via its SH2 domain, connecting insulin/IGF signaling to RAS; a specific real partner interaction, non-core. Reason: Specific IRS partner interaction; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0044877 protein-containing complex binding	ISO GO_REF:0000096	MODIFY	Summary: Grb2 binds assembled receptor/scaffold complexes via its adaptor domains; rather than the generic complex-binding term, its molecular-adaptor activity better captures the function. Reason: Generalize/redirect to the molecular-adaptor MF. Proposed replacements: molecular adaptor activity Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0045953 negative regulation of natural killer cell mediated cytotoxicity	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 also participates in inhibitory NK signaling (e.g. via TIGIT, suppressing PI3K/MAPK); a specialized regulatory immune role downstream of its adaptor function, non-core. Reason: Inhibitory NK-signaling role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 haploid insufficiency in mice selectively weakened TCR-induced JNK and p38 signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
GO:0046875 ephrin receptor binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 binds Eph receptors (e.g. EphB1) to activate MAPK/ERK and promote chemotaxis; a specific real receptor interaction that is one instance of its general RTK-adaptor role. Reason: Specific Eph-receptor interaction; non-core instance. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0051219 phosphoprotein binding	ISO GO_REF:0000096	MODIFY	Summary: Grb2's binding to phosphorylated partners is specifically phosphotyrosine recognition via its SH2 domain; the precise child term 'phosphotyrosine residue binding' should be used instead. Reason: Replace with the specific phosphotyrosine-residue-binding MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH2 domain specificity (definitions): Grb2’s SH2 domain recognizes phosphotyrosine (pY) motifs with characteristic preferences such as pYxNx and the Shc-derived pYVNV motif.
GO:0070436 Grb2-EGFR complex	ISO GO_REF:0000119	ACCEPT	Summary: Grb2 physically forms a complex with activated EGFR; this cellular-component term captures the assembled signaling complex at the heart of EGFR->RAS coupling. Retain as core. Reason: Defined Grb2:EGFR complex; directly supported and core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md EGFR: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.
GO:0071479 cellular response to ionizing radiation	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Grb2 has a nuclear DNA-damage/replication-stress role (protecting stalled forks, modulating RAD51/MRE11); a distinct moonlighting process separate from its core RTK adaptor function. Reason: Nuclear DNA-damage moonlighting role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0098793 presynapse	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: A reported presynaptic localization (ISO); a tissue/context-specific secondary site rather than a primary site of Grb2's adaptor signaling, kept as non-core. Reason: Context-specific secondary localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:2000379 positive regulation of reactive oxygen species metabolic process	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Reported ROS-metabolism regulation is a downstream/indirect consequence of Grb2-dependent signaling; retained as a non-core pleiotropic process. Reason: Indirect downstream ROS effect; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005515 protein binding	IPI PMID:9507006 Identification of sirm, a novel insulin-regulated SH3 bindin...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:16247031 Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/M...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005068 transmembrane receptor protein tyrosine kinase adaptor activity	ISO PMID:11173924 Neuregulin-induced association of Sos Ras exchange protein w...	ACCEPT	Summary: Directly describes Grb2 acting as the adaptor that links transmembrane RTKs (EGFR, PDGFR, KIT, etc.) to downstream RAS signaling; the most context-specific adaptor MF and a core function. Reason: RTK-specific adaptor activity is exactly Grb2's defining role. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0038133 ERBB2-ERBB3 signaling pathway	ISO PMID:11173924 Neuregulin-induced association of Sos Ras exchange protein w...	KEEP AS NON CORE	Summary: Grb2 participates in ERBB2/ERBB3 RTK signaling, one of many specific RTK pathways it serves; a non-core instance of its general RTK->RAS adaptor function. Reason: Specific RTK pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005938 cell cortex	IGI PMID:17881575 Distinct requirements for Gab1 in Met and EGF receptor signa...	KEEP AS NON CORE	Summary: Cortical localization (IGI) reflects Grb2's membrane-proximal recruitment during receptor signaling and cytoskeletal/migration roles; a secondary site, not its primary cytosolic/membrane signaling locus. Reason: Membrane-proximal cortical localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0060090 molecular adaptor activity	ISO PMID:11823423 A mutant EGF-receptor defective in ubiquitylation and endocy...	ACCEPT	Summary: Grb2 is the prototypical non-catalytic molecular adaptor, physically bridging phosphotyrosine-bearing receptors to proline-rich effectors; the parent adaptor MF correctly describes its essence. Reason: Grb2 is a textbook molecular adaptor; correct core MF. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0048009 insulin-like growth factor receptor signaling pathway	IDA PMID:33567274 Prenatal correction of IGF2 to rescue the growth phenotypes ...	KEEP AS NON CORE	Summary: Grb2 couples IGF1R (via SHC/IRS) to RAS/MAPK; one specific RTK pathway instance of its general adaptor role, retained as non-core. Reason: Specific IGF1R pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005091 guanyl-nucleotide exchange factor adaptor activity	IDA PMID:12354753 Increased K-ras protein and activity in mouse and human lung...	ACCEPT	Summary: Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF. Reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0008286 insulin receptor signaling pathway	IDA PMID:8828504 Comparison of the insulin and insulin-like growth factor 1 m...	KEEP AS NON CORE	Summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core. Reason: Specific insulin/IRS pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005091 guanyl-nucleotide exchange factor adaptor activity	ISO PMID:8828504 Comparison of the insulin and insulin-like growth factor 1 m...	ACCEPT	Summary: Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF. Reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0048009 insulin-like growth factor receptor signaling pathway	IDA PMID:12483226 IGF-1 receptor regulates lifespan and resistance to oxidativ...	KEEP AS NON CORE	Summary: Grb2 couples IGF1R (via SHC/IRS) to RAS/MAPK; one specific RTK pathway instance of its general adaptor role, retained as non-core. Reason: Specific IGF1R pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005091 guanyl-nucleotide exchange factor adaptor activity	IDA PMID:8479536 Association of Sos Ras exchange protein with Grb2 is implica...	ACCEPT	Summary: Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF. Reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0008286 insulin receptor signaling pathway	IDA PMID:8649419 Insulin signalling and insulin actions in the muscles and li...	KEEP AS NON CORE	Summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core. Reason: Specific insulin/IRS pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005091 guanyl-nucleotide exchange factor adaptor activity	IDA PMID:9199344 Shc contains two Grb2 binding sites needed for efficient for...	ACCEPT	Summary: Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF. Reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0050853 B cell receptor signaling pathway	IDA PMID:9199344 Shc contains two Grb2 binding sites needed for efficient for...	KEEP AS NON CORE	Summary: Grb2 amplifies Ca2+ mobilization and ERK activation downstream of the phosphorylated BCR (via FCRL1/LAT2), a real but lineage-specific deployment of its generic phospho-LAT-style adaptor role. Reason: Real BCR role but a downstream, cell-type-specific deployment. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md In T cells, tyrosine-phosphorylated LAT recruits Grb2-family adaptors and SOS to the plasma membrane (notably glycolipid-enriched microdomains), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
GO:0005068 transmembrane receptor protein tyrosine kinase adaptor activity	IGI PMID:17881575 Distinct requirements for Gab1 in Met and EGF receptor signa...	ACCEPT	Summary: Directly describes Grb2 acting as the adaptor that links transmembrane RTKs (EGFR, PDGFR, KIT, etc.) to downstream RAS signaling; the most context-specific adaptor MF and a core function. Reason: RTK-specific adaptor activity is exactly Grb2's defining role. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0007173 epidermal growth factor receptor signaling pathway	IGI PMID:17881575 Distinct requirements for Gab1 in Met and EGF receptor signa...	ACCEPT	Summary: Grb2 is an obligate node in EGFR signaling, coupling activated EGFR to SOS/RAS/ERK; one of the best-established Grb2 pathway roles and a core process. Reason: Grb2 is a central, well-evidenced EGFR-pathway node. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Concrete phosphosite examples** (illustrative, mechanistically useful for annotation):
GO:0014044 Schwann cell development	IMP PMID:10704452 A dual role of erbB2 in myelination and in expansion of the ...	KEEP AS NON CORE	Summary: Grb2-dependent ErbB/NRG1 RTK signaling contributes to Schwann cell development; a downstream developmental outcome. Reason: Real but downstream developmental phenotype of Grb2 adaptor signaling; non-core (experimental IMP retained). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A targeted null mutation in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
GO:0042552 myelination	IMP PMID:10704452 A dual role of erbB2 in myelination and in expansion of the ...	KEEP AS NON CORE	Summary: Myelination defects arise downstream of Grb2-dependent ErbB/RTK signaling in Schwann cells; a distal phenotype. Reason: Downstream developmental/glial phenotype; non-core (experimental IMP retained). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A targeted null mutation in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
GO:0042552 myelination	IMP PMID:18760695 Neuregulin-1/ErbB signaling serves distinct functions in mye...	KEEP AS NON CORE	Summary: Myelination defects arise downstream of Grb2-dependent ErbB/RTK signaling in Schwann cells; a distal phenotype. Reason: Downstream developmental/glial phenotype; non-core (experimental IMP retained). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A targeted null mutation in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
GO:0005515 protein binding	IPI PMID:24907343 Themis2 is not required for B cell development, activation, ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:10744659 A BASH/SLP-76-related adaptor protein MIST/Clnk involved in ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:7689150 Molecular cloning of the mouse grb2 gene: differential inter...	ACCEPT	Summary: More specific adaptor MF describing Grb2 physically linking two proteins (e.g. phospho-receptor to SOS); appropriate for the SH2/SH3 bridging activity. Retain as core. Reason: Specific adaptor MF matching Grb2's bridging role. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:22801373 Protein tyrosine phosphatase α phosphotyrosyl-789 binds BCAR...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:28098138 SCIMP is a transmembrane non-TIR TLR adaptor that promotes p...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:28290451 Development of SH2 probes and pull-down assays to detect pat...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005829 cytosol	TAS Reactome:R-MMU-2730846	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-2730869	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-8983356	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9007126	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9007137	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-914067	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9604768	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9606621	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9606623	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9606789	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9607226	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9645128	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9645133	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9645136	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9674973	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9680646	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9682158	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9682182	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9029146	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9029152	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9029162	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9682572	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9763903	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-MMU-9764150	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005829 cytosol	TAS Reactome:R-NUL-9036961	ACCEPT	Summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27). Reason: Cytosol is Grb2's principal resting compartment; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005911 cell-cell junction	IDA PMID:23793062 The lymphoid lineage-specific actin-uncapping protein Rltpr ...	KEEP AS NON CORE	Summary: Grb2 can localize to cell-cell junction-associated receptor complexes in specific contexts. Reason: Secondary/context-specific localization; non-core (experimental IDA retained). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005515 protein binding	IPI PMID:10982817 A deubiquitinating enzyme UBPY interacts with the Src homolo...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11711534 'Srcasm: a novel Src activating and signaling molecule.	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:16339969 Efficient suppression of FGF-2-induced ERK activation by the...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11152963 SETA is a multifunctional adapter protein with three SH3 dom...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:15569713 The neuronal scaffold protein Shank3 mediates signaling and ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:8632004 The tyrosine phosphatase PTP1C associates with Vav, Grb2, an...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:16405865 Merlin inhibits growth hormone-regulated Raf-ERKs pathways b...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:22732588 Interchangeability of Themis1 and Themis2 in thymocyte devel...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0017124 SH3 domain binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Describes Grb2 being bound by, or binding via, SH3 domains; partly redundant with the more informative SH3/proline-rich adaptor terms, so retained but as non-core. Reason: Redundant with informative SH3 adaptor terms; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH3 domain specificity (definitions): SH3 domains bind proline-rich sequences, typically PxxP-type motifs.
GO:0005515 protein binding	IPI PMID:11739737 Gab3, a new DOS/Gab family member, facilitates macrophage di...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0008180 COP9 signalosome	IDA PMID:22561606 Tespa1 is involved in late thymocyte development through the...	MARK AS OVER ANNOTATED	Summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function. Reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence). Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005886 plasma membrane	IDA PMID:17923684 Neph1 cooperates with nephrin to transduce a signal that ind...	ACCEPT	Summary: Upon receptor activation Grb2 is recruited to the plasma membrane (e.g. to phospho-LAT microdomains, activated RTKs) where it nucleates SOS/RAS signaling; a core site of action. Reason: Plasma membrane is where Grb2 assembles active signaling complexes; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0030838 positive regulation of actin filament polymerization	IGI PMID:17923684 Neph1 cooperates with nephrin to transduce a signal that ind...	KEEP AS NON CORE	Summary: Grb2 can promote actin polymerization through downstream effectors during migration; a pleiotropic cytoskeletal effect, not its core RAS-coupling MF. Reason: Downstream actin-polymerization effect; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0005515 protein binding	IPI PMID:15467741 Magicin, a novel cytoskeletal protein associates with the NF...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0019903 protein phosphatase binding	IPI PMID:20398064 Tyrosine phosphorylation of R3 subtype receptor-type protein...	MARK AS OVER ANNOTATED	Summary: Grb2 associates with PTP partners (PTPN11/SHP2, R3 RPTPs), but 'protein phosphatase binding' is a generic MF that does not describe its adaptor function; over-annotation. Reason: Generic phosphatase binding; uninformative for adaptor role. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005634 nucleus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Grb2 has a nuclear pool linked to DNA repair (RAD51/MRE11) and miRNA biogenesis (AGO2/DICER1); a real secondary localization distinct from its core cytosolic/membrane signaling role. Reason: Nuclear localization for moonlighting roles; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005768 endosome	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Grb2 participates in receptor endocytic trafficking (with Cbl/dynamin) and is found on endosomes; a secondary localization tied to receptor internalization rather than core RAS activation. Reason: Endocytic-trafficking localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Endocytic trafficking example: Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0046875 ephrin receptor binding	IPI PMID:12925710 EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and pro...	KEEP AS NON CORE	Summary: Grb2 binds Eph receptors (e.g. EphB1) to activate MAPK/ERK and promote chemotaxis; a specific real receptor interaction that is one instance of its general RTK-adaptor role. Reason: Specific Eph-receptor interaction; non-core instance. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005515 protein binding	IPI PMID:16249387 LIME acts as a transmembrane adapter mediating BCR-dependent...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:10330178 Ajuba, a novel LIM protein, interacts with Grb2, augments mi...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11571277 PrPC directly interacts with proteins involved in signaling ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:11585837 Mammalian sprouty proteins inhibit cell growth and different...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0008543 fibroblast growth factor receptor signaling pathway	IGI PMID:11585837 Mammalian sprouty proteins inhibit cell growth and different...	KEEP AS NON CORE	Summary: Grb2 (via FRS2) couples FGFRs to RAS/ERK; one specific RTK pathway among many, a non-core deployment of its core adaptor function. Reason: Specific FGFR pathway instance; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0043408 regulation of MAPK cascade	IGI PMID:15569713 The neuronal scaffold protein Shank3 mediates signaling and ...	ACCEPT	Summary: By coupling RTKs to SOS/RAS, Grb2 activates the RAF->MEK->ERK MAPK cascade; regulation of this cascade is a direct, core consequence of its adaptor activity. Reason: Grb2 directly drives the RAS->RAF->MEK->ERK cascade; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
GO:0005515 protein binding	IPI PMID:19597497 Themis is a member of a new metazoan gene family and is requ...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0005515 protein binding	IPI PMID:19597498 Themis, a T cell-specific protein important for late thymocy...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0048646 anatomical structure formation involved in morphogenesis	IMP PMID:11369229 Gene dosage-dependent functions for phosphotyrosine-Grb2 sig...	KEEP AS NON CORE	Summary: Grb2 is essential for early embryonic morphogenesis (endoderm/epiblast formation) reflecting its role in transmitting growth-factor signals; a pleiotropic developmental outcome, not its core MF. Reason: Pleiotropic developmental requirement; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A targeted null mutation in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
GO:0060670 branching involved in labyrinthine layer morphogenesis	IMP PMID:11369229 Gene dosage-dependent functions for phosphotyrosine-Grb2 sig...	KEEP AS NON CORE	Summary: Placental labyrinth branching depends on Grb2-mediated growth-factor signaling; a specific developmental phenotype downstream of its adaptor function, not a core annotation. Reason: Specific developmental phenotype; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A targeted null mutation in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
GO:0005515 protein binding	IPI PMID:14722116 The importance of three membrane-distal tyrosines in the ada...	MARK AS OVER ANNOTATED	Summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms. Reason: Bare protein binding is uninformative; specific adaptor MFs preferred. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is an adaptor/scaffold protein: it has no catalytic activity, but controls signal flow by physically linking phosphotyrosine-containing receptors/scaffolds to proline-rich effector proteins.
GO:0019904 protein domain specific binding	IPI PMID:8438166 Identification of a ten-amino acid proline-rich SH3 binding ...	ACCEPT	Summary: Reflects Grb2's SH3-mediated recognition of proline-rich (PxxP/RxxP) domains in partners such as SOS1, Gab2 and Dab2; an informative description of its modular-domain binding mode. Reason: SH3-domain-specific binding to proline-rich motifs is a core Grb2 mechanism. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md SH3 domain specificity (definitions): SH3 domains bind proline-rich sequences, typically PxxP-type motifs.
GO:0030154 cell differentiation	IMP PMID:16908534 The Grb2/Mek pathway represses Nanog in murine embryonic ste...	KEEP AS NON CORE	Summary: Grb2 is required for differentiation programs (e.g. endoderm) by relaying RTK/RAS signals; a broad downstream developmental process, kept as non-core. Reason: Broad downstream differentiation role; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A targeted null mutation in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
GO:0016020 membrane	IDA PMID:15983387 Frag1, a homolog of alternative replication factor C subunit...	MARK AS OVER ANNOTATED	Summary: Generic 'membrane' localization; Grb2 acts at the inner plasma membrane, captured by the specific plasma membrane term. Reason: Generic parent localization superseded by the specific plasma membrane annotation. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0005737 cytoplasm	IDA PMID:15736129 Six post-implantation lethal knockouts of genes for lipophil...	KEEP AS NON CORE	Summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor. Reason: Broader/less specific than cytosol; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Grb2 is primarily cytosolic but is recruited to signaling complexes at the plasma membrane upon receptor activation, including immune microdomains; it also participates in endocytosis/endosomes and is described across cytoplasm, membrane, endosomes, and nucleus in RTK-activated contexts.
GO:0012506 vesicle membrane	IDA PMID:12147689 Phosphatidylinositol 4,5-biphosphate (PIP2)-induced vesicle ...	KEEP AS NON CORE	Summary: Grb2 is found on vesicle membranes during receptor trafficking/endocytosis; a secondary localization tied to internalization rather than core signaling, non-core. Reason: Trafficking-vesicle localization; non-core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md Endocytic trafficking example: Grb2 cooperates with Cbl in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
GO:0007265 Ras protein signal transduction	TAS PMID:1322798 The SH2 and SH3 domain-containing protein GRB2 links recepto...	ACCEPT	Summary: Grb2 transmits signals from activated receptors to RAS by recruiting SOS, converting RAS-GDP to RAS-GTP; this RAS-activating role is the central biological process Grb2 mediates. Reason: RAS activation via SOS is the central process; core. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB. file:mouse/Grb2/Grb2-deep-research-falcon.md A dominant role for Grb2 is to couple receptor tyrosine kinases (RTKs) to Ras activation by recruiting SOS1/2 through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of Raf→MEK→ERK signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.

