{"gene":"GRB7","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1994,"finding":"GRB7 SH2 domain binds directly to tyrosine-phosphorylated HER2/ErbB2, and a large fraction of phosphorylated HER2 in SKBR-3 cells is bound to GRB7; GRB7 can also bind tyrosine-phosphorylated SHC at lower affinity than GRB2.","method":"Bacterial expression cloning using phosphorylated EGFR C-terminus as probe; co-immunoprecipitation from breast cancer cell lines","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from endogenous proteins in cancer cells plus direct binding demonstrated; replicated in multiple subsequent studies","pmids":["7907978"],"is_preprint":false},{"year":1996,"finding":"GRB7 SH2 domain directly binds autophosphorylated PDGF beta-receptor in vitro; binding is dramatically reduced by mutation of Tyr-716 or Tyr-775 to Phe; GRB7 associates with activated PDGF beta-receptor in vivo and forms a complex with Shc after PDGF alpha- or beta-receptor stimulation.","method":"In vitro GST-SH2 pull-down with autophosphorylated receptor; site-directed mutagenesis; co-immunoprecipitation from cells; phosphopeptide competition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding assay with mutagenesis and confirmed in vivo by Co-IP, single lab with multiple orthogonal methods","pmids":["8940081"],"is_preprint":false},{"year":1996,"finding":"GRB7 associates with the Ret receptor tyrosine kinase via its SH2 domain in vitro and in vivo; binding is dependent on Ret autophosphorylation since a kinase-defective Ret mutant cannot bind GRB7.","method":"In vitro pull-down; co-immunoprecipitation; kinase-dead Ret mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding demonstrated in vitro, confirmed in vivo by Co-IP, and mechanism (autophosphorylation dependence) established by mutagenesis","pmids":["8631863"],"is_preprint":false},{"year":1996,"finding":"GRB7 SH2 domain interacts with tyrosine-phosphorylated SHPTP2 at Tyr-580 of SHPTP2, as identified by a modified yeast two-hybrid system with exogenous tyrosine kinase and confirmed by in vitro binding under phosphorylated conditions.","method":"Yeast two-hybrid with exogenous tyrosine kinase; in vitro GST pull-down under phosphorylation conditions","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (modified Y2H and in vitro pull-down), single lab","pmids":["8622870"],"is_preprint":false},{"year":1997,"finding":"Grb7 SH2 domain binds preferentially to Tyr-1139 of ErbB2; a betaD6 position Leu residue in the Grb7 SH2 domain (vs. Gln in Grb14) is a key specificity determinant — swapping this residue transfers high-affinity ErbB2 binding between family members.","method":"Phosphopeptide competition; site-directed mutagenesis of SH2 domain; in vitro binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted binding in vitro with reciprocal mutagenesis defining the structural determinant of specificity","pmids":["9079677"],"is_preprint":false},{"year":1998,"finding":"Grb7 SH2 domain directly and preferentially binds ErbB3 at Tyr-1180 (major) and Tyr-1243 (minor) upon heregulin stimulation, and binds ErbB4; an Arg at +3 relative to pTyr acts as a selectivity determinant distinguishing Grb7 from Grb2 binding sites.","method":"Co-immunoprecipitation in breast cancer cell lines; ErbB3 point mutants with ErbB2 co-expression; phosphopeptide competition; GST pull-down","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, pull-down, peptide competition) establishing binding sites and selectivity determinant","pmids":["9516479"],"is_preprint":false},{"year":1999,"finding":"Grb7 SH2 domain directly interacts with FAK through Tyr-397, a major autophosphorylation site of FAK, both in vitro and in vivo; this interaction is cell adhesion-dependent, suggesting involvement in integrin signaling; overexpression of Grb7 enhances cell migration toward fibronectin, whereas its SH2 domain alone (dominant negative) inhibits migration.","method":"In vitro GST pull-down; co-immunoprecipitation; tetracycline-regulated expression; cell migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated in vitro and in vivo with defined binding site; functional consequence (migration) established by gain- and loss-of-function; replicated in multiple subsequent studies","pmids":["10446223"],"is_preprint":false},{"year":1999,"finding":"Grb7 binds selectively to phosphorylated Tyr-936 in the C-terminal tail of c-Kit/SCFR (in contrast to Grb2 which binds both Tyr-703 and Tyr-936); binding is mediated through the Grb7 SH2 domain.","method":"In vivo autophosphorylation mapping; SH2 domain binding assays; site-directed mutagenesis of c-Kit","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding with identified phosphorylation sites using mutagenesis and SH2 binding assays","pmids":["10377264"],"is_preprint":false},{"year":2000,"finding":"Phosphorylation of caveolin-1 on Tyr-14 confers binding to Grb7 SH2 domain both in vitro and in vivo; this interaction functionally augments anchorage-independent growth and EGF-stimulated cell migration.","method":"Phospho-specific monoclonal antibody; in vitro and in vivo co-immunoprecipitation; functional cell migration and anchorage-independent growth assays","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding demonstrated in vitro and in vivo with defined phosphorylation site; functional assays performed; single lab","pmids":["11075810"],"is_preprint":false},{"year":2000,"finding":"Grb7 is phosphorylated by FAK in a FAK kinase activity-dependent manner (but independent of Src family kinases); cell adhesion enhances Grb7 phosphorylation in FAK+/+ but not FAK-/- cells, establishing Grb7 as a physiological FAK substrate; focal contact localization via the SH2 domain is required for Grb7-stimulated cell migration; FAK-null cells cannot be stimulated by Grb7.","method":"FAK kinase assay; FAK+/+ vs FAK-/- cells; cell adhesion assay; chimeric FAT-SH2 domain molecules; tetracycline-regulated expression; cell migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal approaches including genetic (FAK KO cells), biochemical (kinase assay), and functional (migration) assays in a single focused study; replicated by other labs","pmids":["10893408"],"is_preprint":false},{"year":2000,"finding":"Grb7 binds the activated insulin receptor via two domains: the SH2 domain and the PIR (phosphotyrosine interacting region); Grb7 binds the tyrosine kinase activation loop of the insulin receptor but is not a substrate of insulin receptor tyrosine kinase activity.","method":"Yeast two-hybrid; GST pull-down; co-immunoprecipitation; domain deletion experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays with domain mapping, single lab, negative result (not a substrate) also confirmed","pmids":["10803466"],"is_preprint":false},{"year":2000,"finding":"Grb7 interacts with Rnd1, a constitutively GTP-bound Rho family GTPase; the interaction involves the switch II loop of Rnd1 and the Grb7 SH2 domain; confirmed in yeast two-hybrid, in vitro, and pull-down from SKBR3 cells.","method":"Yeast two-hybrid; in vitro binding; GST pull-down from breast cancer cell lysate","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods (Y2H, in vitro, pull-down) from single lab; domain mapping partially defined","pmids":["10664463"],"is_preprint":false},{"year":2001,"finding":"Targeting Grb7 to focal contacts via a FAT-chimera stimulates cell migration (similar to Src-FAT and p85-FAT), while targeting Grb2 to focal contacts increases cell cycle progression; demonstrating that distinct FAK signaling complexes regulate migration versus cell cycle progression.","method":"Chimeric FAT-fusion molecules; cell migration assay; cell cycle analysis; paxillin and p130cas phosphorylation assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric molecule approach with functional readouts, single lab, distinguishes Grb7 (migration) from Grb2 (cell cycle) functions","pmids":["11418135"],"is_preprint":false},{"year":2002,"finding":"Grb7 PH domain mediates binding to phosphoinositides in vitro and in intact cells, with strongest affinity for D3- and D5-phosphoinositides; PH domain interaction with phosphoinositides is required for Grb7 phosphorylation by FAK (though not for FAK binding or focal contact recruitment); PI 3-kinase activity promotes Grb7 association with phosphoinositides and migration stimulation.","method":"In vitro phospholipid binding assay; phosphoinositide overlay in intact cells; deletion mutants; PI3K inhibitor treatment; cell migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (in vitro, intact cell, domain deletions, pharmacological inhibition) establishing PH domain-phosphoinositide interaction and its functional consequences; single lab","pmids":["12021278"],"is_preprint":false},{"year":2002,"finding":"EphB1 receptor tyrosine kinase associates with Grb7 via Tyr-928 of EphB1 (primary binding site) through the SH2 domain of Grb7; EphB1 phosphorylates Grb7; EphB1-Grb7 association correlates with EphB1-stimulated cell migration, and dominant-negative Grb7-SH2 abolishes EphB1-stimulated migration.","method":"Yeast two-hybrid screening; co-immunoprecipitation; site-directed mutagenesis; ephrinB1 stimulation; cell migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Y2H identification confirmed by Co-IP, binding site mapped by mutagenesis, phosphorylation demonstrated, functional consequence shown by dominant-negative; single lab","pmids":["12223469"],"is_preprint":false},{"year":2002,"finding":"Non-phosphorylated cyclic peptides containing a YXN motif bind specifically to the Grb7 SH2 domain and competitively inhibit Grb7 association with ErbB receptors (particularly ErbB3) in cell lysates; the cyclic structure is required for Grb7 SH2 binding; peptide G7-18 does not bind Grb2 or Grb14 SH2 domains.","method":"Phage display random peptide library screening; peptide competition in cell lysates; specificity testing against related SH2 domains","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phage display with binding confirmation and functional competition assay; defines SH2 selectivity; single lab","pmids":["11809769"],"is_preprint":false},{"year":2003,"finding":"NMR solution structure of the Grb7 SH2 domain in complex with ErbB2 pY1139 phosphopeptide reveals an SH2 topology with central beta-sheet and terminal alpha-helices; the ErbB2 peptide binds in a beta-turn conformation (not extended), similar to Grb2-SH2; a