Growth factor receptor-bound protein 2 is a non-enzymatic SH2/SH3 adaptor that links phosphorylated receptors and scaffolds to SOS-family Ras guanine nucleotide exchange factors. It nucleates signaling complexes downstream of EGFR, other receptor tyrosine kinases, antigen receptors, and immune receptors, thereby propagating RAS-MAPK and related signaling pathways.
| 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 Β· 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 Β· 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 **RafβMEKβERK** 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):** Grb2βs 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 Β· 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 Β· 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 ... | REMOVE | Summary: Grb2 association with Sam68 (WITH/FROM Q60749) reported in a study characterising the Sam68-like proteins SLM-1/SLM-2, which bind SH2/SH3 domains of several signalling proteins. Reason: The study characterises Sam68-family proteins as ligands for the SH2/SH3 domains of Fyn, Grb-2, PLCgamma-1 and rasGAP; Grb2 is one of several domain probes and no informative Grb2 MF (e.g. adaptor activity) is demonstrated. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:10077576 SLM-1 bound the SH2 and SH3 domains of p59(fyn), Grb-2, phospholipase Cgamma-1 (PLCgamma-1), and/or p120(rasGAP) UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | MODIFY | Summary: Grb2 (as a Grb2-Sos complex) binds directly to the phosphorylated Y828ENV motif of the B-cell co-receptor CD22 (WITH/FROM P35329). Reason: Phosphopeptide mapping shows Grb2 binding is specific to one phosphotyrosine motif of CD22 and direct (Far Western), i.e. SH2-mediated phosphotyrosine recognition; replace bare protein binding with phosphotyrosine residue binding. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10373493 the Grb2.Sos complex was observed to bind exclusively to the fourth phosphotyrosine motif (Y828ENV) from CD22 and does so via a direct interaction UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 binds the autophosphorylated receptor tyrosine kinase Tek/Tie2 (WITH/FROM Q02858) through its SH2 domain in a phosphotyrosine-dependent manner. Reason: The paper shows SH2-mediated, phosphotyrosine-dependent binding of Grb2 to Tek; phosphotyrosine residue binding captures the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10521483 Grb2, Grb7, Grb14, Shp2, and the p85 subunit of phosphatidylinositol 3-kinase can interact with Tek in a phosphotyrosine-dependent manner through their SH2 domains UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | MODIFY | Summary: Grb2 interaction with the adaptor Shc (WITH/FROM P98083) within a CD22-Grb2-Shc-SHIP complex in BCR-stimulated B cells. Reason: The WITH/FROM partner is ShcA; deferring to the IntAct curator on the interaction itself. Grb2 binds tyrosine-phosphorylated Shc via its SH2 domain (Shc pTyr-317 phosphopeptide displaces Shc from Grb2, PMID:7529871), so phosphotyrosine residue binding is the informative MF. The cached abstract itself only shows complex formation, so this rests partly on the partner. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10748054 The adapter proteins Grb2 and Shc were found to interact with distinct and specific regions of the CD22 cytoplasmic domain PMID:7529871 a phosphopeptide corresponding to the sequence surrounding Tyr-317 of Shc, which displaces Shc from Grb2, abolished the enhanced association between Grb2 and mSOS UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Grb2 constitutive complex with the docking protein Gab1 (WITH/FROM Q9QYY0), mapped to Gab1 proline-rich SH3-binding motifs. Reason: This is an SH3-proline-rich-motif association (constitutive, not phosphotyrosine-dependent). The paper does not demonstrate a distinct Grb2 activity beyond the physical association, and Grb2 SH3-ligand binding is already covered by other terms in this review. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:10871282 Association with Grb2 was mapped to two sites: a classical SH3-binding site (PXXP) and a novel Grb2 SH3 consensus-binding motif (PX(V/I)(D/N)RXXKP) UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Insulin-induced Grb2 associations with tyrosine-phosphorylated IRS-1 (Tyr895) and Shc (WITH/FROM P98083) in brown adipocytes, required for MAPK activation. Reason: Grb2 binding depends on tyrosine phosphorylation of its partners (IRS-1 Y895F abolishes IRS-1-Grb2 binding); phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:11259577 Reconstitution of IRS-1-deficient brown adipocytes with the IRS-1 mutant Tyr895Phe, which lacks IRS-1-Grb-2 binding UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: IntAct Grb2-Gab1 (WITH/FROM Q9QYY0) record from a study of ERK-regulated Gab1-PI3K (p85) association after HGF stimulation. Reason: The cached abstract concerns Gab1-p85 binding and does not describe the Grb2 interaction; deferring to the IntAct curator that the Grb2-Gab1 association was observed, but no informative Grb2 MF can be assigned from this study. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Grb2 SH3 domains bind proline-rich sequences of alpha1-syntrophin (WITH/FROM Q61234) in blot overlay assays. Reason: In vitro SH3-proline-rich binding (KD ~0.56 microM) without demonstration of a Grb2 adaptor or signalling function toward syntrophin; no informative MF beyond the physical association applies. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:11551227 Grb2-C-SH3 domain bound syntrophin with slightly higher affinity than Grb2-N-SH3 domain UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 is inducibly recruited to phosphorylated Tyr-828 of CD22 (WITH/FROM P35329) after BCR ligation. Reason: Recruitment requires a specific CD22 tyrosine (Tyr-828), consistent with SH2-mediated phosphotyrosine recognition; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:11551923 The tyrosine residue in CD22 required for Grb2 recruitment (Tyr-828) is distinct and independent from the two ITIM tyrosines UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: IntAct Grb2-SHP2/PTPN11 (WITH/FROM P35235) record from a study of phosphotyrosine-mimetic incorporation at SHP-2 tail tyrosines. Reason: The cached abstract does not name Grb2; deferring to the IntAct curator (full text) for the interaction. The study concerns SHP-2 tail tyrosine phosphorylation (Tyr542/Tyr580) and MAP kinase activation, and Grb2 engagement of tyrosine-phosphorylated SHP-2 is an SH2-phosphotyrosine interaction, so phosphotyrosine residue binding is the informative MF. Spot-check against the full text. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:11684012 Microinjection experiments indicate that a single phosphorylation of Tyr-542 of SHP-2 is sufficient to activate the MAP kinase pathway in living cells UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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. | REMOVE | Summary: Multiple IntAct Grb2 interaction records (partners including Sam68, Gab1, Sos2, Btk, Mig6) attributed to a review on bioinformatics and cellular signalling (AfCS Molecule Pages). Reason: The cited paper is a general review of signalling databases and contains no Grb2-specific experimental data; the rows cover many partners with different binding modes, so no single informative MF can be assigned. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:15102471 This information is being collected and curated in databases such as the Alliance for Cellular Signaling (AfCS) Molecule Pages UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | REMOVE | Summary: NMR/spectroscopic binding of the Grb2 C-terminal SH3 domain to a proline-containing segment (residues 100-109) of the prion protein PrP (WITH/FROM P04925). Reason: An in vitro SH3-proline motif interaction (KD 5.5 microM) of unclear physiological significance; no informative Grb2 MF beyond physical association. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:15301538 The protein-protein interaction, with a K(D) value of 5.5 microM, is abolished when either of these two prolines is replaced by leucine UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 associates with SOS2 and PLCgamma1 (WITH/FROM Q02384, Q62077) downstream of the EPO receptor, coupling EPO-R Y479 to ERK activation. Reason: The partners are the Ras GEF SOS2 and PLCgamma1, which recruits Grb2-SOS2 to EPO-R to activate ERK; Grb2 bridging a GEF to the activated receptor complex is guanyl-nucleotide exchange factor adaptor activity. The paper emphasises PLCgamma1 as the novel adapter, so this assignment relies on the canonical Grb2-SOS coupling. Proposed replacements: guanyl-nucleotide exchange factor adaptor activity Supporting Evidence: PMID:15953601 we