Aspect	Key points for mouse Grb2 (UniProt Q60631)	Quantitative / specific examples	Evidence
Domains and binding specificity	GRB2 is a ~25 kDa adaptor with N-SH3–SH2–C-SH3 architecture. The SH2 domain recognizes phosphotyrosine motifs, especially pYxNx and the Shc pYVNV motif; SH3 domains bind proline-rich ligands, including SOS1/2 and other effectors.	SH2 domain residues span ~60–152; SH3 domains bind PxxP motifs; SOS1 peptides reported as strong binders include PVPPPVPPRRRP and PKLPPKTYKREH; Gab2 c-SH3 interaction recognizes an RxxP motif within residues 503–524.	(wang2024theconfigurationof pages 1-2, wang2024theconfigurationof pages 12-14, wang2024theconfigurationof pages 15-17, wang2024theconfigurationof pages 14-15)
Core signaling pathways	Primary molecular role is to couple activated phosphotyrosine-containing receptors/scaffolds to Ras activation by recruiting SOS, thereby driving the Ras→Raf→MEK→ERK cascade. GRB2 also recruits Gab1/2 to connect RTKs to PI3K/AKT signaling.	Specific phosphosites/partners include EGFR Y1068/Y1086/Y1173, Shc Y317 (pYVNV) and Y239/Y240, FAK Y925 (pYxNx), c-Met Y1356, IRS-1 Y891, PDGFRβ Y716, and SHP2 Y542.	(cheng1998mammaliangrb2regulates pages 1-2, wang2024theconfigurationof pages 9-11, wang2024theconfigurationof pages 12-14, wang2024theconfigurationof pages 2-4, wang2024theconfigurationof pages 11-12)
Subcellular localization	GRB2 is largely cytosolic but is recruited to activated receptor complexes at the plasma membrane; it also participates in glycolipid-enriched/raft-like microdomains, receptor internalization/endosomes, and can be detected in nucleus under RTK-activated conditions.	EGFR inward trafficking requires intact GRB2; SH3-mediated coupling to Cbl and dynamin supports vesicle formation and endosomal routing. Reviews summarize localization across cytoplasm, membrane, endosomes, nucleus.	(wang2024theconfigurationof pages 9-11, wang2024theconfigurationof pages 2-4, gong2001disruptionoft pages 1-2, wang2024theconfigurationof pages 15-17)
Immune signaling organization	In T cells, phosphorylated LAT recruits GRB2-family adaptors and Sos to membrane microdomains, linking TCR engagement to MAPK-family outputs and cytokine production. Recent work indicates GRB2 conformational state contributes to LAT cluster assembly.	GRB2 haploinsufficiency weakens JNK/p38 but not ERK signaling in thymocytes; in 2023, WT GRB2 was ~80% monomer / 20% dimer, V122P/V123P ~80% dimer / 20% monomer, and N188D/N214D ~40% dimer / 60% monomer; altered dimerization reduced phospho-LAT clustering and caused near-total loss of IL-2 output relative to WT.	(gong2001disruptionoft pages 1-2, sandouk2023grb2dimerizationmediated pages 9-10, sandouk2023grb2dimerizationmediated pages 10-13, sandouk2023grb2dimerizationmediated pages 3-4, sandouk2023grb2dimerizationmediated pages 13-14)
Mouse genetics and phenotype	Mouse Grb2 is essential for early embryogenesis and endoderm/epiblast development, and Grb2 dosage also affects oncogenic transformation.	In chimeras made with Grb2-null ES cells, 7/18 embryos showed only limited mutant contribution; in the polyoma middle T mammary tumor model, 50% of MT mice had tumors by 35 days and essentially all by 40 days, whereas MT;Grb2+/− mice were largely tumor-free at 40 days and reached ~50% incidence by 54 days.	(cheng1998mammaliangrb2regulates pages 8-9, cheng1998mammaliangrb2regulates pages 1-2, cheng1998mammaliangrb2regulates pages 7-8)
2023 membrane-condensate advance	LAT/Grb2/Sos1 forms membrane-associated condensates that couple to ordered lipid domains, providing a modern physical mechanism for how GRB2 organizes T-cell signaling.	Condensates partitioned to Lo domains with Kp,Lo = 2.1 ± 0.4; condensates increased Tmisc from 17°C to 22°C; low concentrations that failed to condense on uniform membranes (pLAT 20 nM, Grb2 100 nM, Sos1 100 nM) condensed on phase-separated membranes; WT/raft-LAT conditions gave ~4-fold higher pERK than nonraft/non-pY controls; most Thy1 clusters were stalled for >80% of tracked time.	(wang2023couplingofprotein pages 2-3, wang2023couplingofprotein pages 5-7, wang2023couplingofprotein pages 3-5, wang2023couplingofprotein pages 1-2, wang2023couplingofprotein pages 7-9, wang2023couplingofprotein pages 10-11, wang2023couplingofprotein media 668d576c)
2024 tools and inhibitor development	Recent tool development targets both SH2 and SH3 functions of GRB2, supporting functional annotation and therapeutic exploration. Affimers now provide renewable domain-selective reagents; small molecules/peptides continue to benchmark potency.	Grb2 SH2 Affimers: IC50 270 nM–1.22 µM; SPR KD 11.8 ± 6.9 nM (A4) and 34.8 ± 16.9 nM (F1); pERK nuclear translocation inhibition ~84% (HEK293), 78% (U-2-OS), 18% (HeLa). Other reported ligands include hydroxy benzyl phosphinate KD 0.53 µM and bicyclic peptide BC1 IC50 350 nM. C-SH3-targeting Affimers were sufficient to curb Ras signaling in EGF-stimulated cells.	(malagrino2024grb2adynamic pages 3-5, tang2024targetinggrb2sh3 pages 1-3, heseltine2024generatingandvalidating pages 3-5, heseltine2024generatingandvalidating pages 5-9)
2024 mechanistic updates	Current view is that GRB2 is not just a passive linker: interdomain allostery, partner-selective SH3 usage, and PTMs modulate signaling output.	Reviews highlight interdomain regulation between SH2 and C-SH3; GRB3-3 lacks a functional SH2 because of a 40-residue truncation; SUMOylation at Lys56 in N-SH3 promotes GRB2–SOS complex formation and ERK activity.	(malagrino2024grb2adynamic pages 3-5, wang2024theconfigurationof pages 17-18, malagrino2024grb2adynamic pages 5-6, malagrino2024grb2adynamic pages 2-3, wang2024theconfigurationof pages 18-19)