four-residue insert between betaE and EF loop influences the complex structure.","method":"NMR solution structure determination","journal":"Journal of biomolecular NMR","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation of binding conformation; provides atomic-level mechanistic detail; single lab","pmids":["12975581"],"is_preprint":false},{"year":2003,"finding":"Grb7 (but not Grb10) binds to and inhibits FGF receptor-induced oocyte maturation in Xenopus; this inhibition correlates with Grb7 binding to the receptor and inhibition of the Ras-dependent pathway; the PIR and SH2 domains of Grb7 are both implicated.","method":"Xenopus oocyte injection and maturation assay; FGF receptor expression system; domain mutants","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain-of-function in Xenopus model with domain dissection; single lab, model organism","pmids":["12885405"],"is_preprint":false},{"year":2005,"finding":"Grb7 and Grb7V are calmodulin (CaM)-binding proteins; the CaM-binding domain is located in residues 243-256 within the proximal PH domain region; CaM binding is Ca2+-dependent; CaM regulates Grb7 membrane association; deletion of the CaM-binding domain reduces membrane association; direct CaM-Grb7 interaction at the plasma membrane demonstrated by FRET in living cells.","method":"Ca2+-dependent CaM-affinity chromatography; biotinylated CaM overlay; deletion mutants; cell fractionation; FRET in living cells; CaM antagonist treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemical binding, domain deletion, live-cell FRET, pharmacological inhibition) establishing CaM-Grb7 interaction and its functional consequence on localization; single lab with comprehensive approach","pmids":["15806159"],"is_preprint":false},{"year":2005,"finding":"Grb7 SH2 domain forms a homodimer with a dissociation constant of ~11 µM; mutation of Phe-511 to Arg produces a monomeric form, identifying this residue as essential for dimerization.","method":"Sedimentation equilibrium ultracentrifugation; size-exclusion chromatography; site-directed mutagenesis","journal":"European biophysics journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative biophysical measurement of dimerization with mutagenesis defining key residue; single lab","pmids":["15841400"],"is_preprint":false},{"year":2007,"finding":"Grb7 is an RNA-binding protein that binds specifically to the first stem loop of kor mRNA 5'-UTR through a novel RNA-binding domain in its amino terminus; when bound to capped target mRNA, Grb7 blocks eIF4E recruitment and renders mRNA untranslatable; FAK-mediated hyperphosphorylation of two Tyr residues in Grb7's carboxyl terminus reduces its RNA-binding and translation-repressive activity.","method":"RNA-protein binding assay; mRNA translation assay; Netrin-1/FAK signaling; mutagenesis of phosphorylation sites","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct RNA binding demonstrated, translation repression mechanism established, FAK-dependent phosphorylation as regulatory switch shown with multiple methods; single lab","pmids":["17318180"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the Grb7 SH2 domain solved to 2.1 Å resolution; the structure reveals the peptide binding site, a dimer interface, and that the SH2 domain forms a physiological dimer; the inhibitory peptide G7-18NATE binds with Kd ~35.7 µM and perturbs both the ligand-binding surface and the dimer interface.","method":"X-ray crystallography; analytical ultracentrifugation; ITC; NMR titration","journal":"BMC structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.1 Å, quantitative binding measurement, NMR mapping of binding surface; multiple orthogonal methods in one study","pmids":["17894853"],"is_preprint":false},{"year":2007,"finding":"GRB7 overexpression in breast cancer cells facilitates activation of HER2/ErbB2 tyrosine phosphorylation; GRB7 knockdown decreases HER2 phosphorylation; GRB7 overexpression activates downstream PLC-γ1 recruitment to HER2, PKC pathway (MARCKS phosphorylation), and AKT phosphorylation.","method":"Overexpression in MCF-7/HER2 cells; siRNA knockdown in SKBR-3 and MB-453; immunoblotting; immunoprecipitation; xenograft tumor assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined downstream readouts; single lab","pmids":["17916906"],"is_preprint":false},{"year":2008,"finding":"Grb7 is an integral component of stress granules (SGs) and is required for SG formation; Grb7 directly interacts with HuR (Hu antigen R); upon stress termination, FAK hyperphosphorylates Grb7, causing loss of HuR interaction and dissociation from SG components, thereby driving SG disassembly; dominant-negative hypophospho mutants of FAK and Grb7 significantly attenuate SG disassembly.","method":"SG localization assay; co-immunoprecipitation of Grb7-HuR; FAK kinase assay; dominant-negative mutants; SG dynamics measurement","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein-protein interaction, kinase assay establishing FAK as the writer, dominant-negative experiments defining functional consequence; multiple methods in one study","pmids":["18273060"],"is_preprint":false},{"year":2009,"finding":"Grb7 interacts with the transcriptional regulator FHL2 specifically through the Grb7 RA and PH domains; Grb7 must be tyrosine phosphorylated for this interaction to occur; intramolecular ITC measurements suggest Grb7-RA-PH domains can bind the Grb7-SH2 domain with micromolar affinity, supporting a head-to-tail autoinhibitory conformation.","method":"Yeast two-hybrid; co-immunoprecipitation; ITC; immunofluorescence","journal":"Journal of molecular recognition","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H and Co-IP confirm interaction with domain mapping; ITC provides quantitative support for autoinhibitory model; single lab","pmids":["18853468"],"is_preprint":false},{"year":2010,"finding":"EGF-induced Grb7 tyrosine phosphorylation/activation recruits and activates Ras-GTPases, subsequently promotes ERK1/2 phosphorylation, and stimulates tumor growth; Grb7 forms a novel EGFR-Grb7-Ras signaling complex.","method":"Co-immunoprecipitation; Ras-GTP pull-down; siRNA knockdown; proliferation and tumor growth assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defining complex, Ras-GTP pull-down confirming activation, functional knockdown; single lab","pmids":["20622016"],"is_preprint":false},{"year":2010,"finding":"Grb7 upregulation following HER2/PI3K inhibition by lapatinib is mediated by de-repression of Akt-dependent transcriptional repression of Grb7; constitutively active Akt prevents lapatinib-induced Grb7 upregulation; Grb7 removal by RNA interference reduces breast cancer cell viability and increases lapatinib activity.","method":"siRNA knockdown; constitutively active Akt retroviral transgenesis; low-density array and qPCR; PI3K inhibitor treatment; in vivo xenograft model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (constitutively active Akt prevents Grb7 upregulation) defining pathway; in vitro and in vivo functional readouts; single lab","pmids":["20126311"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of Grb7 SH2 domain in complex with the non-phosphorylated cyclic inhibitor peptide G7-18NATE solved; structural basis for peptide interaction identified: F2, G4, F9, and YDN motif residues are the main contacts; SH2 dimer interface is also visible in the structure.","method":"X-ray crystallography; phage display for analogue identification; ITC","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of protein-peptide complex with ITC quantification; defines binding interface at atomic resolution","pmids":["21802427"],"is_preprint":false},{"year":2012,"finding":"Grb7 SH2 domain dimerization state influences its ability to bind tyrosine-phosphorylated ligands; a phosphomimetic mutation (Y80E) or dimerization-deficient mutation (F99R) both reduce dimerization and alter thermodynamic binding characteristics for the ErbB2 pY peptide, suggesting phosphorylation state of Grb7 SH2 domain tyrosines regulates dimerization.","method":"ITC; circular dichroism; NMR; analytical ultracentrifugation; site-directed mutagenesis","journal":"Journal of molecular recognition","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — multiple biophysical methods with mutagenesis; single lab; functional consequence of dimerization on ligand binding established","pmids":["22811067"],"is_preprint":false},{"year":2012,"finding":"GRB7 modulates ErbB2 signaling through enhanced phosphorylation of ErbB2 and Akt, identified as a context-dependent oncogene in the 17q12-21 amplicon.","method":"Retrovirus-mediated gene transfer; phosphorylation assays; functional cancer cell assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function assay with defined biochemical readout (ErbB2 and Akt phosphorylation); single lab","pmids":["22584052"],"is_preprint":false},{"year":2012,"finding":"GRB7 promotes ERK phosphorylation and FOXM1 expression in ovarian cancer cells; GRB7 knockdown reduces ERK phosphorylation and FOXM1; enforced FOXM1 expression cannot alter GRB7 or ERK levels, establishing GRB7 acts upstream of ERK which in turn controls FOXM1; GRB7 enhances cell migration/invasion through JNK signaling while promoting proliferation through ERK.","method":"Overexpression and knockdown (siRNA/shRNA); MEK inhibitors; western blot; in vitro and in vivo functional assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by inhibitor and OE/KD experiments; pathway ordering demonstrated; single lab","pmids":["23285101"],"is_preprint":false},{"year":2013,"finding":"GRB7 recruits SHC into the HER2-GRB7 signaling complex leading to RAS-GTP activation (proliferative signal); following integrin engagement, GRB7 is phosphorylated at tyrosine in a p-FAK(Y397)-dependent manner, and FAK-GRB7 complex activates RAC1-GTP through recruitment of VAV2, mediating cell migration.","method":"Co-immunoprecipitation; RAS-GTP and RAC1-GTP pull-down assays; siRNA knockdown; fibronectin engagement assay","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying complex components, active GTPase pull-downs, siRNA validation; single lab, multiple orthogonal methods","pmids":["23593540"],"is_preprint":false},{"year":2013,"finding":"Grb7 interacts with Filamin-a via the Grb7 RA-PH domains and Filamin-a immunoglobulin-like repeat domains 16-19; Grb7 and Filamin-a co-localize to membrane ruffles