Affinage

GRB2

Growth factor receptor-bound protein 2 · UniProt P62993

Length
217 aa
Mass
25.2 kDa
Annotated
2026-06-10
100 papers in source corpus 49 papers cited in narrative 49 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRB2 is a non-enzymatic adaptor protein with a single SH2 domain flanked by two SH3 domains that couples activated receptor tyrosine kinases to Ras/MAPK signaling and is genetically required for early Ras-pathway-dependent development (PMID:1322798, PMID:9865697). Its SH2 domain reads phosphotyrosines on activated receptors and docking proteins—binding EGFR directly at pY1068 (and Shc-bridged at Y1173) (PMID:7518560), FAK at pY925 to link integrin adhesion to Ras/MAPK (PMID:7997267), and SHP2/Syp to couple PDGFR indirectly (PMID:8264620)—while its SH3 domains constitutively engage the proline-rich C-terminus of the Ras guanine-nucleotide exchange factor SOS1, an interaction blocked by PPVPPR-containing peptides (PMID:8479541, PMID:8386805). Through this SH2-phosphotyrosine/SH3-SOS bridging architecture GRB2 also assembles signaling at the docking protein Gab1 and nucleates LAT microclusters in T cells, where SH3-mediated cluster assembly drives MAPK activation, Ca2+ flux and cytokine production (PMID:10871282, PMID:25870599). GRB2 function is gated by a monomer–dimer equilibrium in which only monomeric GRB2 binds SOS and signals to ERK, with phosphorylation of Tyr160 or SH2-ligand binding driving dimer dissociation (PMID:26103942); monomeric GRB2 additionally activates SHP2 phosphatase through a phosphorylation-independent bidentate interaction that releases SHP2 autoinhibition (PMID:33795832), and intramolecular allostery links SH2 phosphopeptide occupancy to enhanced SH3–SOS1 engagement (PMID:34232285). At FGFR2, dimeric GRB2 bridges two receptors into a signaling-incompetent heterotetramer that restrains basal kinase activity, with FGFR2-mediated GRB2 tyrosine phosphorylation releasing GRB2 to permit full activation, and GRB2 competing with PLCγ1 for the receptor C-terminus (PMID:22726438, PMID:23420874, PMID:24440983). GRB2 abundance is controlled by ubiquitin-mediated turnover, stabilized by the deubiquitinase PSMD14 and destabilized by the E3 ligases RNF173 and RBBP6 (PMID:31634528, PMID:37626338, PMID:34348893). Beyond cytoplasmic signaling, nuclear GRB2 acts in genome maintenance: it inhibits RAD51 ATPase activity to protect stalled replication forks (PMID:38459011) and targets MRE11 to double-strand breaks to promote homology-directed repair over alternative end-joining, with a separation-of-function mutant causing HDR deficiency and PARP-inhibitor synthetic lethality (PMID:34348893). Mouse genetics establish dose-dependent roles in primitive endoderm/epiblast lineage segregation via Ras-MAPK-driven Gata6 expression and Nanog repression (PMID:9865697, PMID:16678776, PMID:16908534) and in B- and T-cell development and selection (PMID:21427701, PMID:11135575).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1992 High

    Established GRB2 as a modular SH2/SH3 protein that physically links growth factor receptors to Ras, answering how phosphorylated RTKs connect to downstream proliferative signaling.

    Evidence Domain mapping, receptor co-IP, and microinjection of GRB2 plus H-Ras into quiescent fibroblasts

    PMID:1322798

    Open questions at the time
    • Did not identify the effector linking GRB2 to Ras
    • No structural basis for SH2 phosphotyrosine recognition
  2. 1993 High

    Identified SOS as the GRB2 SH3-domain partner that delivers nucleotide exchange activity to Ras, defining the core RTK–GRB2–SOS–Ras module.