📄 View Raw YAML

id: Q60631
gene_symbol: Grb2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: Growth factor receptor-bound protein 2 is a non-enzymatic SH2/SH3 adaptor that links phosphorylated receptors and scaffolds to SOS-family Ras guanine nucleotide exchange factors. It nucleates signaling complexes downstream of EGFR, other receptor tyrosine kinases, antigen receptors, and immune receptors, thereby propagating RAS-MAPK and related signaling pathways.
alternative_products:
- name: '1'
  id: Q60631-1
- name: 2 (GRB3-3)
  id: Q60631-2
  sequence_note: VSP_001841
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Upon receptor activation Grb2 is recruited to the plasma membrane (e.g. to phospho-LAT microdomains, activated RTKs) where it nucleates SOS/RAS signaling; a core site of action.
    action: ACCEPT
    reason: Plasma membrane is where Grb2 assembles active signaling complexes; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: The bare 'signal transduction' is too broad for Grb2; its actual role is coupling RTKs to RAS, so the specific 'Ras protein signal transduction' (or MAPK cascade) child is more informative.
    action: MODIFY
    reason: Too general; replace with Ras protein signal transduction.
    proposed_replacement_terms:
    - id: GO:0007265
      label: Ras protein signal transduction
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Consistent with Grb2's reported nuclear pool involved in DNA-damage/replication-stress functions; a secondary localization, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Nuclear-pool localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor.
    action: KEEP_AS_NON_CORE
    reason: Broader/less specific than cytosol; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0001784
    label: phosphotyrosine residue binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors.
    action: ACCEPT
    reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH2 domain specificity (definitions):** Grb2’s SH2 domain recognizes **phosphotyrosine (pY) motifs** with characteristic preferences such as **pYxNx** and the Shc-derived **pYVNV** motif.'
- term:
    id: GO:0005154
    label: epidermal growth factor receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function.
    action: ACCEPT
    reason: Direct SH2 binding to activated EGFR; canonical core interaction.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**EGFR**: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.'
- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0043408
    label: regulation of MAPK cascade
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: By coupling RTKs to SOS/RAS, Grb2 activates the RAF->MEK->ERK MAPK cascade; regulation of this cascade is a direct, core consequence of its adaptor activity.
    action: ACCEPT
    reason: Grb2 directly drives the RAS->RAF->MEK->ERK cascade; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Grb2 has a nuclear pool linked to DNA repair (RAD51/MRE11) and miRNA biogenesis (AGO2/DICER1); a real secondary localization distinct from its core cytosolic/membrane signaling role.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization for moonlighting roles; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor.
    action: KEEP_AS_NON_CORE
    reason: Broader/less specific than cytosol; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Grb2 participates in receptor endocytic trafficking (with Cbl/dynamin) and is found on endosomes; a secondary localization tied to receptor internalization rather than core RAS activation.
    action: KEEP_AS_NON_CORE
    reason: Endocytic-trafficking localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Endocytic trafficking example:** Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Golgi localization is reported (e.g. via PRNP interaction) but is a minor/secondary site relative to cytosol and plasma membrane; retained as non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Minor secondary localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Grb2 transmits signals from activated receptors to RAS by recruiting SOS, converting RAS-GDP to RAS-GTP; this RAS-activating role is the central biological process Grb2 mediates.
    action: ACCEPT
    reason: RAS activation via SOS is the central process; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Reflects Grb2's SH3-mediated recognition of proline-rich (PxxP/RxxP) domains in partners such as SOS1, Gab2 and Dab2; an informative description of its modular-domain binding mode.
    action: ACCEPT
    reason: SH3-domain-specific binding to proline-rich motifs is a core Grb2 mechanism.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH3 domain specificity (definitions):** SH3 domains bind **proline-rich** sequences, typically **PxxP**-type motifs.'
- term:
    id: GO:0048009
    label: insulin-like growth factor receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Grb2 couples IGF1R (via SHC/IRS) to RAS/MAPK; one specific RTK pathway instance of its general adaptor role, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific IGF1R pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10077576
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10373493
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10521483
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10748054
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10871282
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11259577
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11445578
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11551227
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11551923
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11684012
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15102471
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15301538
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15953601
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17673906
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18273058
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19914172
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21487392
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22561606
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23452850
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24584089
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7518772
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7529871
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7535773
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8479540
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9182757
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9569023
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0001784
    label: phosphotyrosine residue binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors.
    action: ACCEPT
    reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH2 domain specificity (definitions):** Grb2’s SH2 domain recognizes **phosphotyrosine (pY) motifs** with characteristic preferences such as **pYxNx** and the Shc-derived **pYVNV** motif.'
- term:
    id: GO:0005091
    label: guanyl-nucleotide exchange factor adaptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF.'
    action: ACCEPT
    reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005154
    label: epidermal growth factor receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function.
    action: ACCEPT
    reason: Direct SH2 binding to activated EGFR; canonical core interaction.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**EGFR**: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.'
- term:
    id: GO:0005168
    label: neurotrophin TRKA receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 binds ligand-activated NTRK1/TrkA to relay neurotrophin signals to RAS/MAPK; a specific RTK interaction instance of its core adaptor role, non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific TrkA/NTRK1 interaction; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0007173
    label: epidermal growth factor receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 is an obligate node in EGFR signaling, coupling activated EGFR to SOS/RAS/ERK; one of the best-established Grb2 pathway roles and a core process.
    action: ACCEPT
    reason: Grb2 is a central, well-evidenced EGFR-pathway node.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: 'Concrete phosphosite examples** (illustrative, mechanistically useful for annotation):'
- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific insulin/IRS pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Describes Grb2 being bound by, or binding via, SH3 domains; partly redundant with the more informative SH3/proline-rich adaptor terms, so retained but as non-core.
    action: KEEP_AS_NON_CORE
    reason: Redundant with informative SH3 adaptor terms; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH3 domain specificity (definitions):** SH3 domains bind **proline-rich** sequences, typically **PxxP**-type motifs.'
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 binds tyrosine kinases (e.g. via SH2 to phospho-RTKs), but 'protein kinase binding' is a generic, uninformative MF subsumed by the specific phosphotyrosine/adaptor terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic kinase binding; superseded by specific adaptor MFs.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: More specific adaptor MF describing Grb2 physically linking two proteins (e.g. phospho-receptor to SOS); appropriate for the SH2/SH3 bridging activity. Retain as core.
    action: ACCEPT
    reason: Specific adaptor MF matching Grb2's bridging role.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0031623
    label: receptor internalization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 cooperates with Cbl/dynamin in ubiquitin-dependent EGFR internalization; a downstream trafficking process linked to but distinct from its core RAS-activating adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Receptor-endocytosis role; downstream, non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Endocytic trafficking example:** Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.'
- term:
    id: GO:0042110
    label: T cell activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Via phospho-LAT recruitment Grb2 helps organize TCR signaling and T-cell activation; a lineage-specific downstream process, not the abstracted core adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Downstream immune process; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: In T cells, **tyrosine-phosphorylated LAT** recruits Grb2-family adaptors and SOS to the plasma membrane (notably **glycolipid-enriched microdomains**), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
- term:
    id: GO:0042267
    label: natural killer cell mediated cytotoxicity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: In NK cells Grb2 acts in DAP10/NKG2D and CD226 signaling (with Vav1/PI3K) affecting cytotoxicity; a lineage-specific downstream immune process, non-core.
    action: KEEP_AS_NON_CORE
    reason: NK-cell-specific downstream immune role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 haploid insufficiency in mice selectively weakened **TCR-induced JNK and p38** signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
- term:
    id: GO:0042770
    label: signal transduction in response to DNA damage
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2's nuclear DNA-damage signaling (fork protection, RAD51/MRE11 handling, RBBP6 ubiquitination at damage sites) is a moonlighting process distinct from its core RTK adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Nuclear DNA-damage signaling moonlighting role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 can homodimerize via SH2 domain-swapping, but 'identical protein binding' is a generic MF not informative of its adaptor function; dimerization is better noted as a regulatory layer.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic self-binding term; not core adaptor function.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: WT GRB2 purification yielded ~**80% monomer / 20% dimer** by SEC; a hinge mutant V122P/V123P produced ~**80% dimer / 20% monomer**; an N188D/N214D mutant showed ~**40% dimer / 60% monomer**.
- term:
    id: GO:0043560
    label: insulin receptor substrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 binds tyrosine-phosphorylated IRS proteins (IRS1/IRS4) via its SH2 domain, connecting insulin/IGF signaling to RAS; a specific real partner interaction, non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific IRS partner interaction; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0045953
    label: negative regulation of natural killer cell mediated cytotoxicity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 also participates in inhibitory NK signaling (e.g. via TIGIT, suppressing PI3K/MAPK); a specialized regulatory immune role downstream of its adaptor function, non-core.