upon EGF stimulation, connecting Grb7 signaling to cytoskeletal remodeling.","method":"Yeast two-hybrid; in vitro binding; co-immunoprecipitation; immunofluorescence microscopy","journal":"Journal of molecular recognition","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H, in vitro binding, and Co-IP with domain mapping; co-localization provides mechanistic link to cytoskeleton; single lab","pmids":["24089360"],"is_preprint":false},{"year":2013,"finding":"Deletion of the calmodulin-binding domain of Grb7 (residues 243-256) impairs cell migration, cell attachment to extracellular matrix, and actin cytoskeleton reorganization; CaM antagonists W-7 and W-13 inhibit migration of cells expressing wild-type Grb7 but not the CaM-binding-deficient mutant, establishing CaM binding to Grb7 as functionally required for migration.","method":"Deletion mutant expression; cell migration assay; cell adhesion assay; actin cytoskeleton staining; CaM antagonist treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutant compared to wild-type with pharmacological validation; single lab","pmids":["23743201"],"is_preprint":false},{"year":2012,"finding":"Calmodulin (CaM) regulates translocation of Grb7 into the nucleus; a nuclear localization signal (NLS) overlaps the CaM-binding domain (residues 243-256); deletion of the CaM-BD prevents nuclear localization; CaM antagonist W-7 enhances Grb7 nuclear presence, indicating CaM binding occludes the NLS.","method":"Deletion mutants; subcellular fractionation; CaM antagonist treatment; fluorescence microscopy","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutants and pharmacological perturbation establish CaM-regulated nuclear localization; single lab","pmids":["22673522"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Grb7 SH2 domain in apo form reveals malonate bound in the phosphotyrosine binding pocket; peptide analogues incorporating phosphotyrosine mimetics (cmF and cF) bind Grb7-SH2 with up to 9-fold improved affinity (Kd = 2.1-5.7 µM) and are specific for Grb7-SH2 over Grb2-SH2 and Grb10-SH2; X-ray structure of cmF-containing peptide-Grb7 SH2 complex reveals precise contacts.","method":"X-ray crystallography; SPR binding assays; rational design based on crystal structure","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus quantitative binding measurements and specificity profiling; single lab with multiple structural and biophysical methods","pmids":["26359549"],"is_preprint":false},{"year":2016,"finding":"Grb7 protein is regulated by phosphorylation on Ser194-Pro motif by c-Jun N-terminal kinase (JNK), which facilitates binding to the WW domain of Pin1; Pin1 then promotes ubiquitin- and proteasome-dependent degradation of Grb7; this regulatory mechanism controls Grb7 stability during G2-M cell cycle progression.","method":"Pin1-WW domain binding assay; phosphorylation mutagenesis; proteasome inhibitor treatment; cell cycle analysis; ubiquitination assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified kinase (JNK) writing the phosphorylation, reader (Pin1 WW domain) and eraser pathway (proteasome); multiple methods; single lab","pmids":["27658202"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of bicyclic peptide G7-B1 and G7-B4 in complex with Grb7 SH2 domain reveal unexpected binding modes; Arg-462 in the BC loop of Grb7-SH2 is a key specificity determinant for G7-18NATE binding (mutation reduces affinity 3.3-fold); βD6 Leu is also required; G7-18NATE is confirmed specific for Grb7 over 79 SH2 domains by microarray.","method":"X-ray crystallography; site-directed mutagenesis; SPR; SH2 domain microarray","journal":"Scientific reports / Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with mutagenesis and SPR quantification; specificity confirmed against 79 SH2 domains; two related papers provide convergent structural evidence","pmids":["27257138","29018805"],"is_preprint":false},{"year":2017,"finding":"X-ray crystal structures of bicyclic peptide inhibitors (bearing cmF and cF phosphotyrosine mimetics) in complex with Grb7-SH2 domain reveal structural basis for potent (Kd = 0.13 µM for optimized inhibitor) and specific Grb7-SH2 binding; cell-permeable versions block Grb7-mediated interactions in breast cancer cells.","method":"X-ray crystallography; SPR binding assays; cell-based inhibition assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with quantitative binding measurements and cellular validation; single lab with multiple orthogonal methods","pmids":["29083893"],"is_preprint":false},{"year":2020,"finding":"Direct interaction between full-length Grb7 and calmodulin (CaM) is Ca2+-dependent; CaM binding is localized to the Grb7 RA-PH domain (high-micromolar affinity by SPR); no CaM binding was detected to the SH2 domain alone.","method":"Surface plasmon resonance with purified proteins; Ca2+-dependent binding assay; domain constructs","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct binding measurement with purified proteins and quantitative SPR; single lab; confirms and localizes previously described interaction","pmids":["32079204"],"is_preprint":false},{"year":2021,"finding":"GRB7 mediates primary resistance to MEK inhibitors in KRAS-mutant colorectal cancer through the RTK pathway; PLK1 is identified as the predominant interacting kinase of GRB7 by mass spectrometry of GRB7 immunoprecipitates; PLK1 inhibition suppresses downstream FAK, STAT3, AKT, and 4EBP1 signaling.","method":"Genome-wide CRISPR/Cas9 screen; mass spectrometry of GRB7 immunoprecipitates; loss-of-function and gain-of-function assays; PLK1 inhibitor treatment; in vitro and in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen identifying GRB7, MS identifying PLK1 as binding partner confirmed by Co-IP, functional validation with inhibitors; single lab","pmids":["34718347"],"is_preprint":false},{"year":2016,"finding":"Grb7 and Hax-1 interact via the Grb7 RA-PH domains; Grb7 and Hax1 may co-localize partially to mitochondria in EGF-treated SKBR3 cells; Grb7 can affect Caspase-3 cleavage of Hax1 isoform 1 in vitro and may slow Caspase-3 cleavage of Hax1 in apoptotic cells, increasing cell viability.","method":"Co-immunoprecipitation; confocal immunofluorescence; in vitro Caspase-3 cleavage assay; cell viability assay","journal":"Journal of molecular recognition","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and partial mechanistic follow-up (caspase cleavage), single lab, mitochondrial co-localization described as partial and conditional","pmids":["26869103"],"is_preprint":false},{"year":2003,"finding":"Grb7 SH2 domain binds to phosphorylated Tyr-281 of the immunoreceptor G6f (an MHC-encoded immunoglobulin superfamily member) via the YXN consensus motif; this interaction is phosphorylation-dependent; cross-linking of G6f induces transient ERK1/2 MAP kinase phosphorylation preventable by MEK inhibitors.","method":"GST pull-down; co-immunoprecipitation; cell stimulation with pervanadate or antibody cross-linking; MEK inhibitor treatment","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding and phosphorylation dependence demonstrated by pull-down and Co-IP; signaling consequence shown; single lab","pmids":["12852788"],"is_preprint":false}],"current_model":"GRB7 is a multi-domain adaptor protein (containing RA, PH, and SH2 domains) that is recruited via its SH2 domain to numerous tyrosine-autophosphorylated receptor tyrosine kinases (including HER2/ErbB2, ErbB3, ErbB4, FAK, EphB1, PDGF receptor, c-Kit, Ret, and the insulin receptor), thereby coupling them to downstream signaling cascades: in the context of proliferation, GRB7 forms an EGFR/HER2-GRB7-SHC-RAS complex that activates RAS-GTP and ERK; in the context of migration, integrin-activated FAK phosphorylates GRB7 (a phosphorylation that requires PH domain-phosphoinositide interaction and focal contact localization), and FAK-GRB7 promotes RAC1 activation via VAV2 recruitment; GRB7 also functions as a stress granule component and translational repressor by binding mRNA 5'-UTRs and blocking eIF4E recruitment, a function relieved by FAK-mediated hyperphosphorylation; GRB7's cellular localization and activity are further regulated by Ca²⁺-dependent calmodulin binding to its RA-PH domain (which occludes an overlapping nuclear localization signal) and by JNK-mediated phosphorylation of Ser194 leading to Pin1-dependent proteasomal degradation."},"narrative":{"mechanistic_narrative":"GRB7 is a multidomain signaling adaptor that couples activated receptor and non-receptor tyrosine kinases to proliferative and migratory responses, principally through its C-terminal SH2 domain, which binds phosphotyrosine motifs (notably YXN/R+3-containing sites) on diverse partners [PMID:7907978, PMID:9516479]. Its SH2 domain engages tyrosine-autophosphorylated HER2/ErbB2 at pTyr1139, ErbB3 (pTyr1180) and ErbB4, the PDGF beta-receptor, Ret, c-Kit (pTyr936), the insulin receptor, EphB1 (pTyr928), and FAK (pTyr397), with binding strictly dependent on receptor autophosphorylation [PMID:7907978, PMID:8940081, PMID:8631863, PMID:9079677, PMID:9516479, PMID:10377264, PMID:10803466, PMID:12223469, PMID:10446223]. Specificity within the Grb family is set by a betaD6 Leu and a preference for an Arg at the +3 position relative to phosphotyrosine [PMID:9079677, PMID:9516479]. In proliferative signaling, GRB7 enhances HER2/ErbB2 phosphorylation and assembles an EGFR/HER2-GRB7-SHC complex that activates RAS-GTP and ERK, driving downstream FOXM1 expression and AKT signaling [PMID:17916906, PMID:20622016, PMID:23593540, PMID:23285101]. In migration, GRB7 is recruited to focal contacts via its SH2 domain and is phosphorylated there by FAK in a kinase-dependent, adhesion-stimulated manner; this requires PH domain engagement of D3/D5 phosphoinositides, and the FAK-GRB7 module activates RAC1 through VAV2 recruitment [PMID:10446223, PMID:10893408, PMID:12021278, PMID:23593540]. GRB7 also acts as an RNA-binding translational repressor, binding target mRNA 5'-UTRs through an N-terminal RNA-binding domain to block eIF4E recruitment, and is an integral, HuR-interacting component required for stress granule formation; FAK-mediated hyperphosphorylation relieves both the RNA-binding/repressive and stress-granule functions [PMID:17318180, PMID:18273060]. GRB7 localization and stability are tuned by Ca2+-dependent calmodulin binding to its RA-PH domain, which occludes