    Evidence Binding assays, peptide competition (PPVPPR), and nucleotide exchange/Ras-MAPK activation in cells

    PMID:8386805 PMID:8479541

    Open questions at the time
    • Stoichiometry and regulation of the GRB2–SOS complex not resolved
    • Did not address how the complex is turned off
  3. 1994 High

    Mapped the receptor and adaptor phosphotyrosine sites recognized by the GRB2 SH2 domain, showing both direct (EGFR pY1068, FAK pY925) and indirect (Shc, SHP2/Syp) recruitment modes that diversify GRB2 inputs.

    Evidence Receptor point-mutant co-IP, phosphopeptide competition, GST pull-down, and BIAcore affinity measurement

    PMID:7518560 PMID:7520523 PMID:7997267 PMID:8264620

    Open questions at the time
    • Relative in vivo contribution of direct vs. adaptor-bridged recruitment unquantified
    • Did not address spatial compartment of binding
  4. 1994 Medium

    Showed GRB2 SH3 domains can engage alternative proline-rich partners (p85/PI3K, Gab1) and that an SH2-deleted isoform is dominant-negative, broadening GRB2 beyond SOS-only coupling.

    Evidence Yeast two-hybrid, GST pulldown, affinity purification, and dominant-negative microinjection

    PMID:7759531 PMID:8178156 PMID:8596638

    Open questions at the time
    • Functional significance of GRB2–p85 coupling in vivo unclear
    • SH3 partner selectivity rules not defined
  5. 1996 High

    Defined a negative-feedback mechanism in which ERK-driven SOS phosphorylation dissociates the GRB2–SOS complex, providing temporal control of Ras output.

    Evidence Dominant-negative Ras, MEK inhibitor PD98059, and GRB2–SOS co-IP in two cell types

    PMID:8626428

    Open questions at the time
    • SOS phosphosites mediating dissociation not mapped here
    • Did not address GRB2 dimer state in feedback
  6. 1998 High

    Demonstrated GRB2 is genetically required for Ras-pathway-dependent early development and acts as a pure adaptor, since an SH2-SOS1 fusion rescues the null.

    Evidence Mouse knockout, chimera analysis, and SH2-Sos1 fusion rescue plus tumor induction

    PMID:9865697

    Open questions at the time
    • Tissue-specific requirements not dissected
    • Adaptor-only model leaves non-SOS functions unaddressed
  7. 2000 High

    Resolved GRB2 as a conformationally flexible protein and visualized RTK–GRB2 interaction in living cells, locating signaling to membrane ruffles and endosomes.

    Evidence NMR/SAXS solution structure and live-cell FRET of EGFR-CFP/GRB2-YFP

    PMID:11084343 PMID:11178911

    Open questions at the time
    • Did not address dimerization in cells
    • Endosomal vs. plasma-membrane signaling contributions not quantified
  8. 2006 High

    Placed GRB2-Ras-MAPK upstream of lineage-determining transcription factors, showing it drives Gata6 expression and Nanog repression to segregate epiblast and primitive endoderm.

    Evidence GRB2-null embryo lineage markers and GRB2-deficient ES cells with MEK manipulation

    PMID:16678776 PMID:16908534

    Open questions at the time
    • Direct transcriptional targets downstream of MEK not identified
    • Receptor input driving this signal in embryo unresolved
  9. 2012 High

    Revealed a non-canonical inhibitory role in which dimeric GRB2 bridges two FGFR2 receptors into a signaling-incompetent heterotetramer, with receptor-mediated GRB2 phosphorylation releasing the brake.

    Evidence Biochemical reconstitution, biophysical/structural characterization, and FGFR2 phosphorylation/recruitment assays

    PMID:22726438

    Open questions at the time
    • In vivo prevalence of the heterotetramer not established
    • GRB2 phosphosites driving dissociation not fully mapped here
  10. 2013 High

    Showed GRB2 sets FGFR2 phosphorylation homeostasis by simultaneously inhibiting receptor kinase and SHP2 phosphatase, and competing with PLCγ1 for the receptor C-terminus.