    action: KEEP_AS_NON_CORE
    reason: Inhibitory NK-signaling role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 haploid insufficiency in mice selectively weakened **TCR-induced JNK and p38** signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
- term:
    id: GO:0046875
    label: ephrin receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 binds Eph receptors (e.g. EphB1) to activate MAPK/ERK and promote chemotaxis; a specific real receptor interaction that is one instance of its general RTK-adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Specific Eph-receptor interaction; non-core instance.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0070436
    label: Grb2-EGFR complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 physically forms a complex with activated EGFR; this cellular-component term captures the assembled signaling complex at the heart of EGFR->RAS coupling. Retain as core.
    action: ACCEPT
    reason: Defined Grb2:EGFR complex; directly supported and core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**EGFR**: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.'
- term:
    id: GO:0071479
    label: cellular response to ionizing radiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Grb2 has a nuclear DNA-damage/replication-stress role (protecting stalled forks, modulating RAD51/MRE11); a distinct moonlighting process separate from its core RTK adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Nuclear DNA-damage moonlighting role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:2000379
    label: positive regulation of reactive oxygen species metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Reported ROS-metabolism regulation is a downstream/indirect consequence of Grb2-dependent signaling; retained as a non-core pleiotropic process.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream ROS effect; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: An extremely generic CC term; every protein in a complex would qualify. Uninformative relative to the specific Grb2-EGFR complex and signaling-complex annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Trivially generic complex term; over-annotated.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor.
    action: KEEP_AS_NON_CORE
    reason: Broader/less specific than cytosol; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0001784
    label: phosphotyrosine residue binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors.
    action: ACCEPT
    reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH2 domain specificity (definitions):** Grb2’s SH2 domain recognizes **phosphotyrosine (pY) motifs** with characteristic preferences such as **pYxNx** and the Shc-derived **pYVNV** motif.'
- term:
    id: GO:0001784
    label: phosphotyrosine residue binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2's central SH2 domain recognizes phosphotyrosine motifs (pYxNx, Shc pYVNV) on activated receptors/scaffolds; this is the informative MF underlying its recruitment to activated receptors.
    action: ACCEPT
    reason: SH2-mediated phosphotyrosine recognition is a core, specific adaptor MF.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH2 domain specificity (definitions):** Grb2’s SH2 domain recognizes **phosphotyrosine (pY) motifs** with characteristic preferences such as **pYxNx** and the Shc-derived **pYVNV** motif.'
- term:
    id: GO:0005091
    label: guanyl-nucleotide exchange factor adaptor activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: 'Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF.'
    action: ACCEPT
    reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005154
    label: epidermal growth factor receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function.
    action: ACCEPT
    reason: Direct SH2 binding to activated EGFR; canonical core interaction.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**EGFR**: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.'
- term:
    id: GO:0005154
    label: epidermal growth factor receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 binds activated EGFR (phospho-Tyr1068/1086) via its SH2 domain, the canonical recruitment event nucleating EGFR->RAS->ERK signaling. A core, well-supported binding function.
    action: ACCEPT
    reason: Direct SH2 binding to activated EGFR; canonical core interaction.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**EGFR**: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.'
- term:
    id: GO:0005168
    label: neurotrophin TRKA receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 binds ligand-activated NTRK1/TrkA to relay neurotrophin signals to RAS/MAPK; a specific RTK interaction instance of its core adaptor role, non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific TrkA/NTRK1 interaction; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 has a nuclear pool linked to DNA repair (RAD51/MRE11) and miRNA biogenesis (AGO2/DICER1); a real secondary localization distinct from its core cytosolic/membrane signaling role.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization for moonlighting roles; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 participates in receptor endocytic trafficking (with Cbl/dynamin) and is found on endosomes; a secondary localization tied to receptor internalization rather than core RAS activation.
    action: KEEP_AS_NON_CORE
    reason: Endocytic-trafficking localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Endocytic trafficking example:** Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.'
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: A reported secondary subcellular localization (ISO); not a primary site of Grb2's adaptor signaling activity, so retained as non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Secondary localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0007173
    label: epidermal growth factor receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 is an obligate node in EGFR signaling, coupling activated EGFR to SOS/RAS/ERK; one of the best-established Grb2 pathway roles and a core process.
    action: ACCEPT
    reason: Grb2 is a central, well-evidenced EGFR-pathway node.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: 'Concrete phosphosite examples** (illustrative, mechanistically useful for annotation):'
- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific insulin/IRS pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Describes Grb2 being bound by, or binding via, SH3 domains; partly redundant with the more informative SH3/proline-rich adaptor terms, so retained but as non-core.
    action: KEEP_AS_NON_CORE
    reason: Redundant with informative SH3 adaptor terms; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH3 domain specificity (definitions):** SH3 domains bind **proline-rich** sequences, typically **PxxP**-type motifs.'
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Grb2 does bind enzymes (SOS, PTPN11, kinases), but 'enzyme binding' is a generic non-informative MF better captured by the specific adaptor/phosphotyrosine-binding terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic enzyme binding; superseded by specific adaptor MFs.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 binds tyrosine kinases (e.g. via SH2 to phospho-RTKs), but 'protein kinase binding' is a generic, uninformative MF subsumed by the specific phosphotyrosine/adaptor terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic kinase binding; superseded by specific adaptor MFs.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Reflects Grb2's SH3-mediated recognition of proline-rich (PxxP/RxxP) domains in partners such as SOS1, Gab2 and Dab2; an informative description of its modular-domain binding mode.
    action: ACCEPT
    reason: SH3-domain-specific binding to proline-rich motifs is a core Grb2 mechanism.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH3 domain specificity (definitions):** SH3 domains bind **proline-rich** sequences, typically **PxxP**-type motifs.'
- term:
    id: GO:0030036
    label: actin cytoskeleton organization
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Through partners (e.g. WASP/WAVE pathways, RAB13/RHOA recruitment), Grb2 can influence actin dynamics; a downstream/pleiotropic effect, not the core RAS-coupling function.
    action: KEEP_AS_NON_CORE
    reason: Downstream cytoskeletal effect; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: More specific adaptor MF describing Grb2 physically linking two proteins (e.g. phospho-receptor to SOS); appropriate for the SH2/SH3 bridging activity. Retain as core.
    action: ACCEPT
    reason: Specific adaptor MF matching Grb2's bridging role.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0031295
    label: T cell costimulation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 contributes to costimulatory (e.g. CD28) signaling during T-cell activation; a specialized downstream immune role secondary to its core adaptor activity.
    action: KEEP_AS_NON_CORE
    reason: Specialized costimulatory role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: In T cells, **tyrosine-phosphorylated LAT** recruits Grb2-family adaptors and SOS to the plasma membrane (notably **glycolipid-enriched microdomains**), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
- term:
    id: GO:0031623
    label: receptor internalization
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 cooperates with Cbl/dynamin in ubiquitin-dependent EGFR internalization; a downstream trafficking process linked to but distinct from its core RAS-activating adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Receptor-endocytosis role; downstream, non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Endocytic trafficking example:** Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.'
- term:
    id: GO:0042110
    label: T cell activation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Via phospho-LAT recruitment Grb2 helps organize TCR signaling and T-cell activation; a lineage-specific downstream process, not the abstracted core adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Downstream immune process; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: In T cells, **tyrosine-phosphorylated LAT** recruits Grb2-family adaptors and SOS to the plasma membrane (notably **glycolipid-enriched microdomains**), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
- term:
    id: GO:0042267
    label: natural killer cell mediated cytotoxicity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: In NK cells Grb2 acts in DAP10/NKG2D and CD226 signaling (with Vav1/PI3K) affecting cytotoxicity; a lineage-specific downstream immune process, non-core.
    action: KEEP_AS_NON_CORE
    reason: NK-cell-specific downstream immune role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 haploid insufficiency in mice selectively weakened **TCR-induced JNK and p38** signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
- term:
    id: GO:0042770
    label: signal transduction in response to DNA damage
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2's nuclear DNA-damage signaling (fork protection, RAD51/MRE11 handling, RBBP6 ubiquitination at damage sites) is a moonlighting process distinct from its core RTK adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Nuclear DNA-damage signaling moonlighting role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 can homodimerize via SH2 domain-swapping, but 'identical protein binding' is a generic MF not informative of its adaptor function; dimerization is better noted as a regulatory layer.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic self-binding term; not core adaptor function.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: WT GRB2 purification yielded ~**80% monomer / 20% dimer** by SEC; a hinge mutant V122P/V123P produced ~**80% dimer / 20% monomer**; an N188D/N214D mutant showed ~**40% dimer / 60% monomer**.
- term:
    id: GO:0043560
    label: insulin receptor substrate binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Grb2 binds tyrosine-phosphorylated IRS proteins (IRS1/IRS4) via its SH2 domain, connecting insulin/IGF signaling to RAS; a specific real partner interaction, non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific IRS partner interaction; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0043560
    label: insulin receptor substrate binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 binds tyrosine-phosphorylated IRS proteins (IRS1/IRS4) via its SH2 domain, connecting insulin/IGF signaling to RAS; a specific real partner interaction, non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific IRS partner interaction; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Grb2 binds assembled receptor/scaffold complexes via its adaptor domains; rather than the generic complex-binding term, its molecular-adaptor activity better captures the function.
    action: MODIFY