an overlapping nuclear localization signal and controls membrane association, and by JNK phosphorylation of Ser194 that recruits Pin1 to drive proteasomal degradation during the cell cycle [PMID:15806159, PMID:22673522, PMID:32079204, PMID:27658202]. Structurally, the SH2 domain forms a physiological homodimer whose dimerization state, modulated by tyrosine phosphorylation, influences phospholigand binding, and this domain has been extensively targeted by selective cyclic and bicyclic peptide inhibitors [PMID:15841400, PMID:17894853, PMID:22811067, PMID:27257138, PMID:29018805, PMID:29083893].","teleology":[{"year":1994,"claim":"Established GRB7 as a direct SH2-domain partner of an oncogenic receptor tyrosine kinase, identifying its core adaptor function.","evidence":"Bacterial expression cloning with phosphopeptide probe and Co-IP from breast cancer cells","pmids":["7907978"],"confidence":"High","gaps":["Did not define downstream effectors recruited by GRB7","Affinity for SHC lower than GRB2, leaving competitive significance unclear"]},{"year":1996,"claim":"Showed GRB7's SH2 domain is a general phosphotyrosine reader engaged by multiple RTKs in an autophosphorylation-dependent manner, generalizing it beyond HER2.","evidence":"GST-SH2 pull-downs, site-directed mutagenesis and Co-IP for PDGFR-beta and Ret","pmids":["8940081","8631863"],"confidence":"High","gaps":["Functional consequence of these RTK associations not established","Did not address signaling output downstream"]},{"year":1998,"claim":"Defined the molecular determinants of GRB7 SH2 selectivity, distinguishing it from related Grb adaptors at specific receptor phosphosites.","evidence":"Phosphopeptide competition and reciprocal SH2-domain mutagenesis on ErbB2/ErbB3/ErbB4 sites","pmids":["9079677","9516479"],"confidence":"High","gaps":["Selectivity determinants tested in vitro, not in physiological competition with full adaptor repertoire"]},{"year":2000,"claim":"Identified GRB7 as a FAK substrate and focal-contact effector for migration, separating its migratory role from cell-cycle functions of other adaptors.","evidence":"FAK kinase assays, FAK+/+ vs FAK-/- cells, FAT-SH2 chimeras and migration assays","pmids":["10446223","10893408","11418135"],"confidence":"High","gaps":["Identity of the GTPase effectors downstream of FAK-GRB7 not yet defined","Phosphorylated tyrosine residues on GRB7 not mapped here"]},{"year":2002,"claim":"Revealed the PH domain as a phosphoinositide sensor required for FAK-mediated GRB7 phosphorylation, linking lipid signaling to GRB7 activation.","evidence":"Lipid-binding assays, intact-cell overlays, deletion mutants and PI3K inhibition with migration readouts","pmids":["12021278"],"confidence":"High","gaps":["Did not resolve how PH-lipid binding positions GRB7 for FAK phosphorylation","EphB1 link established separately"]},{"year":2003,"claim":"Provided the first atomic-resolution view of GRB7 SH2-phosphopeptide recognition, defining the bound peptide conformation.","evidence":"NMR solution structure of SH2 domain with ErbB2 pY1139 peptide","pmids":["12975581"],"confidence":"High","gaps":["Full-length protein architecture not resolved","Did not address dimerization in solution"]},{"year":2007,"claim":"Uncovered an RNA-binding, translation-repressive function for GRB7 controlled by FAK phosphorylation, expanding its role beyond a kinase adaptor.","evidence":"RNA-protein binding, translation assays, and FAK-dependent phosphosite mutagenesis; SH2 crystal structure resolved separately","pmids":["17318180","17894853"],"confidence":"High","gaps":["Full spectrum of mRNA targets beyond kor not defined","Structural basis of the N-terminal RNA-binding domain unresolved"]},{"year":2008,"claim":"Defined GRB7 as a stress granule component whose HuR interaction and FAK-driven disassembly couple kinase signaling to mRNA granule dynamics.","evidence":"Stress granule localization, GRB7-HuR Co-IP, FAK kinase assay and dominant-negative mutants","pmids":["18273060"],"confidence":"High","gaps":["Mechanism by which GRB7 nucleates granule assembly not detailed","Relationship between RNA-binding and HuR-binding surfaces unclear"]},{"year":2010,"claim":"Established that GRB7 actively amplifies RTK output, assembling an EGFR-GRB7-RAS complex and being feedback-induced upon HER2/PI3K inhibition.","evidence":"Co-IP, RAS-GTP pull-down, siRNA and lapatinib/Akt epistasis with xenograft assays","pmids":["20622016","20126311","17916906"],"confidence":"Medium","gaps":["Direct vs indirect recruitment of RAS not fully resolved","Single-lab functional readouts"]},{"year":2012,"claim":"Linked GRB7 SH2 dimerization state to phospholigand binding and identified calmodulin-regulated nuclear localization, defining conformational and localization control.","evidence":"ITC/CD/NMR/AUC of dimer mutants; deletion mutants and CaM antagonists for nuclear translocation","pmids":["22811067","22673522"],"confidence":"Medium","gaps":["Physiological tyrosine phosphorylation regulating dimerization not directly demonstrated in vivo","Nuclear function of GRB7 unknown"]},{"year":2013,"claim":"Resolved the bifurcated GRB7 signaling logic: SHC/RAS for proliferation versus FAK-VAV2-RAC1 for migration, with cytoskeletal coupling via Filamin-A.","evidence":"Co-IP, RAS-GTP and RAC1-GTP pull-downs, siRNA, fibronectin engagement, and domain-mapped Filamin-A interaction","pmids":["23593540","24089360","23743201"],"confidence":"Medium","gaps":["Stoichiometry and temporal sequence of complex assembly not defined","Single-lab evidence for VAV2 recruitment"]},{"year":2016,"claim":"Identified JNK-Pin1-proteasome degradation of GRB7 at Ser194, defining cell-cycle-coupled control of GRB7 abundance.","evidence":"Pin1-WW binding, phospho-site mutagenesis, proteasome inhibition and ubiquitination assays","pmids":["27658202"],"confidence":"Medium","gaps":["E3 ligase mediating degradation not identified","Single-lab finding"]},{"year":2020,"claim":"Confirmed and localized direct Ca2+-dependent calmodulin binding to the GRB7 RA-PH domain, anchoring the localization-regulatory mechanism in purified-protein measurements.","evidence":"SPR with full-length and domain constructs under Ca2+-dependent conditions","pmids":["32079204"],"confidence":"Medium","gaps":["High-micromolar affinity raises questions on cellular occupancy","Functional consequence inferred from earlier deletion studies"]},{"year":2021,"claim":"Implicated GRB7 in MEK-inhibitor resistance and identified PLK1 as a predominant GRB7-interacting kinase coupling it to FAK/STAT3/AKT/4EBP1 output.","evidence":"Genome-wide CRISPR screen, mass spectrometry of GRB7 IPs, and PLK1 inhibition in tumor models","pmids":["34718347"],"confidence":"Medium","gaps":["Direct vs indirect GRB7-PLK1 binding not structurally defined","Mechanism of resistance not fully dissected"]},{"year":null,"claim":"How GRB7's distinct functional modes — RTK adaptor, FAK-coupled migration effector, translational repressor, and stress granule component — are dynamically partitioned in a single cell, and the in vivo role of its nuclear translocation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model of how phosphorylation, lipid, and calmodulin inputs switch GRB7 between adaptor and RNA-regulatory states","Nuclear function uncharacterized","Physiological RNA target repertoire undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,31,25]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[20]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[20]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[18,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[34]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[32,33]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,25,31]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[20,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[22,26,40]}],"complexes":["stress granule","EGFR/HER2-GRB7-SHC complex","FAK-GRB7-VAV2 complex"],"partners":["ERBB2","ERBB3","PTK2","SHC1","VAV2","CALM1","ELAVL1","PLK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14451","full_name":"Growth factor receptor-bound protein 7","aliases":["B47","Epidermal growth factor receptor GRB-7","GRB7 adapter protein"],"length_aa":532,"mass_kda":59.7,"function":"Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling. Promotes activation of down-stream protein kinases, including STAT3, AKT1, MAPK1 and/or MAPK3. Promotes activation of HRAS. Plays a role in signal transduction in response to EGF. Plays a role in the regulation of cell proliferation and cell migration. Plays a role in the assembly and stability of RNA stress granules. Binds to the 5'UTR of target mRNA molecules and represses translation of target mRNA species, when not phosphorylated. Phosphorylation impairs RNA binding and promotes stress granule disassembly during recovery after cellular stress (By similarity)","subcellular_location":"Cytoplasm; Cell junction, focal adhesion; Cell membrane; Cytoplasmic granule; Cell projection","url":"https://www.uniprot.org/uniprotkb/Q14451/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRB7","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRB7","total_profiled":1310},"omim":[{"mim_id":"611802","title":"MIGRATION AND INVASION ENHANCER 1; MIEN1","url":"https://www.omim.org/entry/611802"},{"mim_id":"611801","title":"POST-GPI ATTACHMENT TO PROTEINS 3; PGAP3","url":"https://www.omim.org/entry/611801"},{"mim_id":"611404","title":"LYMPHOCYTE ANTIGEN 6 FAMILY, MEMBER G6F; LY6G6F","url":"https://www.omim.org/entry/611404"},{"mim_id":"611221","title":"GASDERMIN B; GSDMB","url":"https://www.omim.org/entry/611221"},{"mim_id":"609038","title":"RHO FAMILY GTPase 1; RND1","url":"https://www.omim.org/entry/609038"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":58.0},{"tissue":"kidney","ntpm":59.1}],"url":"https://www.proteinatlas.org/search/GRB7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q14451","domains":[{"cath_id":"3.10.20.90","chopping":"101-182","consensus_level":"high","plddt":93.8984,"start":101,"end":182},{"cath_id":"2.30.29.30","chopping":"188-351","consensus_level":"high","plddt":88.3569,"start":188,"end":351},{"cath_id":"3.30.505.10","chopping":"426-525","consensus_level":"high","plddt":94.143,"start":426,"end":525}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14451","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14451-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14451-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRB7","jax_strain_url":"https://www.jax.org/strain/search?query=GRB7"},"sequence":{"accession":"Q14451","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14451.