    Evidence FLIM-FRET in live cells, in vitro kinase/phosphatase assays, and competition binding/invasion assays

    PMID:23420874 PMID:24440983

    Open questions at the time
    • Quantitative balance between competing partners in vivo unclear
    • Generality beyond FGFR2 not tested
  11. 2015 High

    Established the monomer–dimer equilibrium as a master switch in which only monomeric GRB2 binds SOS and signals, with Tyr160 phosphorylation driving dissociation and pY160 marking malignancy.

    Evidence Dimerization and SOS-binding biochemistry, ERK readout, and phospho-specific detection in tumor tissue

    PMID:26103942

    Open questions at the time
    • Kinase responsible for Y160 phosphorylation in cells not defined
    • Dimer function beyond SOS sequestration not fully resolved here
  12. 2014 Medium

    Identified post-translational tuning of GRB2 by SUMO1 modification at Lys56, which enhances GRB2–SOS1 complex formation and downstream ERK-driven motility and tumorigenesis.

    Evidence In vivo/in vitro SUMOylation assays, co-IP, ERK assays, and xenograft rescue with K56R mutant

    PMID:24775912

    Open questions at the time
    • SUMO ligase/protease controlling K56 unidentified
    • Interplay between SUMOylation and dimer state untested
  13. 2021 High

    Uncovered nuclear and DNA-repair functions of GRB2, showing it forms a complex with MRE11 targeted to DSBs by its SH2 domain and channels repair toward HDR, with loss conferring PARP-inhibitor synthetic lethality.

    Evidence Biophysical binding, ubiquitination mapping, RBBP6 depletion, GRB2 KO/reconstitution, DSB repair assays, and PARP-inhibitor sensitivity

    PMID:34348893

    Open questions at the time
    • How GRB2 is imported/retained in the nucleus unknown
    • Phosphotyrosine ligand directing GRB2 to γH2AX not identified
  14. 2021 High

    Defined a phosphorylation-independent enzymatic-activation role in which monomeric GRB2 releases SHP2 autoinhibition through a bidentate interaction, distinguishing monomer and dimer functions.

    Evidence In vitro phosphatase activity assays with monomer/dimer-resolved binding and NMR/biophysical interface mapping

    PMID:33795832

    Open questions at the time
    • Cellular conditions favoring this activation not delineated
    • Relationship to GRB2's FGFR2 SHP2-inhibitory role unresolved
  15. 2024 High

    Showed nuclear GRB2 protects stalled replication forks by inhibiting RAD51 ATPase activity within the BRCA2 fork-protection axis, with depletion plus PARP inhibition triggering cGAS-STING anti-tumor immunity.

    Evidence GRB2 depletion, RAD51 ATPase inhibition assay, DNA fiber fork-protection assays, cGAS-STING readout, and syngeneic ovarian cancer model

    PMID:38459011

    Open questions at the time
    • Signal recruiting GRB2 to stalled forks unknown
    • Coordination between fork protection and DSB-repair functions unresolved
  16. 2023 Medium

    Mapped a ubiquitin-degradation axis controlling GRB2 abundance, with PSMD14 stabilizing and RNF173/RBBP6 destabilizing GRB2 to tune RAF/MEK/ERK output and tumor behavior.