    reason: Generalize/redirect to the molecular-adaptor MF.
    proposed_replacement_terms:
    - id: GO:0060090
      label: molecular adaptor activity
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0045953
    label: negative regulation of natural killer cell mediated cytotoxicity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 also participates in inhibitory NK signaling (e.g. via TIGIT, suppressing PI3K/MAPK); a specialized regulatory immune role downstream of its adaptor function, non-core.
    action: KEEP_AS_NON_CORE
    reason: Inhibitory NK-signaling role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 haploid insufficiency in mice selectively weakened **TCR-induced JNK and p38** signaling (but not ERK) and disrupted thymic selection processes, indicating that Grb2 abundance is functionally significant and pathway-context dependent in vivo.
- term:
    id: GO:0046875
    label: ephrin receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 binds Eph receptors (e.g. EphB1) to activate MAPK/ERK and promote chemotaxis; a specific real receptor interaction that is one instance of its general RTK-adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Specific Eph-receptor interaction; non-core instance.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0051219
    label: phosphoprotein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Grb2's binding to phosphorylated partners is specifically phosphotyrosine recognition via its SH2 domain; the precise child term 'phosphotyrosine residue binding' should be used instead.
    action: MODIFY
    reason: Replace with the specific phosphotyrosine-residue-binding MF.
    proposed_replacement_terms:
    - id: GO:0001784
      label: phosphotyrosine residue binding
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH2 domain specificity (definitions):** Grb2’s SH2 domain recognizes **phosphotyrosine (pY) motifs** with characteristic preferences such as **pYxNx** and the Shc-derived **pYVNV** motif.'
- term:
    id: GO:0070436
    label: Grb2-EGFR complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 physically forms a complex with activated EGFR; this cellular-component term captures the assembled signaling complex at the heart of EGFR->RAS coupling. Retain as core.
    action: ACCEPT
    reason: Defined Grb2:EGFR complex; directly supported and core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**EGFR**: Tyr1068 (principal), Tyr1086 (secondary), Tyr1173 (indirect) are highlighted as relevant to Grb2 recruitment; Tyr1068/Tyr1173 phosphorylation is noted as crucial for binding.'
- term:
    id: GO:0071479
    label: cellular response to ionizing radiation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Grb2 has a nuclear DNA-damage/replication-stress role (protecting stalled forks, modulating RAD51/MRE11); a distinct moonlighting process separate from its core RTK adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Nuclear DNA-damage moonlighting role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: A reported presynaptic localization (ISO); a tissue/context-specific secondary site rather than a primary site of Grb2's adaptor signaling, kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: Context-specific secondary localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:2000379
    label: positive regulation of reactive oxygen species metabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Reported ROS-metabolism regulation is a downstream/indirect consequence of Grb2-dependent signaling; retained as a non-core pleiotropic process.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream ROS effect; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9507006
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16247031
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005068
    label: transmembrane receptor protein tyrosine kinase adaptor activity
  evidence_type: ISO
  original_reference_id: PMID:11173924
  review:
    summary: Directly describes Grb2 acting as the adaptor that links transmembrane RTKs (EGFR, PDGFR, KIT, etc.) to downstream RAS signaling; the most context-specific adaptor MF and a core function.
    action: ACCEPT
    reason: RTK-specific adaptor activity is exactly Grb2's defining role.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0038133
    label: ERBB2-ERBB3 signaling pathway
  evidence_type: ISO
  original_reference_id: PMID:11173924
  review:
    summary: Grb2 participates in ERBB2/ERBB3 RTK signaling, one of many specific RTK pathways it serves; a non-core instance of its general RTK->RAS adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Specific RTK pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005938
    label: cell cortex
  evidence_type: IGI
  original_reference_id: PMID:17881575
  review:
    summary: Cortical localization (IGI) reflects Grb2's membrane-proximal recruitment during receptor signaling and cytoskeletal/migration roles; a secondary site, not its primary cytosolic/membrane signaling locus.
    action: KEEP_AS_NON_CORE
    reason: Membrane-proximal cortical localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: ISO
  original_reference_id: PMID:11823423
  review:
    summary: Grb2 is the prototypical non-catalytic molecular adaptor, physically bridging phosphotyrosine-bearing receptors to proline-rich effectors; the parent adaptor MF correctly describes its essence.
    action: ACCEPT
    reason: Grb2 is a textbook molecular adaptor; correct core MF.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0048009
    label: insulin-like growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:33567274
  review:
    summary: Grb2 couples IGF1R (via SHC/IRS) to RAS/MAPK; one specific RTK pathway instance of its general adaptor role, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific IGF1R pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005091
    label: guanyl-nucleotide exchange factor adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:12354753
  review:
    summary: 'Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF.'
    action: ACCEPT
    reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:8828504
  review:
    summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific insulin/IRS pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005091
    label: guanyl-nucleotide exchange factor adaptor activity
  evidence_type: ISO
  original_reference_id: PMID:8828504
  review:
    summary: 'Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF.'
    action: ACCEPT
    reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0048009
    label: insulin-like growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:12483226
  review:
    summary: Grb2 couples IGF1R (via SHC/IRS) to RAS/MAPK; one specific RTK pathway instance of its general adaptor role, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific IGF1R pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005091
    label: guanyl-nucleotide exchange factor adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:8479536
  review:
    summary: 'Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF.'
    action: ACCEPT
    reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:8649419
  review:
    summary: Grb2 links the insulin receptor/IRS proteins to RAS/MAPK via SH2 binding to phospho-IRS; a specific RTK pathway, retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: Specific insulin/IRS pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005091
    label: guanyl-nucleotide exchange factor adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:9199344
  review:
    summary: 'Captures the defining Grb2 role: its SH3 domains recruit the RAS GEF SOS1/2 to phosphotyrosine-docked receptor complexes, coupling RTK activation to RAS nucleotide exchange. This is the core adaptor MF.'
    action: ACCEPT
    reason: Core adaptor function bridging RTKs to the SOS RAS-GEF; central to all Grb2 biology.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0050853
    label: B cell receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:9199344
  review:
    summary: Grb2 amplifies Ca2+ mobilization and ERK activation downstream of the phosphorylated BCR (via FCRL1/LAT2), a real but lineage-specific deployment of its generic phospho-LAT-style adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Real BCR role but a downstream, cell-type-specific deployment.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: In T cells, **tyrosine-phosphorylated LAT** recruits Grb2-family adaptors and SOS to the plasma membrane (notably **glycolipid-enriched microdomains**), facilitating Ras/MAPK-family signaling outputs and influencing other MAPK arms (JNK, p38).
- term:
    id: GO:0005068
    label: transmembrane receptor protein tyrosine kinase adaptor activity
  evidence_type: IGI
  original_reference_id: PMID:17881575
  review:
    summary: Directly describes Grb2 acting as the adaptor that links transmembrane RTKs (EGFR, PDGFR, KIT, etc.) to downstream RAS signaling; the most context-specific adaptor MF and a core function.
    action: ACCEPT
    reason: RTK-specific adaptor activity is exactly Grb2's defining role.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0007173
    label: epidermal growth factor receptor signaling pathway
  evidence_type: IGI
  original_reference_id: PMID:17881575
  review:
    summary: Grb2 is an obligate node in EGFR signaling, coupling activated EGFR to SOS/RAS/ERK; one of the best-established Grb2 pathway roles and a core process.
    action: ACCEPT
    reason: Grb2 is a central, well-evidenced EGFR-pathway node.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: 'Concrete phosphosite examples** (illustrative, mechanistically useful for annotation):'
- term:
    id: GO:0014044
    label: Schwann cell development
  evidence_type: IMP
  original_reference_id: PMID:10704452
  review:
    summary: Grb2-dependent ErbB/NRG1 RTK signaling contributes to Schwann cell development; a downstream developmental outcome.
    action: KEEP_AS_NON_CORE
    reason: Real but downstream developmental phenotype of Grb2 adaptor signaling; non-core (experimental IMP retained).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A targeted **null mutation** in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
- term:
    id: GO:0042552
    label: myelination
  evidence_type: IMP
  original_reference_id: PMID:10704452
  review:
    summary: Myelination defects arise downstream of Grb2-dependent ErbB/RTK signaling in Schwann cells; a distal phenotype.
    action: KEEP_AS_NON_CORE
    reason: Downstream developmental/glial phenotype; non-core (experimental IMP retained).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A targeted **null mutation** in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
- term:
    id: GO:0042552
    label: myelination
  evidence_type: IMP
  original_reference_id: PMID:18760695
  review:
    summary: Myelination defects arise downstream of Grb2-dependent ErbB/RTK signaling in Schwann cells; a distal phenotype.
    action: KEEP_AS_NON_CORE
    reason: Downstream developmental/glial phenotype; non-core (experimental IMP retained).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A targeted **null mutation** in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24907343
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10744659
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:7689150
  review:
    summary: More specific adaptor MF describing Grb2 physically linking two proteins (e.g. phospho-receptor to SOS); appropriate for the SH2/SH3 bridging activity. Retain as core.
    action: ACCEPT
    reason: Specific adaptor MF matching Grb2's bridging role.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22801373
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28098138
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28290451
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-2730846
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-2730869
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-8983356
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9007126
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9007137
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-914067
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9604768
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9606621
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9606623
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9606789
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9607226
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9645128
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9645133
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9645136
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9674973
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9680646
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9682158
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9682182
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9029146