demonstrate interaction of PLCgamma1 with Grb2 and SOS2 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | MODIFY | Summary: TGF-beta-induced tyrosine phosphorylation of ShcA (WITH/FROM P98083) by TbetaRI induces ShcA association with Grb2 and Sos, linking to Erk activation. Reason: Grb2 association with ShcA is induced by ShcA tyrosine phosphorylation, i.e. SH2 phosphotyrosine recognition; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:17673906 TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: IntAct Grb2-ShcA (WITH/FROM P98083) record from an in vivo study of phosphotyrosine-deficient ShcA alleles in mammary tumorigenesis. Reason: Deferring to the IntAct curator for the interaction; the study uses ShcA tyrosine-to-phenylalanine alleles, and Grb2 binds phosphorylated ShcA via its SH2 domain (PMID:7529871). Phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:18273058 we used mice expressing several phosphotyrosine-deficient ShcA alleles PMID:7529871 a phosphopeptide corresponding to the sequence surrounding Tyr-317 of Shc, which displaces Shc from Grb2, abolished the enhanced association between Grb2 and mSOS UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: The atypical kinesin KIF26A (WITH/FROM Q52KG5) binds directly to Grb2 and inhibits GDNF-Ret signalling. Reason: Grb2 is the target inhibited by KIF26A; this does not describe a Grb2 molecular function and no informative Grb2 MF term applies. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:19914172 KIF26A suppressed GDNF-Ret signaling by direct binding and inhibition of Grb2 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 PLCΞ³1 activation and thymocyte p... | MODIFY | Summary: IntAct Grb2-LAT (WITH/FROM O54957) record from a study of LKB1 in TCR-mediated PLCgamma1 activation and the LAT signalosome. Reason: The cached abstract focuses on LKB1 and does not name Grb2; deferring to the IntAct curator for the Grb2-LAT interaction. Grb2 docks on TCR-induced phosphotyrosines of LAT via its SH2 domain, so phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:21487392 Loss of LKB1 led to impaired recruitment of PLCΞ³1 to the LAT signalosome UniProt:Q60631 engagement of the TCR leads to phosphorylation of the adapter protein LAT, which serves as docking site for GRB2 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: IntAct Grb2 interactions with LAT and PLCgamma1 (WITH/FROM O54957, Q62077) in a study of Tespa1 in the TCR signalosome. Reason: Deferring to the IntAct curator for the interactions. Grb2 is recruited to the TCR signalosome by docking on tyrosine-phosphorylated LAT through its SH2 domain; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:22561606 Tespa1 associated with the TCR signaling components PLC-Ξ³1 and Grb2 UniProt:Q60631 engagement of the TCR leads to phosphorylation of the adapter protein LAT, which serves as docking site for GRB2 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 and its partner Sos1 (WITH/FROM includes Sos1, Sos2, Shc, Shp2, Gab1, Frs2, Ptpra) couple FGF signalling to Ras-Erk activation in embryonic stem cells, requiring cooperative binding of multiple Sos1/Grb2 domains. Reason: The study characterises Grb2 as the adaptor that couples the Ras GEF Sos1 to FGF receptor signalling; guanyl-nucleotide exchange factor adaptor activity is the informative MF. Proposed replacements: guanyl-nucleotide exchange factor adaptor activity Supporting Evidence: PMID:23452850 The Ras guanine nucleotide exchange factor (RasGEF) Sos1 and its adaptor Grb2 are multidomain proteins that couple fibroblast growth factor (FGF) signaling to activation of the Ras-Erk pathway UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | MODIFY | Summary: Grb2-LAT (WITH/FROM O54957) interaction captured by quantitative affinity-purification mass spectrometry of Lat/Zap70/SLP-76 signalosomes in primary T cells. Reason: Deferring to the IntAct curator for the interaction (the cached abstract does not name Grb2). Grb2 docks on TCR-induced LAT phosphotyrosines via its SH2 domain; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:24584089 determine the composition and dynamics of multiprotein complexes that formed around the kinase Zap70 and the adaptors Lat and SLP-76 UniProt:Q60631 engagement of the TCR leads to phosphorylation of the adapter protein LAT, which serves as docking site for GRB2 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 