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14451/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14451"}},"corpus_meta":[{"pmid":"11075810","id":"PMC_11075810","title":"Constitutive 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Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/24637751","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49933,"output_tokens":10718,"usd":0.155284,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21185,"output_tokens":4762,"usd":0.112488,"stage2_stop_reason":"end_turn"},"total_usd":0.267772,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"GRB7 SH2 domain binds directly to tyrosine-phosphorylated HER2/ErbB2, and a large fraction of phosphorylated HER2 in SKBR-3 cells is bound to GRB7; GRB7 can also bind tyrosine-phosphorylated SHC at lower affinity than GRB2.\",\n      \"method\": \"Bacterial expression cloning using phosphorylated EGFR C-terminus as probe; co-immunoprecipitation from breast cancer cell lines\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from endogenous proteins in cancer cells plus direct binding demonstrated; replicated in multiple subsequent studies\",\n      \"pmids\": [\"7907978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"GRB7 SH2 domain directly binds autophosphorylated PDGF beta-receptor in vitro; binding is dramatically reduced by mutation of Tyr-716 or Tyr-775 to Phe; GRB7 associates with activated PDGF beta-receptor in vivo and forms a complex with Shc after PDGF alpha- or beta-receptor stimulation.\",\n      \"method\": \"In vitro GST-SH2 pull-down with autophosphorylated receptor; site-directed mutagenesis; co-immunoprecipitation from cells; phosphopeptide competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding assay with mutagenesis and confirmed in vivo by Co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"8940081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"GRB7 associates with the Ret receptor tyrosine kinase via its SH2 domain in vitro and in vivo; binding is dependent on Ret autophosphorylation since a kinase-defective Ret mutant cannot bind GRB7.\",\n      \"method\": \"In vitro pull-down; co-immunoprecipitation; kinase-dead Ret mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding demonstrated in vitro, confirmed in vivo by Co-IP, and mechanism (autophosphorylation dependence) established by mutagenesis\",\n      \"pmids\": [\"8631863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"GRB7 SH2 domain interacts with tyrosine-phosphorylated SHPTP2 at Tyr-580 of SHPTP2, as identified by a modified yeast two-hybrid system with exogenous tyrosine kinase and confirmed by in vitro binding under phosphorylated conditions.\",\n      \"method\": \"Yeast two-hybrid with exogenous tyrosine kinase; in vitro GST pull-down under phosphorylation conditions\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (modified Y2H and in vitro pull-down), single lab\",\n      \"pmids\": [\"8622870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Grb7 SH2 domain binds preferentially to Tyr-1139 of ErbB2; a betaD6 position Leu residue in the Grb7 SH2 domain (vs. Gln in Grb14) is a key specificity determinant — swapping this residue transfers high-affinity ErbB2 binding between family members.\",\n      \"method\": \"Phosphopeptide competition; site-directed mutagenesis of SH2 domain; in vitro binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted binding in vitro with reciprocal mutagenesis defining the structural determinant of specificity\",\n      \"pmids\": [\"9079677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Grb7 SH2 domain directly and preferentially binds ErbB3 at Tyr-1180 (major) and Tyr-1243 (minor) upon heregulin stimulation, and binds ErbB4; an Arg at +3 relative to pTyr acts as a selectivity determinant distinguishing Grb7 from Grb2 binding sites.\",\n      \"method\": \"Co-immunoprecipitation in breast cancer cell lines; ErbB3 point mutants with ErbB2 co-expression; phosphopeptide competition; GST pull-down\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, pull-down, peptide competition) establishing binding sites and selectivity determinant\",\n      \"pmids\": [\"9516479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Grb7 SH2 domain directly interacts with FAK through Tyr-397, a major autophosphorylation site of FAK, both in vitro and in vivo; this interaction is cell adhesion-dependent, suggesting involvement in integrin signaling; overexpression of Grb7 enhances cell migration toward fibronectin, whereas its SH2 domain alone (dominant negative) inhibits migration.\",\n      \"method\": \"In vitro GST pull-down; co-immunoprecipitation; tetracycline-regulated expression; cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated in vitro and in vivo with defined binding site; functional consequence (migration) established by gain- and loss-of-function; replicated in multiple subsequent studies\",\n      \"pmids\": [\"10446223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Grb7 binds selectively to phosphorylated Tyr-936 in the C-terminal tail of c-Kit/SCFR (in contrast to Grb2 which binds both Tyr-703 and Tyr-936); binding is mediated through the Grb7 SH2 domain.\",\n      \"method\": \"In vivo autophosphorylation mapping; SH2 domain binding assays; site-directed mutagenesis of c-Kit\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding with identified phosphorylation sites using mutagenesis and SH2 binding assays\",\n      \"pmids\": [\"10377264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Phosphorylation of caveolin-1 on Tyr-14 confers binding to Grb7 SH2 domain both in vitro and in vivo; this interaction functionally augments anchorage-independent growth and EGF-stimulated cell migration.\",\n      \"method\": \"Phospho-specific monoclonal antibody; in vitro and in vivo co-immunoprecipitation; functional cell migration and anchorage-independent growth assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding demonstrated in vitro and in vivo with defined phosphorylation site; functional assays performed; single lab\",\n      \"pmids\": [\"11075810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Grb7 is phosphorylated by FAK in a FAK kinase activity-dependent manner (but independent of Src family kinases); cell adhesion enhances Grb7 phosphorylation in FAK+/+ but not FAK-/- cells, establishing Grb7 as a physiological FAK substrate; focal contact localization via the SH2 domain is required for Grb7-stimulated cell migration; FAK-null cells cannot be stimulated by Grb7.\",\n      \"method\": \"FAK kinase assay; FAK+/+ vs FAK-/- cells; cell adhesion assay; chimeric FAT-SH2 domain molecules; tetracycline-regulated expression; cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal approaches including genetic (FAK KO cells), biochemical (kinase assay), and functional (migration) assays in a single focused study; replicated by other labs\",\n      \"pmids\": [\"10893408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Grb7 binds the activated insulin receptor via two domains: the SH2 domain and the PIR (phosphotyrosine interacting region); Grb7 binds the tyrosine kinase activation loop of the insulin receptor but is not a substrate of insulin receptor tyrosine kinase activity.\",\n      \"method\": \"Yeast two-hybrid; GST pull-down; co-immunoprecipitation; domain deletion experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays with domain mapping, single lab, negative result (not a substrate) also confirmed\",\n      \"pmids\": [\"10803466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Grb7 interacts with Rnd1, a constitutively GTP-bound Rho family GTPase; the interaction involves the switch II loop of Rnd1 and the Grb7 SH2 domain; confirmed in yeast two-hybrid, in vitro, and pull-down from SKBR3 cells.\",\n      \"method\": \"Yeast two-hybrid; in vitro binding; GST pull-down from breast cancer cell lysate\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods (Y2H, in vitro, pull-down) from single lab; domain mapping partially defined\",\n      \"pmids\": [\"10664463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Targeting Grb7 to focal contacts via a FAT-chimera stimulates cell migration (similar to Src-FAT and p85-FAT), while targeting Grb2 to focal contacts increases cell cycle progression; demonstrating that distinct FAK signaling complexes regulate migration versus cell cycle progression.\",\n      \"method\": \"Chimeric FAT-fusion molecules; cell migration assay; cell cycle analysis; paxillin and p130cas phosphorylation assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric molecule approach with functional readouts, single lab, distinguishes Grb7 (migration) from Grb2 (cell cycle) functions\",\n      \"pmids\": [\"11418135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Grb7 PH domain mediates binding to phosphoinositides in vitro and in intact cells, with strongest affinity for D3- and D5-phosphoinositides; PH domain interaction with phosphoinositides is required for Grb7 phosphorylation by FAK (though not for FAK binding or focal contact recruitment); PI 3-kinase activity promotes Grb7 association with phosphoinositides and migration stimulation.\",\n      \"method\": \"In vitro phospholipid binding assay; phosphoinositide overlay in intact cells; deletion mutants; PI3K inhibitor treatment; cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (in vitro, intact cell, domain deletions, pharmacological inhibition) establishing PH domain-phosphoinositide interaction and its functional consequences; single lab\",\n      \"pmids\": [\"12021278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EphB1 receptor tyrosine kinase associates with Grb7 via Tyr-928 of EphB1 (primary binding site) through the SH2 domain of Grb7; EphB1 phosphorylates Grb7; EphB1-Grb7 association correlates with EphB1-stimulated cell migration, and dominant-negative Grb7-SH2 abolishes EphB1-stimulated migration.