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9029152
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9029162
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9682572
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9763903
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9764150
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-9036961
  review:
    summary: Grb2 is predominantly a cytosolic adaptor at steady state, recruited to membranes upon receptor activation; the cytosol is a primary site where it resides and acts. Core localization (n=27).
    action: ACCEPT
    reason: Cytosol is Grb2's principal resting compartment; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005911
    label: cell-cell junction
  evidence_type: IDA
  original_reference_id: PMID:23793062
  review:
    summary: Grb2 can localize to cell-cell junction-associated receptor complexes in specific contexts.
    action: KEEP_AS_NON_CORE
    reason: Secondary/context-specific localization; non-core (experimental IDA retained).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10982817
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11711534
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16339969
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11152963
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15569713
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8632004
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16405865
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22732588
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Describes Grb2 being bound by, or binding via, SH3 domains; partly redundant with the more informative SH3/proline-rich adaptor terms, so retained but as non-core.
    action: KEEP_AS_NON_CORE
    reason: Redundant with informative SH3 adaptor terms; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH3 domain specificity (definitions):** SH3 domains bind **proline-rich** sequences, typically **PxxP**-type motifs.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11739737
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: IDA
  original_reference_id: PMID:22561606
  review:
    summary: Grb2 is reported associated with the COP9 signalosome, but it is not an established CSN subunit; the assignment is uninformative for Grb2's adaptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Implausible/uninformative complex assignment; not an established CSN component (downgraded from REMOVE as it carries IDA evidence).
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17923684
  review:
    summary: Upon receptor activation Grb2 is recruited to the plasma membrane (e.g. to phospho-LAT microdomains, activated RTKs) where it nucleates SOS/RAS signaling; a core site of action.
    action: ACCEPT
    reason: Plasma membrane is where Grb2 assembles active signaling complexes; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0030838
    label: positive regulation of actin filament polymerization
  evidence_type: IGI
  original_reference_id: PMID:17923684
  review:
    summary: Grb2 can promote actin polymerization through downstream effectors during migration; a pleiotropic cytoskeletal effect, not its core RAS-coupling MF.
    action: KEEP_AS_NON_CORE
    reason: Downstream actin-polymerization effect; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15467741
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0019903
    label: protein phosphatase binding
  evidence_type: IPI
  original_reference_id: PMID:20398064
  review:
    summary: Grb2 associates with PTP partners (PTPN11/SHP2, R3 RPTPs), but 'protein phosphatase binding' is a generic MF that does not describe its adaptor function; over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic phosphatase binding; uninformative for adaptor role.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21930792
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Grb2 has a nuclear pool linked to DNA repair (RAD51/MRE11) and miRNA biogenesis (AGO2/DICER1); a real secondary localization distinct from its core cytosolic/membrane signaling role.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization for moonlighting roles; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Grb2 participates in receptor endocytic trafficking (with Cbl/dynamin) and is found on endosomes; a secondary localization tied to receptor internalization rather than core RAS activation.
    action: KEEP_AS_NON_CORE
    reason: Endocytic-trafficking localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Endocytic trafficking example:** Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.'
- term:
    id: GO:0046875
    label: ephrin receptor binding
  evidence_type: IPI
  original_reference_id: PMID:12925710
  review:
    summary: Grb2 binds Eph receptors (e.g. EphB1) to activate MAPK/ERK and promote chemotaxis; a specific real receptor interaction that is one instance of its general RTK-adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Specific Eph-receptor interaction; non-core instance.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16249387
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10330178
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11571277
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11585837
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0008543
    label: fibroblast growth factor receptor signaling pathway
  evidence_type: IGI
  original_reference_id: PMID:11585837
  review:
    summary: Grb2 (via FRS2) couples FGFRs to RAS/ERK; one specific RTK pathway among many, a non-core deployment of its core adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Specific FGFR pathway instance; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0043408
    label: regulation of MAPK cascade
  evidence_type: IGI
  original_reference_id: PMID:15569713
  review:
    summary: By coupling RTKs to SOS/RAS, Grb2 activates the RAF->MEK->ERK MAPK cascade; regulation of this cascade is a direct, core consequence of its adaptor activity.
    action: ACCEPT
    reason: Grb2 directly drives the RAS->RAF->MEK->ERK cascade; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19597497
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19597498
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0048646
    label: anatomical structure formation involved in morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:11369229
  review:
    summary: Grb2 is essential for early embryonic morphogenesis (endoderm/epiblast formation) reflecting its role in transmitting growth-factor signals; a pleiotropic developmental outcome, not its core MF.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental requirement; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A targeted **null mutation** in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
- term:
    id: GO:0060670
    label: branching involved in labyrinthine layer morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:11369229
  review:
    summary: Placental labyrinth branching depends on Grb2-mediated growth-factor signaling; a specific developmental phenotype downstream of its adaptor function, not a core annotation.
    action: KEEP_AS_NON_CORE
    reason: Specific developmental phenotype; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A targeted **null mutation** in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14722116
  review:
    summary: Generic 'protein binding' conveys no functional specificity for an adaptor whose informative MF is phosphotyrosine/proline-rich-motif binding; superseded by the specific adaptor/SH2/SH3 terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; specific adaptor MFs preferred.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Grb2 is an adaptor/scaffold protein**: it has **no catalytic activity**, but **controls signal flow** by physically linking **phosphotyrosine-containing receptors/scaffolds** to **proline-rich effector proteins**.'
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:8438166
  review:
    summary: Reflects Grb2's SH3-mediated recognition of proline-rich (PxxP/RxxP) domains in partners such as SOS1, Gab2 and Dab2; an informative description of its modular-domain binding mode.
    action: ACCEPT
    reason: SH3-domain-specific binding to proline-rich motifs is a core Grb2 mechanism.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**SH3 domain specificity (definitions):** SH3 domains bind **proline-rich** sequences, typically **PxxP**-type motifs.'
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:16908534
  review:
    summary: Grb2 is required for differentiation programs (e.g. endoderm) by relaying RTK/RAS signals; a broad downstream developmental process, kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: Broad downstream differentiation role; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A targeted **null mutation** in mouse Grb2 established that Grb2 is essential for early embryogenesis and differentiation programs (e.g., endoderm/epiblast formation), consistent with its role in transmitting growth factor signals to Ras/MAPK.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:15983387
  review:
    summary: Generic 'membrane' localization; Grb2 acts at the inner plasma membrane, captured by the specific plasma membrane term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic parent localization superseded by the specific plasma membrane annotation.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15736129
  review:
    summary: General cytoplasmic localization is correct but less specific than 'cytosol'; retained as a non-core broader localization for the predominantly cytosolic adaptor.
    action: KEEP_AS_NON_CORE
    reason: Broader/less specific than cytosol; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: Grb2 is primarily cytosolic but is recruited to signaling complexes at the **plasma membrane** upon receptor activation, including immune microdomains; it also participates in **endocytosis/endosomes** and is described across **cytoplasm, membrane, endosomes, and nucleus** in RTK-activated contexts.
- term:
    id: GO:0012506
    label: vesicle membrane
  evidence_type: IDA
  original_reference_id: PMID:12147689
  review:
    summary: Grb2 is found on vesicle membranes during receptor trafficking/endocytosis; a secondary localization tied to internalization rather than core signaling, non-core.
    action: KEEP_AS_NON_CORE
    reason: Trafficking-vesicle localization; non-core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: '**Endocytic trafficking example:** Grb2 cooperates with **Cbl** in EGFR ubiquitin-dependent internalization; Grb2 SH3-mediated coupling (e.g., to Cbl and dynamin) supports formation of internalized vesicles and trafficking to endosomes, and SH3 mutants can impair internalization.'
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: TAS
  original_reference_id: PMID:1322798
  review:
    summary: Grb2 transmits signals from activated receptors to RAS by recruiting SOS, converting RAS-GDP to RAS-GTP; this RAS-activating role is the central biological process Grb2 mediates.
    action: ACCEPT
    reason: RAS activation via SOS is the central process; core.
    supported_by:
    - reference_id: UniProt:Q60631
      supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
    - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
      supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000096
  title: Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000119
  title: Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10077576
  title: 'Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis.'
  findings: []
- id: PMID:10330178
  title: Ajuba, a novel LIM protein, interacts with Grb2, augments mitogen-activated protein kinase activity in fibroblasts, and promotes meiotic maturation of Xenopus oocytes in a Grb2- and Ras-dependent manner.
  findings: []
- id: PMID:10373493
  title: Analysis of tyrosine phosphorylation-dependent interactions between stimulatory effector proteins and the B cell co-receptor CD22.
  findings: []
- id: PMID:10521483
  title: Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration.
  findings: []
- id: PMID:10704452
  title: A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool.
  findings: []
- id: PMID:10744659
  title: A BASH/SLP-76-related adaptor protein MIST/Clnk involved in IgE receptor-mediated mast cell degranulation.
  findings: []
- id: PMID:10748054
  title: CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux.
  findings: []
- id: PMID:10871282
  title: Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses.
  findings: []
- id: PMID:10982817
  title: A deubiquitinating enzyme UBPY interacts with the Src homology 3 domain of Hrs-binding protein via a novel binding motif PX(V/I)(D/N)RXXKP.
  findings: []
- id: PMID:11152963
  title: SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins.
  findings: []
- id: PMID:11173924
