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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN005273574 SUPPORTS TRANSFER GRB2-clade node in PTHR46037. Every seed this review identified is a GRB2 ortholog (FB:FBgn0004638, WB:WBGene00004774, RGD:619758, MGI:MGI:95805, UniProtKB:P62993), spanning fly, worm, rodent and human, so adapter-mediated coupling of activated receptors to downstream signalling is soundly ancestral. Checked in the ontology: GO:0007265 is a descendant of GO:0007165, so the replacement is a straightforward parent-to-child refinement and the transfer itself is not in question. MGI:MGI:95805 · Grb2 SUPPORTS TRANSFER The target's own IBD seed. Mouse Grb2's own experimental annotation is one of the descendant evidences the PAINT curator used to place the IBD at PTN005273574, so its appearance in this row's WITH/FROM is expected and is a marker that experimental grounding exists on the target itself. The annotation is GO:0005091 guanyl-nucleotide exchange factor adaptor activity (ECO:0000314 IDA x3, PMID:12354753, PMID:8479536, PMID:9199344), all retained as ACCEPT here - the SOS1-recruitment adapter activity that couples receptors to Ras, which is what this row's GO:0007165 to GO:0007265 refinement asserts. Not the same term as this row, which is the normal case for an IBD seed. Note what is NOT the grounding: Grb2's GO:0008180 COP9 signalosome IDA is nearer by term but is MARK_AS_OVER_ANNOTATED in this file, so citing it would lean on evidence this review rejects. UniProtKB:P62993 · GRB2 SUPPORTS TRANSFER Human GRB2, the target's direct ortholog. UniProt describes the same SH2/SH3 adapter role - LAT and receptor docking, SOS1 recruitment, KRAS and RAF1 activation - that GO:0007265 names specifically. 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: Not a mis-transfer of complex membership: the WITH/FROM for this row is only Grb2 itself (MGI:MGI:95805) and human GRB2 (UniProtKB:P62993) at the GRB2-clade node PANTHER:PTN005273574, with no COP9 signalosome subunit (COPS1-COPS8) and no CSN-subunit family anywhere in it, so the propagation step is a faithful GRB2-to-GRB2 ortholog transfer rather than a pattern-10 leak from a CSN family node. What is over-scoped is the source annotation: GRB2 is a 25 kDa SH3-SH2-SH3 adapter, not one of the eight canonical CSN subunits, so the part_of qualifier asserts structural membership where an association is what is documented, and the term says nothing about Grb2's adaptor function. Kept rather than removed because the mouse row does carry experimental (IDA) evidence whose full text is not available here. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN005273574 SUPPORTS TRANSFER This is specifically NOT a pattern-10 mis-transfer of complex membership. The whole WITH/FROM is GRB2 itself (MGI:MGI:95805) plus its human ortholog (UniProtKB:P62993) at the GRB2-clade node of PTHR46037; no COP9 signalosome subunit (COPS1-COPS8) and no CSN-subunit family appears anywhere in it, so the propagation step is a faithful GRB2-to-GRB2 ortholog transfer with no complex-membership leak from a CSN family node. The reservation lies in the scope of the source annotation rather than in the propagation: GRB2 is a 25 kDa SH3-SH2-SH3 adapter and not one of the eight canonical CSN subunits, so a part_of qualifier states structural membership of the complex where an association is what is actually documented. MGI:MGI:95805 · Grb2 SUPPORTS TRANSFER The target's own IBD seed. Mouse Grb2 carries its own experimental annotation for GO:0008180 (IDA, PMID:22561606), which is one of the descendant evidences behind the IBD at this node, so its presence here is expected. The cached record for that publication is abstract-only (a Tespa1/TCR-signalling study), so the CSN association could not be read in full here; per the project's rule on not overruling curators from incomplete evidence the row is kept as over-annotated rather than removed. UniProtKB:P62993 · GRB2 SUPPORTS TRANSFER Human GRB2, the target's direct ortholog and the origin of the mouse ISO and IEA rows for the same term. Its UniProt function statement describes only the receptor-to-RAS adapter role, with no CSN subunit 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 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.

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

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