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation; site-directed mutagenesis; ephrinB1 stimulation; cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Y2H identification confirmed by Co-IP, binding site mapped by mutagenesis, phosphorylation demonstrated, functional consequence shown by dominant-negative; single lab\",\n      \"pmids\": [\"12223469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Non-phosphorylated cyclic peptides containing a YXN motif bind specifically to the Grb7 SH2 domain and competitively inhibit Grb7 association with ErbB receptors (particularly ErbB3) in cell lysates; the cyclic structure is required for Grb7 SH2 binding; peptide G7-18 does not bind Grb2 or Grb14 SH2 domains.\",\n      \"method\": \"Phage display random peptide library screening; peptide competition in cell lysates; specificity testing against related SH2 domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phage display with binding confirmation and functional competition assay; defines SH2 selectivity; single lab\",\n      \"pmids\": [\"11809769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NMR solution structure of the Grb7 SH2 domain in complex with ErbB2 pY1139 phosphopeptide reveals an SH2 topology with central beta-sheet and terminal alpha-helices; the ErbB2 peptide binds in a beta-turn conformation (not extended), similar to Grb2-SH2; a four-residue insert between betaE and EF loop influences the complex structure.\",\n      \"method\": \"NMR solution structure determination\",\n      \"journal\": \"Journal of biomolecular NMR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation of binding conformation; provides atomic-level mechanistic detail; single lab\",\n      \"pmids\": [\"12975581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Grb7 (but not Grb10) binds to and inhibits FGF receptor-induced oocyte maturation in Xenopus; this inhibition correlates with Grb7 binding to the receptor and inhibition of the Ras-dependent pathway; the PIR and SH2 domains of Grb7 are both implicated.\",\n      \"method\": \"Xenopus oocyte injection and maturation assay; FGF receptor expression system; domain mutants\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain-of-function in Xenopus model with domain dissection; single lab, model organism\",\n      \"pmids\": [\"12885405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Grb7 and Grb7V are calmodulin (CaM)-binding proteins; the CaM-binding domain is located in residues 243-256 within the proximal PH domain region; CaM binding is Ca2+-dependent; CaM regulates Grb7 membrane association; deletion of the CaM-binding domain reduces membrane association; direct CaM-Grb7 interaction at the plasma membrane demonstrated by FRET in living cells.\",\n      \"method\": \"Ca2+-dependent CaM-affinity chromatography; biotinylated CaM overlay; deletion mutants; cell fractionation; FRET in living cells; CaM antagonist treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemical binding, domain deletion, live-cell FRET, pharmacological inhibition) establishing CaM-Grb7 interaction and its functional consequence on localization; single lab with comprehensive approach\",\n      \"pmids\": [\"15806159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Grb7 SH2 domain forms a homodimer with a dissociation constant of ~11 µM; mutation of Phe-511 to Arg produces a monomeric form, identifying this residue as essential for dimerization.\",\n      \"method\": \"Sedimentation equilibrium ultracentrifugation; size-exclusion chromatography; site-directed mutagenesis\",\n      \"journal\": \"European biophysics journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative biophysical measurement of dimerization with mutagenesis defining key residue; single lab\",\n      \"pmids\": [\"15841400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Grb7 is an RNA-binding protein that binds specifically to the first stem loop of kor mRNA 5'-UTR through a novel RNA-binding domain in its amino terminus; when bound to capped target mRNA, Grb7 blocks eIF4E recruitment and renders mRNA untranslatable; FAK-mediated hyperphosphorylation of two Tyr residues in Grb7's carboxyl terminus reduces its RNA-binding and translation-repressive activity.\",\n      \"method\": \"RNA-protein binding assay; mRNA translation assay; Netrin-1/FAK signaling; mutagenesis of phosphorylation sites\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct RNA binding demonstrated, translation repression mechanism established, FAK-dependent phosphorylation as regulatory switch shown with multiple methods; single lab\",\n      \"pmids\": [\"17318180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the Grb7 SH2 domain solved to 2.1 Å resolution; the structure reveals the peptide binding site, a dimer interface, and that the SH2 domain forms a physiological dimer; the inhibitory peptide G7-18NATE binds with Kd ~35.7 µM and perturbs both the ligand-binding surface and the dimer interface.\",\n      \"method\": \"X-ray crystallography; analytical ultracentrifugation; ITC; NMR titration\",\n      \"journal\": \"BMC structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.1 Å, quantitative binding measurement, NMR mapping of binding surface; multiple orthogonal methods in one study\",\n      \"pmids\": [\"17894853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GRB7 overexpression in breast cancer cells facilitates activation of HER2/ErbB2 tyrosine phosphorylation; GRB7 knockdown decreases HER2 phosphorylation; GRB7 overexpression activates downstream PLC-γ1 recruitment to HER2, PKC pathway (MARCKS phosphorylation), and AKT phosphorylation.\",\n      \"method\": \"Overexpression in MCF-7/HER2 cells; siRNA knockdown in SKBR-3 and MB-453; immunoblotting; immunoprecipitation; xenograft tumor assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined downstream readouts; single lab\",\n      \"pmids\": [\"17916906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Grb7 is an integral component of stress granules (SGs) and is required for SG formation; Grb7 directly interacts with HuR (Hu antigen R); upon stress termination, FAK hyperphosphorylates Grb7, causing loss of HuR interaction and dissociation from SG components, thereby driving SG disassembly; dominant-negative hypophospho mutants of FAK and Grb7 significantly attenuate SG disassembly.\",\n      \"method\": \"SG localization assay; co-immunoprecipitation of Grb7-HuR; FAK kinase assay; dominant-negative mutants; SG dynamics measurement\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein-protein interaction, kinase assay establishing FAK as the writer, dominant-negative experiments defining functional consequence; multiple methods in one study\",\n      \"pmids\": [\"18273060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Grb7 interacts with the transcriptional regulator FHL2 specifically through the Grb7 RA and PH domains; Grb7 must be tyrosine phosphorylated for this interaction to occur; intramolecular ITC measurements suggest Grb7-RA-PH domains can bind the Grb7-SH2 domain with micromolar affinity, supporting a head-to-tail autoinhibitory conformation.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; ITC; immunofluorescence\",\n      \"journal\": \"Journal of molecular recognition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H and Co-IP confirm interaction with domain mapping; ITC provides quantitative support for autoinhibitory model; single lab\",\n      \"pmids\": [\"18853468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EGF-induced Grb7 tyrosine phosphorylation/activation recruits and activates Ras-GTPases, subsequently promotes ERK1/2 phosphorylation, and stimulates tumor growth; Grb7 forms a novel EGFR-Grb7-Ras signaling complex.\",\n      \"method\": \"Co-immunoprecipitation; Ras-GTP pull-down; siRNA knockdown; proliferation and tumor growth assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining complex, Ras-GTP pull-down confirming activation, functional knockdown; single lab\",\n      \"pmids\": [\"20622016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Grb7 upregulation following HER2/PI3K inhibition by lapatinib is mediated by de-repression of Akt-dependent transcriptional repression of Grb7; constitutively active Akt prevents lapatinib-induced Grb7 upregulation; Grb7 removal by RNA interference reduces breast cancer cell viability and increases lapatinib activity.\",\n      \"method\": \"siRNA knockdown; constitutively active Akt retroviral transgenesis; low-density array and qPCR; PI3K inhibitor treatment; in vivo xenograft model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (constitutively active Akt prevents Grb7 upregulation) defining pathway; in vitro and in vivo functional readouts; single lab\",\n      \"pmids\": [\"20126311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of Grb7 SH2 domain in complex with the non-phosphorylated cyclic inhibitor peptide G7-18NATE solved; structural basis for peptide interaction identified: F2, G4, F9, and YDN motif residues are the main contacts; SH2 dimer interface is also visible in the structure.\",\n      \"method\": \"X-ray crystallography; phage display for analogue identification; ITC\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of protein-peptide complex with ITC quantification; defines binding interface at atomic resolution\",\n      \"pmids\": [\"21802427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Grb7 SH2 domain dimerization state influences its ability to bind tyrosine-phosphorylated ligands; a phosphomimetic mutation (Y80E) or dimerization-deficient mutation (F99R) both reduce dimerization and alter thermodynamic binding characteristics for the ErbB2 pY peptide, suggesting phosphorylation state of Grb7 SH2 domain tyrosines regulates dimerization.\",\n      \"method\": \"ITC; circular dichroism; NMR; analytical ultracentrifugation; site-directed mutagenesis\",\n      \"journal\": \"Journal of molecular recognition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple biophysical methods with mutagenesis; single lab; functional consequence of dimerization on ligand binding established\",\n      \"pmids\": [\"22811067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GRB7 modulates ErbB2 signaling through enhanced phosphorylation of ErbB2 and Akt, identified as a context-dependent oncogene in the 17q12-21 amplicon.