binds receptor protein-tyrosine phosphatase alpha (WITH/FROM P18052) at phosphorylated Tyr789 (YANF), in vitro and in NIH 3T3 cells. Reason: Binding is abolished by the Y789F mutation, demonstrating SH2-mediated phosphotyrosine recognition; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:7518772 We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Phosphorylated Shc (WITH/FROM P98083) binds the Grb2 SH2 domain via pTyr-317, regulating Grb2-mSOS association in T cells. Reason: A Shc pTyr-317 phosphopeptide displaces Shc from Grb2, demonstrating SH2-phosphotyrosine recognition; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:7529871 a phosphopeptide corresponding to the sequence surrounding Tyr-317 of Shc, which displaces Shc from Grb2, abolished the enhanced association between Grb2 and mSOS UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Growth hormone promotes tyrosyl phosphorylation of SHC proteins (WITH/FROM P98083) and their association with Grb2. Reason: Grb2 does not bind GHR or JAK2 directly but associates with GH-induced tyrosine-phosphorylated SHC; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:7535773 Grb2 was shown to associate rapidly with SHC proteins in a GH-dependent manner UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: The Grb2 SH3 domains bind the proline-rich C-terminal tail of mSos1 (WITH/FROM Q62245) and the Grb2-mSos1 complex is recruited to the autophosphorylated EGF receptor. Reason: The paper establishes Grb2 as the adaptor linking receptor tyrosine kinases to the Ras exchange factor mSos1; guanyl-nucleotide exchange factor adaptor activity is the informative MF. Proposed replacements: guanyl-nucleotide exchange factor adaptor activity Supporting Evidence: PMID:8479540 Grb2 therefore appears to link tyrosine kinases to a Ras-GNRP in mammalian cells UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 (with Sos) binds the tyrosine-phosphorylated, myristoylated docking protein FRS2 (WITH/FROM Q8C180) after FGF or NGF stimulation. Reason: Grb2 recruitment requires FRS2 tyrosine phosphorylation; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:9182757 FRS2, that is tyrosine phosphorylated and binds to Grb2/Sos in response to FGF or NGF stimulation UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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. | REMOVE | Summary: Both Grb2 SH3 domains bind the C-terminal proline-rich sequences of Disabled-2 (WITH/FROM P98078; also Sos1 Q62245), with Dab2 competing with Sos for Grb2. Reason: Here Grb2 is the object of competition between Dab2 and Sos; the SH3-proline-rich association is not an informative Grb2 MF beyond physical binding (Grb2-Sos adaptor activity is captured in other rows). Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:9569023 These data indicate that Dab2 binds to the SH3 domains of Grb2 via its C-terminal proline-rich sequences UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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):** Grb2βs 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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):** Grb2βs 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):** Grb2βs 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 **RafβMEKβERK** 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 **RafβMEKβERK** 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH 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 **RafβMEKβERK** 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH 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):** Grb2βs 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 **RafβMEKβERK** 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... | REMOVE | Summary: The insulin-regulated proline-rich protein Sirm (WITH/FROM O88466) binds the SH3 domains of Grb-2 and FYN in 3T3-L1 adipocytes; insulin causes dissociation. Reason: An SH3-proline-rich association without a demonstrated Grb2 activity toward Sirm; no informative MF beyond physical binding. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:9507006 Sirm binds to FYN and Grb-2 in 3T3-L1 adipocytes UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Mig6/ERRFI1 (WITH/FROM Q99JZ7) associates with Grb2 in pull-downs; Mig6 negatively regulates HGF/Met-induced migration. Reason: Grb2 is a binding partner/target of the Met inhibitor Mig6; no informative Grb2 MF follows from this interaction. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:16247031 pull-down experiments with GST-tagged Mig6 confirmed the association with growth factor receptorβbound protein 2 (Grb2) UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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, ... | REMOVE | Summary: Themis2 (with Lyn and PLCgamma2; WITH/FROM Q91YX0, P25911, Q8CIH5) associates with Grb2 in B cells. Reason: Constitutive Themis-family association with Grb2 (via a proline-rich SH3 recognition motif) without a demonstrated Grb2 activity; no informative MF beyond physical association. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:24907343 The related Themis2 protein is expressed in B cells where it associates with signaling proteins Grb2 and Vav1 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | MODIFY | Summary: Upon FcepsilonRI cross-linking the adaptor MIST/Clnk (WITH/FROM Q9QZE2) is tyrosine phosphorylated and associates with Grb2, PLCgamma, Vav and LAT in mast cells. Reason: Grb2 association accompanies receptor-induced tyrosine phosphorylation of the SH2-ligand adaptor MIST/Clnk, consistent with SH2-phosphotyrosine recognition; phosphotyrosine residue binding is the informative MF (phospho-dependence is inferred from the stimulation-dependence rather than mapped). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10744659 Upon FcepsilonRI cross-linking, MIST/Clnk is tyrosine phosphorylated and associates with signaling proteins, phospholipase Cgamma, Vav, Grb2 and linker for activation of T cells (LAT) UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 Ξ± phosphotyrosyl-789 binds BCAR... | MODIFY | Summary: Grb2-PTPalpha (WITH/FROM P18052) record from a study showing PTPalpha pTyr789 binds BCAR3 to position Cas at focal adhesions. Reason: The cached abstract concerns BCAR3; deferring to the curator for the Grb2 interaction. Grb2 binds PTPalpha at phosphorylated Tyr789 via its SH2 domain (PMID:7518772), so phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:22801373 phospho-Tyr789 PTPΞ± serving as the first defined cellular ligand for the BCAR3 SH2 domain PMID:7518772 We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Grb2 co-immunoprecipitates with the transmembrane TLR adaptor SCIMP (WITH/FROM Q3UU41) in LPS-activated macrophages, where it is constitutively bound. Reason: The paper reports constitutive association and does not dissect a Grb2 activity; phospho-dependent recruitment of Grb2 to SCIMP is captured in the PMID:28290451 row. No informative MF beyond physical association here. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:28098138 immunoblotting confirmed the co-immunoprecipitation of Lyn and Grb2, which were constitutively bound to SCIMP UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 SH2-domain probes pull down SCIMP (WITH/FROM Q3UU41) phosphorylated at specific tyrosines after LPS/TLR4 stimulation. Reason: Site-specific tyrosine phosphorylation of SCIMP governs Grb2 recruitment, i.e. SH2-phosphotyrosine recognition; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:28290451 demonstrate the specificity of LPS/TLR4-induced, site-specific phosphorylation of SCIMP for the temporal recruitment of the effectors Grb2, Csk and SLP65 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Grb2 interaction with the deubiquitinase UBPY/USP8 (WITH/FROM Q80U87), from a study identifying a PX(V/I)(D/N)RXXKP SH3-binding motif in UBPY for the Hbp/STAM2 SH3 domain. Reason: The paper focuses on UBPY binding the Hbp SH3 domain; the Grb2 association is an SH3-motif interaction with no demonstrated Grb2 activity, so no informative MF applies. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:10982817 Mutagenic analysis identified a consensus sequence PX(V/I)(D/N)RXXKP as the Hbp-SH3 domain binding motif UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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. | MODIFY | Summary: The Fyn substrate Srcasm/TOM1L1 (WITH/FROM Q923U0) interacts with Grb2 in a phosphorylation-dependent manner. Reason: Phosphorylation-dependent association with a Src-kinase substrate is SH2-mediated phosphotyrosine recognition; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:11711534 Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Sprouty1 (WITH/FROM Q9QXV9, Q8C180 FRS2) interacts with Grb2; Sprouty hetero-oligomers suppress association of the Grb2-Sos1 complex with FRS2. Reason: Grb2 is the target of Sprouty-mediated inhibition here; this interaction does not describe an informative Grb2 MF. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:16339969 Sprouty1 specifically interacts with Grb2, whereas Sprouty4 interacts with Sos1 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: The SH3-domain adaptor SETA/SH3KBP1 (WITH/FROM Q6P7W2, Q8R550) binds Grb2. Reason: The study characterises SETA as a multi-SH3 adapter binding Grb2, Cbl and SB1; no informative Grb2 MF is demonstrated. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:11152963 Evidence that SETA binds to the CD2 protein, the proto-oncogene c-Cbl, and the signal transduction molecule Grb2 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | REMOVE | Summary: The scaffold Shank3 (WITH/FROM Q4ACU6) recruits Grb2 to mediate sustained Erk and PI3K signalling downstream of Ret9. Reason: The adaptor role described is attributed to Shank3 recruiting Grb2; the paper does not assign a distinct Grb2 activity, so no informative MF beyond physical association applies. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:15569713 Shank3 protein mediates sustained Erk-MAPK and PI3K signaling, which is crucial for tubule formation, through recruitment of the adaptor protein Grb2 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: The tyrosine phosphatase PTP1C/SHP-1 (WITH/FROM P29351) associates with Vav, Grb2 and mSos1 in hematopoietic cells. Reason: Co-association of Grb2 with PTP1C is reported without mechanism or demonstrated Grb2 activity toward the phosphatase; no informative MF applies. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:8632004 the results reveal PTP1C association with two other molecules implicated in Ras activation, the Grb2 adaptor protein and mSos1 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: The NF2 tumour suppressor merlin (WITH/FROM P46662) interacts with endogenous Grb2 and inhibits GH-induced Raf-ERK signalling. Reason: Grb2 is the target inhibited by merlin; this does not describe an informative Grb2 molecular function. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:16405865 merlin interacted with endogenous growth factor receptor bound 2 (Grb2) protein and inhibited its expression UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Themis1 and Themis2 (WITH/FROM Q8BGW0, Q91YX0) bind Grb2 and are recruited within Grb2 signalling complexes to LAT after TCR engagement. Reason: Themis proteins bind Grb2 constitutively (via a proline-rich SH3 recognition motif); the paper does not define a Grb2 activity beyond the association. No informative MF applies. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:22732588 Both proteins were tyrosine phosphorylated and were recruited within Grb2 signaling complexes to LAT following TCR engagement UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Grb2-Gab3 (WITH/FROM Q8BSM5) record from the characterisation of the DOS/Gab-family docking protein Gab3 in macrophage differentiation. Reason: The cached abstract does not describe the Grb2 interaction (Gab3 has polyproline motifs potentially binding SH3 domains); deferring to the MGI curator that it was observed, but no informative Grb2 MF can be assigned. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:11739737 two major polyproline motifs potentially interacting with SH3 domains UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: The cytoskeletal protein magicin (WITH/FROM Q920D3) binds Grb2 and forms a ternary complex with merlin and Grb2. Reason: Physical association demonstrated by affinity binding, overlay and co-IP, without a demonstrated Grb2 activity; no informative MF beyond physical association. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:15467741 we demonstrate an interaction between Grb2 and magicin UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Grb2-SCIMP (WITH/FROM Q3UU41) record from the discovery paper of the transmembrane adaptor SCIMP in MHC-II signalling. Reason: The cached abstract does not describe the Grb2 interaction; deferring to the curator that it was observed. The phospho-dependent recruitment of Grb2 to SCIMP is captured in the PMID:28290451 row, so no additional informative MF is supported here. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 **RafβMEKβERK** 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... | MODIFY | Summary: The transmembrane adaptor LIME (WITH/FROM Q9EQR5) is tyrosine phosphorylated by Lyn upon BCR cross-linking and associates with Grb2, PLCgamma2 and PI3K. Reason: Grb2 association follows Lyn-mediated tyrosine phosphorylation of the LAT-like transmembrane adaptor, consistent with SH2-phosphotyrosine docking; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:16249387 LIME was tyrosine phosphorylated by Lyn and associated with Lyn, Grb2, PLC-gamma2, and PI3K UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: The LIM protein Ajuba (WITH/FROM Q91XC0) binds either Grb2 SH3 domain via its N-terminal proline-rich pre-LIM region. Reason: An SH3-proline-rich association; Ajuba's effects are Grb2-dependent but no distinct Grb2 activity toward Ajuba is defined, so no informative MF beyond physical binding. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:10330178 The interaction between these proteins was mediated by either SH3 domain of Grb2 and the N-terminal proline-rich pre-LIM domain of Ajuba UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 ... | REMOVE | Summary: Yeast two-hybrid and co-IP interaction of the cellular prion protein PrPC (WITH/FROM P04925) with Grb2. Reason: A screen-derived interaction of uncertain physiological significance; no informative Grb2 MF beyond physical association. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:11571277 These candidates were the neuronal phosphoprotein synapsin Ib, the adaptor protein Grb2, and the still uncharacterized prion interactor Pint1 UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Grb2-Sprouty (WITH/FROM Q9QXV8) record from a study showing mammalian Sprouty1/2 block Ras activation downstream of the SNT/FRS2-Grb2-Sos complex. Reason: Sprouty acts on the Grb2-Sos pathway; the interaction does not define an informative Grb2 MF. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:11585837 Sprouty1 and Sprouty2 do no prevent the formation of a SNT.Grb2.Sos complex upon fibroblast growth factor stimulation, yet block Ras activation UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 **RafβMEKβERK** 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 **RafβMEKβERK** 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... | REMOVE | Summary: Themis (WITH/FROM Q8BGW0) identified as a Grb2 binding partner in a study of Themis in thymocyte positive selection. Reason: Constitutive Themis-Grb2 association without a demonstrated Grb2 activity; no informative MF beyond physical association. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:19597497 From this analysis, Grb2 was discovered as a binding partner UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | REMOVE | Summary: Themis (WITH/FROM Q8BGW0), via a C-terminal proline-rich class II SH3 recognition motif, binds Grb2 in an SH3 array screen. Reason: An SH3-proline-rich association without a demonstrated Grb2 activity; no informative MF beyond physical association. Removal does not mean the reported interaction is false; the bare protein binding term simply carries no functional information about Grb2. Supporting Evidence: PMID:19597498 a carboxy terminal proline-rich site (PPPRPPKxP) that matches a Class II SH3 recognition motif UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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... | MODIFY | Summary: Grb2 binds three membrane-distal phosphotyrosines (Tyr136, Tyr193, Tyr233) of the transmembrane adaptor NTAL/LAB (WITH/FROM O43561 as recorded by UniProt). Reason: Mutation of the three tyrosines abolished Grb2 binding, demonstrating phosphotyrosine-dependent SH2 docking; phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:14722116 Mutation of these three tyrosines abolished Grb2 binding and LAB function UniProt:Q60631 FUNCTION: Non-enzymatic adapter protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses. Engagement of the TCR leads to phosphorylation of LAT, which serves as docking site for GRB2. In turn, GRB2 establishes a connection with SOS1 that acts as a guanine nucleotide exchange factor and serves as a critical regulator of KRAS/RAF1 leading to MAPKs 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 **RafβMEKβERK** signaling; activated ERK can translocate to the nucleus and regulate transcriptional programs. |
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)