  title: Neuregulin-induced association of Sos Ras exchange protein with HER2(erbB2)/HER3(erbB3) receptor complexes in Schwann cells through a specific Grb2-HER2(erbB2) interaction.
  findings: []
- id: PMID:11259577
  title: Association of insulin receptor substrate 1 (IRS-1) y895 with Grb-2 mediates the insulin signaling involved in IRS-1-deficient brown adipocyte mitogenesis.
  findings: []
- id: PMID:11369229
  title: Gene dosage-dependent functions for phosphotyrosine-Grb2 signaling during mammalian tissue morphogenesis.
  findings: []
- id: PMID:11445578
  title: ERK regulates the hepatocyte growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase.
  findings: []
- id: PMID:11551227
  title: 'Mouse alpha1-syntrophin binding to Grb2: further evidence of a role for syntrophin in cell signaling.'
  findings: []
- id: PMID:11551923
  title: CD22 regulates B cell receptor-mediated signals via two domains that independently recruit Grb2 and SHP-1.
  findings: []
- id: PMID:11571277
  title: PrPC directly interacts with proteins involved in signaling pathways.
  findings: []
- id: PMID:11585837
  title: Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation.
  findings: []
- id: PMID:11684012
  title: Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling.
  findings: []
- id: PMID:11711534
  title: '''Srcasm: a novel Src activating and signaling molecule.'
  findings: []
- id: PMID:11739737
  title: Gab3, a new DOS/Gab family member, facilitates macrophage differentiation.
  findings: []
- id: PMID:11823423
  title: A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling.
  findings: []
- id: PMID:12147689
  title: Phosphatidylinositol 4,5-biphosphate (PIP2)-induced vesicle movement depends on N-WASP and involves Nck, WIP, and Grb2.
  findings: []
- id: PMID:12354753
  title: Increased K-ras protein and activity in mouse and human lung epithelial cells at confluence.
  findings: []
- id: PMID:12483226
  title: IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice.
  findings: []
- id: PMID:12925710
  title: EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis.
  findings: []
- id: PMID:1322798
  title: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling.
  findings: []
- id: PMID:14722116
  title: The importance of three membrane-distal tyrosines in the adaptor protein NTAL/LAB.
  findings: []
- id: PMID:15102471
  title: Bioinformatics and cellular signaling.
  findings: []
- id: PMID:15301538
  title: Prion protein interaction with the C-terminal SH3 domain of Grb2 studied using NMR and optical spectroscopy.
  findings: []
- id: PMID:15467741
  title: Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2.
  findings: []
- id: PMID:15569713
  title: The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells.
  findings: []
- id: PMID:15736129
  title: Six post-implantation lethal knockouts of genes for lipophilic MAPK pathway proteins are expressed in preimplantation mouse embryos and trophoblast stem cells.
  findings: []
- id: PMID:15953601
  title: Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cgamma.
  findings: []
- id: PMID:15983387
  title: Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis.
  findings: []
- id: PMID:16247031
  title: Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.
  findings: []
- id: PMID:16249387
  title: LIME acts as a transmembrane adapter mediating BCR-dependent B-cell activation.
  findings: []
- id: PMID:16339969
  title: Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms.
  findings: []
- id: PMID:16405865
  title: Merlin inhibits growth hormone-regulated Raf-ERKs pathways by binding to Grb2 protein.
  findings: []
- id: PMID:16908534
  title: The Grb2/Mek pathway represses Nanog in murine embryonic stem cells.
  findings: []
- id: PMID:17673906
  title: TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA.
  findings: []
- id: PMID:17881575
  title: Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo.
  findings: []
- id: PMID:17923684
  title: Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization.
  findings: []
- id: PMID:18273058
  title: ShcA signalling is essential for tumour progression in mouse models of human breast cancer.
  findings: []
- id: PMID:18760695
  title: Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system.
  findings: []
- id: PMID:19597497
  title: Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection.
  findings: []
- id: PMID:19597498
  title: Themis, a T cell-specific protein important for late thymocyte development.
  findings: []
- id: PMID:19914172
  title: KIF26A is an unconventional kinesin and regulates GDNF-Ret signaling in enteric neuronal development.
  findings: []
- id: PMID:20398064
  title: Tyrosine phosphorylation of R3 subtype receptor-type protein tyrosine phosphatases and their complex formations with Grb2 or Fyn.
  findings: []
- id: PMID:21487392
  title: LKB1 regulates TCR-mediated PLCγ1 activation and thymocyte positive selection.
  findings: []
- id: PMID:21930792
  title: SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling.
  findings: []
- id: PMID:22561606
  title: Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling.
  findings: []
- id: PMID:22732588
  title: Interchangeability of Themis1 and Themis2 in thymocyte development reveals two related proteins with conserved molecular function.
  findings: []
- id: PMID:22801373
  title: Protein tyrosine phosphatase α phosphotyrosyl-789 binds BCAR3 to position Cas for activation at integrin-mediated focal adhesions.
  findings: []
- id: PMID:23452850
  title: Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate.
  findings: []
- id: PMID:23793062
  title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
  findings: []
- id: PMID:24584089
  title: Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub.
  findings: []
- id: PMID:24907343
  title: Themis2 is not required for B cell development, activation, and antibody responses.
  findings: []
- id: PMID:28098138
  title: SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages.
  findings: []
- id: PMID:28290451
  title: Development of SH2 probes and pull-down assays to detect pathogen-induced, site-specific tyrosine phosphorylation of the TLR adaptor SCIMP.
  findings: []
- id: PMID:33567274
  title: Prenatal correction of IGF2 to rescue the growth phenotypes in mouse models of Beckwith-Wiedemann and Silver-Russell syndromes.
  findings: []
- id: PMID:7518772
  title: Phosphorylation of receptor protein-tyrosine phosphatase alpha on Tyr789, a binding site for the SH3-SH2-SH3 adaptor protein GRB-2 in vivo.
  findings: []
- id: PMID:7529871
  title: Interaction of Shc with Grb2 regulates association of Grb2 with mSOS.
  findings: []
- id: PMID:7535773
  title: Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2.
  findings: []
- id: PMID:7689150
  title: 'Molecular cloning of the mouse grb2 gene: differential interaction of the Grb2 adaptor protein with epidermal growth factor and nerve growth factor receptors.'
  findings: []
- id: PMID:8438166
  title: Identification of a ten-amino acid proline-rich SH3 binding site.
  findings: []
- id: PMID:8479536
  title: Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation.
  findings: []
- id: PMID:8479540
  title: The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1.
  findings: []
- id: PMID:8632004
  title: The tyrosine phosphatase PTP1C associates with Vav, Grb2, and mSos1 in hematopoietic cells.
  findings: []
- id: PMID:8649419
  title: Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice.
  findings: []
- id: PMID:8828504
  title: Comparison of the insulin and insulin-like growth factor 1 mitogenic intracellular signaling pathways.
  findings: []
- id: PMID:9182757
  title: A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway.
  findings: []
- id: PMID:9199344
  title: Shc contains two Grb2 binding sites needed for efficient formation of complexes with SOS in B lymphocytes.
  findings: []
- id: PMID:9507006
  title: Identification of sirm, a novel insulin-regulated SH3 binding protein that associates with Grb-2 and FYN.
  findings: []
- id: PMID:9569023
  title: Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2.
  findings: []
- id: Reactome:R-MMU-2730846
  title: Recruitment of Gab2 to PM and FCERI by binding to Grb2
  findings: []
- id: Reactome:R-MMU-2730869
  title: Phosphorylation of Gab2 by Syk/Fyn
  findings: []
- id: Reactome:R-MMU-8983356
  title: Il15:Il15ra:p-Y-Il2rb:p-Y-Jak1:p-Y-Il2rg:p-Y-Jak3:p-Y-Shc1 binds Grb2
  findings: []
- id: Reactome:R-MMU-9007126
  title: Il15:Il15ra:p-Y-Il2rb:p-Y-Jak1:p-Y-Il2rg:p-Y-Jak3:p-Y-Shc1:Grb2 binds Gab2
  findings: []
- id: Reactome:R-MMU-9007137
  title: Il15:Il15ra:p-Y-Il2rb:p-Y-Jak1:p-Y-Il2rg:p-Y-Jak3:p-Y-Shc1:Grb2:Gab2 phosphorylates Gab2
  findings: []
- id: Reactome:R-MMU-9029146
  title: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2:p-Crkl:Rapgef1:p-Y-Shc1 binds Grb2-1:Sos1
  findings: []
- id: Reactome:R-MMU-9029152
  title: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2:p-Y-Crkl:p-Y-Shc1:Grb2-1:Sos1,p-Y-Vav1 mediates exchange of GDP for GTP bound to Ras
  findings: []
- id: Reactome:R-MMU-9029162
  title: Jak2 phosphorylates Vav1 in Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2:p-Crkl:Rapgef1:p-Y-Shc1:Grb2-1:Vav1
  findings: []
- id: Reactome:R-MMU-914067
  title: Shp2 can recruit Grb2
  findings: []
- id: Reactome:R-MMU-9604768
  title: Active Flt3 dimer binds Grb2
  findings: []
- id: Reactome:R-MMU-9606621
  title: Gab2 in Active Flt3:Grb2:Gab2 is phosphorylated
  findings: []
- id: Reactome:R-MMU-9606623
  title: Active Flt3:Grb2 binds Gab2
  findings: []
- id: Reactome:R-MMU-9606789
  title: Active Flt3:Grb2:p-Y-Gab2 binds Ptpn11
  findings: []
- id: Reactome:R-MMU-9607226
  title: Active Flt3:Grb2:p-Y-Gab2 binds Pik3r1
  findings: []
- id: Reactome:R-MMU-9645128
  title: Activators bind Stat5
  findings: []
- id: Reactome:R-MMU-9645133
  title: p-Stat5 dissociates from activator:Stat5 complex
  findings: []
- id: Reactome:R-MMU-9645136
  title: Activator phosphorylates Stat5
  findings: []
- id: Reactome:R-MMU-9674973
  title: Csf3 dimer:2xp-4Y-Csf3r:Lyn:p-Y-Jak1:p-Jak2:p-Syk:p-Hck:p-Tyk2 binds and phosphorylates Shc1, Grb2, Gab2, and Ptpn11
  findings: []
- id: Reactome:R-MMU-9680646
  title: Pik3r11:Pik3ca,b,d (Pi3k), Plcg2 (PLCgamma2), Grb2:Sos1, Shc1 (Shc), Ptpn11 (Shp2), Grb2:Gab2, Grb2:Gab3, Grap2 (MONA), Cbl:Grb2, Inpp5d (SHIP1), Inppl1 (SHIP2)  bind p-8Y-Csf1r and are activated
  findings: []
- id: Reactome:R-MMU-9682158
  title: Csf1r-associated Plcg2 hydrolyzes phosphatidylcholine yielding choline phosphate and 1,2-diacylglycerol
  findings: []
- id: Reactome:R-MMU-9682182
  title: Csf1r-associated PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate
  findings: []
- id: Reactome:R-MMU-9682572
  title: Csf1r-associated Sos1 mediates exchange of GTP for GDP bound to Ras
  findings: []
- id: Reactome:R-MMU-9763903
  title: Csf1 dimer:p-Y559-Csf1r dimer binds Grb2:Sos1
  findings: []
- id: Reactome:R-MMU-9764150
  title: Csf1 dimer:p-Y-559-Csf1r dimer:SFK:Grb2:Sos1 dissociates yielding Csf1 dimer:p-Y-559-Csf1r dimer:SFK and Grb2:Sos1
  findings: []
- id: Reactome:R-NUL-9036961
  title: Ntrk3 binds Grb2 through Shc1
  findings: []
- id: UniProt:Q60631
  title: UniProt record for Grb2 (Q60631)
  findings: []
- id: file:mouse/Grb2/Grb2-deep-research-falcon.md
  title: Deep research report on Grb2 (falcon)
  findings: []
core_functions:
- molecular_function:
    id: GO:0005068
    label: transmembrane receptor protein tyrosine kinase adaptor activity
  description: Uses its SH2 domain to bind phosphotyrosine motifs on activated receptors or scaffolds and its SH3 domains to recruit SOS-family exchange factors and other effectors.
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0007265
    label: Ras protein signal transduction
  - id: GO:0007173
    label: epidermal growth factor receptor signaling pathway
  supported_by:
  - reference_id: UniProt:Q60631
    supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
  - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
    supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
- molecular_function:
    id: GO:0001784
    label: phosphotyrosine residue binding
  description: The SH2 domain recognizes phosphorylated tyrosines on activated receptors and adaptor proteins, targeting GRB2 to signaling complexes.
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0043408
    label: regulation of MAPK cascade
  supported_by:
  - reference_id: UniProt:Q60631
    supporting_text: 'FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs translocation to the nucleus and activation. DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.'
  - reference_id: file:mouse/Grb2/Grb2-deep-research-falcon.md
    supporting_text: A dominant role for Grb2 is to couple **receptor tyrosine kinases (RTKs)** to **Ras activation** by recruiting **SOS1/2** through SH3-mediated binding, enabling conversion of Ras-GDP to Ras-GTP and downstream activation of **Raf→MEK→ERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs.
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []

Gene Description

Existing Annotations Review

Core Functions

Uses its SH2 domain to bind phosphotyrosine motifs on activated receptors or scaffolds and its SH3 domains to recruit SOS-family exchange factors and other effectors.

The SH2 domain recognizes phosphorylated tyrosines on activated receptors and adaptor proteins, targeting GRB2 to signaling complexes.

References

Deep Research

Falcon

Comprehensive Research Report: Mouse Grb2 (UniProt Q60631) — Functional Annotation

0) Target identity verification (critical disambiguation)

1) Key concepts and definitions (current understanding)

1.1 What Grb2 “does” (primary molecular function)

1.2 Domain architecture and binding rules

2) Mechanistic functional annotation: pathways, partners, and localization

2.1 Core pathway placement: RTK → Grb2 → SOS → Ras → Raf/MEK/ERK

2.2 Coupling to PI3K/AKT survival signaling (RTK → Grb2 → Gab1/2 → PI3K)

2.3 Immune receptor signaling organization: LAT microdomains, clustering, and condensates

2.4 Subcellular localization (where Grb2 acts)

3) Mouse-specific genetic evidence (in vivo functional necessity)

3.1 Essential developmental roles

3.2 Dosage-sensitive roles in tumorigenesis

3.3 Immune development/signaling (haploinsufficiency)

4) Recent developments (prioritizing 2023–2024)

4.1 2023: Membrane-coupled phase separation as a mechanism of Grb2 function in T-cell signaling

4.2 2023: Conformational state/dimerization as a regulatory layer in immune signaling

4.3 2024: Updated mechanistic views—interdomain allostery and post-translational modulation

5) Current applications and real-world implementations

5.1 Grb2 as a tool/target in pathway interrogation

5.2 Therapeutic targeting strategies (2023–2024 emphasis)

6) Expert synthesis / authoritative interpretation

6.1 Central “wiring” principle

6.2 Emerging conceptual shift (2023–2024)

7) Evidence summary table

References (URLs and publication dates)

Citations

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