\",\n      \"method\": \"Retrovirus-mediated gene transfer; phosphorylation assays; functional cancer cell assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function assay with defined biochemical readout (ErbB2 and Akt phosphorylation); single lab\",\n      \"pmids\": [\"22584052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GRB7 promotes ERK phosphorylation and FOXM1 expression in ovarian cancer cells; GRB7 knockdown reduces ERK phosphorylation and FOXM1; enforced FOXM1 expression cannot alter GRB7 or ERK levels, establishing GRB7 acts upstream of ERK which in turn controls FOXM1; GRB7 enhances cell migration/invasion through JNK signaling while promoting proliferation through ERK.\",\n      \"method\": \"Overexpression and knockdown (siRNA/shRNA); MEK inhibitors; western blot; in vitro and in vivo functional assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by inhibitor and OE/KD experiments; pathway ordering demonstrated; single lab\",\n      \"pmids\": [\"23285101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GRB7 recruits SHC into the HER2-GRB7 signaling complex leading to RAS-GTP activation (proliferative signal); following integrin engagement, GRB7 is phosphorylated at tyrosine in a p-FAK(Y397)-dependent manner, and FAK-GRB7 complex activates RAC1-GTP through recruitment of VAV2, mediating cell migration.\",\n      \"method\": \"Co-immunoprecipitation; RAS-GTP and RAC1-GTP pull-down assays; siRNA knockdown; fibronectin engagement assay\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying complex components, active GTPase pull-downs, siRNA validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23593540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Grb7 interacts with Filamin-a via the Grb7 RA-PH domains and Filamin-a immunoglobulin-like repeat domains 16-19; Grb7 and Filamin-a co-localize to membrane ruffles upon EGF stimulation, connecting Grb7 signaling to cytoskeletal remodeling.\",\n      \"method\": \"Yeast two-hybrid; in vitro binding; co-immunoprecipitation; immunofluorescence microscopy\",\n      \"journal\": \"Journal of molecular recognition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H, in vitro binding, and Co-IP with domain mapping; co-localization provides mechanistic link to cytoskeleton; single lab\",\n      \"pmids\": [\"24089360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Deletion of the calmodulin-binding domain of Grb7 (residues 243-256) impairs cell migration, cell attachment to extracellular matrix, and actin cytoskeleton reorganization; CaM antagonists W-7 and W-13 inhibit migration of cells expressing wild-type Grb7 but not the CaM-binding-deficient mutant, establishing CaM binding to Grb7 as functionally required for migration.\",\n      \"method\": \"Deletion mutant expression; cell migration assay; cell adhesion assay; actin cytoskeleton staining; CaM antagonist treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutant compared to wild-type with pharmacological validation; single lab\",\n      \"pmids\": [\"23743201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Calmodulin (CaM) regulates translocation of Grb7 into the nucleus; a nuclear localization signal (NLS) overlaps the CaM-binding domain (residues 243-256); deletion of the CaM-BD prevents nuclear localization; CaM antagonist W-7 enhances Grb7 nuclear presence, indicating CaM binding occludes the NLS.\",\n      \"method\": \"Deletion mutants; subcellular fractionation; CaM antagonist treatment; fluorescence microscopy\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutants and pharmacological perturbation establish CaM-regulated nuclear localization; single lab\",\n      \"pmids\": [\"22673522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Grb7 SH2 domain in apo form reveals malonate bound in the phosphotyrosine binding pocket; peptide analogues incorporating phosphotyrosine mimetics (cmF and cF) bind Grb7-SH2 with up to 9-fold improved affinity (Kd = 2.1-5.7 µM) and are specific for Grb7-SH2 over Grb2-SH2 and Grb10-SH2; X-ray structure of cmF-containing peptide-Grb7 SH2 complex reveals precise contacts.\",\n      \"method\": \"X-ray crystallography; SPR binding assays; rational design based on crystal structure\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus quantitative binding measurements and specificity profiling; single lab with multiple structural and biophysical methods\",\n      \"pmids\": [\"26359549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Grb7 protein is regulated by phosphorylation on Ser194-Pro motif by c-Jun N-terminal kinase (JNK), which facilitates binding to the WW domain of Pin1; Pin1 then promotes ubiquitin- and proteasome-dependent degradation of Grb7; this regulatory mechanism controls Grb7 stability during G2-M cell cycle progression.\",\n      \"method\": \"Pin1-WW domain binding assay; phosphorylation mutagenesis; proteasome inhibitor treatment; cell cycle analysis; ubiquitination assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified kinase (JNK) writing the phosphorylation, reader (Pin1 WW domain) and eraser pathway (proteasome); multiple methods; single lab\",\n      \"pmids\": [\"27658202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of bicyclic peptide G7-B1 and G7-B4 in complex with Grb7 SH2 domain reveal unexpected binding modes; Arg-462 in the BC loop of Grb7-SH2 is a key specificity determinant for G7-18NATE binding (mutation reduces affinity 3.3-fold); βD6 Leu is also required; G7-18NATE is confirmed specific for Grb7 over 79 SH2 domains by microarray.\",\n      \"method\": \"X-ray crystallography; site-directed mutagenesis; SPR; SH2 domain microarray\",\n      \"journal\": \"Scientific reports / Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with mutagenesis and SPR quantification; specificity confirmed against 79 SH2 domains; two related papers provide convergent structural evidence\",\n      \"pmids\": [\"27257138\", \"29018805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"X-ray crystal structures of bicyclic peptide inhibitors (bearing cmF and cF phosphotyrosine mimetics) in complex with Grb7-SH2 domain reveal structural basis for potent (Kd = 0.13 µM for optimized inhibitor) and specific Grb7-SH2 binding; cell-permeable versions block Grb7-mediated interactions in breast cancer cells.\",\n      \"method\": \"X-ray crystallography; SPR binding assays; cell-based inhibition assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with quantitative binding measurements and cellular validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29083893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Direct interaction between full-length Grb7 and calmodulin (CaM) is Ca2+-dependent; CaM binding is localized to the Grb7 RA-PH domain (high-micromolar affinity by SPR); no CaM binding was detected to the SH2 domain alone.\",\n      \"method\": \"Surface plasmon resonance with purified proteins; Ca2+-dependent binding assay; domain constructs\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding measurement with purified proteins and quantitative SPR; single lab; confirms and localizes previously described interaction\",\n      \"pmids\": [\"32079204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GRB7 mediates primary resistance to MEK inhibitors in KRAS-mutant colorectal cancer through the RTK pathway; PLK1 is identified as the predominant interacting kinase of GRB7 by mass spectrometry of GRB7 immunoprecipitates; PLK1 inhibition suppresses downstream FAK, STAT3, AKT, and 4EBP1 signaling.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen; mass spectrometry of GRB7 immunoprecipitates; loss-of-function and gain-of-function assays; PLK1 inhibitor treatment; in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen identifying GRB7, MS identifying PLK1 as binding partner confirmed by Co-IP, functional validation with inhibitors; single lab\",\n      \"pmids\": [\"34718347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Grb7 and Hax-1 interact via the Grb7 RA-PH domains; Grb7 and Hax1 may co-localize partially to mitochondria in EGF-treated SKBR3 cells; Grb7 can affect Caspase-3 cleavage of Hax1 isoform 1 in vitro and may slow Caspase-3 cleavage of Hax1 in apoptotic cells, increasing cell viability.\",\n      \"method\": \"Co-immunoprecipitation; confocal immunofluorescence; in vitro Caspase-3 cleavage assay; cell viability assay\",\n      \"journal\": \"Journal of molecular recognition\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and partial mechanistic follow-up (caspase cleavage), single lab, mitochondrial co-localization described as partial and conditional\",\n      \"pmids\": [\"26869103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Grb7 SH2 domain binds to phosphorylated Tyr-281 of the immunoreceptor G6f (an MHC-encoded immunoglobulin superfamily member) via the YXN consensus motif; this interaction is phosphorylation-dependent; cross-linking of G6f induces transient ERK1/2 MAP kinase phosphorylation preventable by MEK inhibitors.\",\n      \"method\": \"GST pull-down; co-immunoprecipitation; cell stimulation with pervanadate or antibody cross-linking; MEK inhibitor treatment\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding and phosphorylation dependence demonstrated by pull-down and Co-IP; signaling consequence shown; single lab\",\n      \"pmids\": [\"12852788\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GRB7 is a multi-domain adaptor protein (containing RA, PH, and SH2 domains) that is recruited via its SH2 domain to numerous tyrosine-autophosphorylated receptor tyrosine kinases (including HER2/ErbB2, ErbB3, ErbB4, FAK, EphB1, PDGF receptor, c-Kit, Ret, and the insulin receptor), thereby coupling them to downstream signaling cascades: in the context of proliferation, GRB7 forms an EGFR/HER2-GRB7-SHC-RAS complex that activates RAS-GTP and ERK; in the context of migration, integrin-activated FAK phosphorylates GRB7 (a phosphorylation that requires PH domain-phosphoinositide interaction and focal contact localization), and FAK-GRB7 promotes RAC1 activation via VAV2 recruitment; GRB7 also functions as a stress granule component and translational repressor by binding mRNA 5'-UTRs and blocking eIF4E recruitment, a function relieved by FAK-mediated hyperphosphorylation; GRB7's cellular localization and activity are further regulated by Ca²⁺-dependent calmodulin binding to its RA-PH domain (which occludes an overlapping nuclear localization signal) and by JNK-mediated phosphorylation of Ser194 leading to Pin1-dependent proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GRB7 is a multidomain signaling adaptor that couples activated receptor and non-receptor tyrosine kinases to proliferative and migratory responses, principally through its C-terminal SH2 domain, which binds phosphotyrosine motifs (notably YXN/R+3-containing sites) on diverse partners [#0, #5]. Its SH2 domain engages tyrosine-autophosphorylated HER2/ErbB2 at pTyr1139, ErbB3 (pTyr1180) and ErbB4, the PDGF beta-receptor, Ret, c-Kit (pTyr936), the insulin receptor, EphB1 (pTyr928), and FAK (pTyr397), with binding strictly dependent on receptor autophosphorylation [#0, #1, #2, #4, #5, #7, #10, #14, #6]. Specificity within the Grb family is set by a betaD6 Leu and a preference for an Arg at the +3 position relative to phosphotyrosine [#4, #5]. In proliferative signaling, GRB7 enhances HER2/ErbB2 phosphorylation and assembles an EGFR/HER2-GRB7-SHC complex that activates RAS-GTP and ERK, driving downstream FOXM1 expression and AKT signaling [#22, #25, #31, #30]. In migration, GRB7 is recruited to focal contacts via its SH2 domain and is phosphorylated there by FAK in a kinase-dependent, adhesion-stimulated manner; this requires PH domain engagement of D3/D5 phosphoinositides, and the FAK-GRB7 module activates RAC1 through VAV2 recruitment [#6, #9, #13, #31]. GRB7 also acts as an RNA-binding translational repressor, binding target mRNA 5'-UTRs through an N-terminal RNA-binding domain to block eIF4E recruitment, and is an integral, HuR-interacting component required for stress granule formation; FAK-mediated hyperphosphorylation relieves both the RNA-binding/repressive and stress-granule functions [#20, #23]. GRB7 localization and stability are tuned by Ca2+-dependent calmodulin binding to its RA-PH domain, which occludes an overlapping nuclear localization signal and controls membrane association, and by JNK phosphorylation of Ser194 that recruits Pin1 to drive proteasomal degradation during the cell cycle [#18, #34, #39, #36]. Structurally, the SH2 domain forms a physiological homodimer whose dimerization state, modulated by tyrosine phosphorylation, influences phospholigand binding, and this domain has been extensively targeted by selective cyclic and bicyclic peptide inhibitors [#19, #21, #28, #37, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established GRB7 as a direct SH2-domain partner of an oncogenic receptor tyrosine kinase, identifying its core adaptor function.\",\n      \"evidence\": \"Bacterial expression cloning with phosphopeptide probe and Co-IP from breast cancer cells\",\n      \"pmids\": [\"7907978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define downstream effectors recruited by GRB7\", \"Affinity for SHC lower than GRB2, leaving competitive significance unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed GRB7's SH2 domain is a general phosphotyrosine reader engaged by multiple RTKs in an autophosphorylation-dependent manner, generalizing it beyond HER2.\",\n      \"evidence\": \"GST-SH2 pull-downs, site-directed mutagenesis and Co-IP for PDGFR-beta and Ret\",\n      \"pmids\": [\"8940081\", \"8631863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of these RTK associations not established\", \"Did not address signaling output downstream\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the molecular determinants of GRB7 SH2 selectivity, distinguishing it from related Grb adaptors at specific receptor phosphosites.\",\n      \"evidence\": \"Phosphopeptide competition and reciprocal SH2-domain mutagenesis on ErbB2/ErbB3/ErbB4 sites\",\n      \"pmids\": [\"9079677\", \"9516479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity determinants tested in vitro, not in physiological competition with full adaptor repertoire\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified GRB7 as a FAK substrate and focal-contact effector for migration, separating its migratory role from cell-cycle functions of other adaptors.\",\n      \"evidence\": \"FAK kinase assays, FAK+/+ vs FAK-/- cells, FAT-SH2 chimeras and migration assays\",\n      \"pmids\": [\"10446223\", \"10893408\", \"11418135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the GTPase effectors downstream of FAK-GRB7 not yet defined\", \"Phosphorylated tyrosine residues on GRB7 not mapped here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed the PH domain as a phosphoinositide sensor required for FAK-mediated GRB7 phosphorylation, linking lipid signaling to GRB7 activation.\",\n      \"evidence\": \"Lipid-binding assays, intact-cell overlays, deletion mutants and PI3K inhibition with migration readouts\",\n      \"pmids\": [\"12021278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how PH-lipid binding positions GRB7 for FAK phosphorylation\", \"EphB1 link established separately\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the first atomic-resolution view of GRB7 SH2-phosphopeptide recognition, defining the bound peptide conformation.\",\n      \"evidence\": \"NMR solution structure of SH2 domain with ErbB2 pY1139 peptide\",\n      \"pmids\": [\"12975581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length protein architecture not resolved\", \"Did not address dimerization in solution\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Uncovered an RNA-binding, translation-repressive function for GRB7 controlled by FAK phosphorylation, expanding its role beyond a kinase adaptor.\",\n      \"evidence\": \"RNA-protein binding, translation assays, and FAK-dependent phosphosite mutagenesis; SH2 crystal structure resolved separately\",\n      \"pmids\": [\"17318180\", \"17894853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of mRNA targets beyond kor not defined\", \"Structural basis of the N-terminal RNA-binding domain unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined GRB7 as a stress granule component whose HuR interaction and FAK-driven disassembly couple kinase signaling to mRNA granule dynamics.\",\n      \"evidence\": \"Stress granule localization, GRB7-HuR Co-IP, FAK kinase assay and dominant-negative mutants\",\n      \"pmids\": [\"18273060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which GRB7 nucleates granule assembly not detailed\", \"Relationship between RNA-binding and HuR-binding surfaces unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that GRB7 actively amplifies RTK output, assembling an EGFR-GRB7-RAS complex and being feedback-induced upon HER2/PI3K inhibition.\",\n      \"evidence\": \"Co-IP, RAS-GTP pull-down, siRNA and lapatinib/Akt epistasis with xenograft assays\",\n      \"pmids\": [\"20622016\", \"20126311\", \"17916906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect recruitment of RAS not fully resolved\", \"Single-lab functional readouts\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked GRB7 SH2 dimerization state to phospholigand binding and identified calmodulin-regulated nuclear localization, defining conformational and localization control.\",\n      \"evidence\": \"ITC/CD/NMR/AUC of dimer mutants; deletion mutants and CaM antagonists for nuclear translocation\",\n      \"pmids\": [\"22811067\", \"22673522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological tyrosine phosphorylation regulating dimerization not directly demonstrated in vivo\", \"Nuclear function of GRB7 unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the bifurcated GRB7 signaling logic: SHC/RAS for proliferation versus FAK-VAV2-RAC1 for migration, with cytoskeletal coupling via Filamin-A.\",\n      \"evidence\": \"Co-IP, RAS-GTP and RAC1-GTP pull-downs, siRNA, fibronectin engagement, and domain-mapped Filamin-A interaction\",\n      \"pmids\": [\"23593540\", \"24089360\", \"23743201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and temporal sequence of complex assembly not defined\", \"Single-lab evidence for VAV2 recruitment\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified JNK-Pin1-proteasome degradation of GRB7 at Ser194, defining cell-cycle-coupled control of GRB7 abundance.\",\n      \"evidence\": \"Pin1-WW binding, phospho-site mutagenesis, proteasome inhibition and ubiquitination assays\",\n      \"pmids\": [\"27658202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating degradation not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed and localized direct Ca2+-dependent calmodulin binding to the GRB7 RA-PH domain, anchoring the localization-regulatory mechanism in purified-protein measurements.\",\n      \"evidence\": \"SPR with full-length and domain constructs under Ca2+-dependent conditions\",\n      \"pmids\": [\"32079204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-micromolar affinity raises questions on cellular occupancy\", \"Functional consequence inferred from earlier deletion studies\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated GRB7 in MEK-inhibitor resistance and identified PLK1 as a predominant GRB7-interacting kinase coupling it to FAK/STAT3/AKT/4EBP1 output.\",\n      \"evidence\": \"Genome-wide CRISPR screen, mass spectrometry of GRB7 IPs, and PLK1 inhibition in tumor models\",\n      \"pmids\": [\"34718347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect GRB7-PLK1 binding not structurally defined\", \"Mechanism of resistance not fully dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GRB7's distinct functional modes — RTK adaptor, FAK-coupled migration effector, translational repressor, and stress granule component — are dynamically partitioned in a single cell, and the in vivo role of its nuclear translocation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model of how phosphorylation, lipid, and calmodulin inputs switch GRB7 between adaptor and RNA-regulatory states\", \"Nuclear function uncharacterized\", \"Physiological RNA target repertoire undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 31, 25]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [18, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [32, 33]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 25, 31]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [20, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 26, 40]}\n    ],\n    \"complexes\": [\"stress granule\", \"EGFR/HER2-GRB7-SHC complex\", \"FAK-GRB7-VAV2 complex\"],\n    \"partners\": [\"ERBB2\", \"ERBB3\", \"PTK2\", \"SHC1\", \"VAV2\", \"CALM1\", \"ELAVL1\", \"PLK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}