    Evidence Ubiquitination assays, mass spectrometry, co-IP, ligase/DUB knockdown and overexpression, and tumor assays

    PMID:31634528 PMID:34348893 PMID:37626338

    Open questions at the time
    • Signals triggering GRB2 ubiquitination not defined
    • Whether degradation discriminates monomer vs. dimer untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRB2's cytoplasmic adaptor functions and its nuclear genome-maintenance functions are spatially partitioned and co-regulated, and what governs its nuclear import, remains unresolved.
  • Nuclear import/retention mechanism unknown
  • Integration of dimer-state, phosphorylation, SUMOylation and ubiquitination control not unified
  • Receptor or damage signals dictating localization choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 2
Localization
GO:0005768 endosome 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-73894 DNA Repair 2
Partners
EGFRFGFR2GAB1MRE11RAD51SHCSHP2SOS1
Complex memberships
GRB2 dimer-FGFR2 heterotetramerGRB2-MRE11 (GM) complexGRB2-SOS1 complexShc-GRB2-SOS complex

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 GRB2 contains one SH2 domain flanked by two SH3 domains; its SH2 domain binds tyrosine-phosphorylated EGFR and PDGFR, and microinjection of GRB2 together with H-Ras stimulates DNA synthesis in quiescent fibroblasts, placing GRB2 upstream of Ras in growth factor signaling. Immunoblotting, co-immunoprecipitation, microinjection into rat fibroblasts Cell High 1322798
1993 The SH3 domains of Grb2 bind the C-terminal proline-rich region of hSos1 (a Ras guanine-nucleotide exchange factor), forming a Grb2/SOS complex that couples activated EGF receptor to Ras signaling; a 10-amino-acid PPVPPR-containing peptide blocks this interaction. Binding assays, synthetic peptide competition, co-immunoprecipitation Nature High 8479541
1993 Overexpression of Grb2 potentiates EGF-induced activation of Ras and MAPK by enhancing guanine nucleotide exchange on Ras, and endogenous Grb2 forms a complex with a guanine-nucleotide exchange factor that binds the ligand-activated EGF receptor. Overexpression studies, Ras nucleotide exchange assays, co-immunoprecipitation Nature High 8386805
1994 GRB2 binds directly to tyrosine-phosphorylated FAK at the YENV motif (Tyr-925); mutation of Tyr-925 to Phe blocks GRB2 SH2 binding in vitro, linking integrin-mediated fibronectin adhesion to the Ras/MAPK pathway. SH2 domain binding assay, site-directed mutagenesis, co-immunoprecipitation in NIH3T3 cells Nature High 7997267
1994 For the PDGF receptor, GRB2 does not bind the receptor directly but instead binds to tyrosine-phosphorylated Syp/SHP2 (at YXNX motifs), which itself binds PDGFR Tyr-1009, thereby acting as an adapter between PDGFR and the GRB2–SOS complex. PDGFR mutant panel, phosphopeptide competition, GST pull-down, co-immunoprecipitation, anti-Syp antibody verification Molecular and cellular biology High 8264620
1994 Grb2 binds directly to EGFR primarily at phosphotyrosine Y-1068 (and to a lesser extent Y-1086) via its SH2 domain; Y-1173 serves as an indirect binding site through Shc. Dissociation constants measured by BIAcore defined affinity hierarchy. Co-immunoprecipitation with EGFR point mutants, phosphopeptide competition, dephosphorylation protection assay, BIAcore (real-time binding kinetics) Molecular and cellular biology High 7518560
1994 Grb2, Shc, Sos1, and a 150 kDa tyrosine-phosphorylated myeloid-specific protein form complexes with the M-CSF receptor Fms after M-CSF stimulation; Grb2 SH2 domain binds tyrosine-phosphorylated Fms and p150, linking Fms to Ras via Sos1. Co-immunoprecipitation, SH2 domain binding assays, Fms mutant analysis Molecular and cellular biology Medium 7520523
1994 The SH3 domains of Grb2 bind proline-rich motifs of p85 (regulatory subunit of PI3-kinase), constitutively and independently of growth factor stimulation; this interaction is exclusive of Sos binding, indicating Grb2 can couple to PI3K signaling. Yeast two-hybrid, in vitro GST pulldown, domain analysis, peptide competition The Journal of biological chemistry Medium 7759531
1994 A Grb2 isoform lacking the SH2 domain (Grb3-3) retains functional SH3 domains, acts as a dominant negative over Grb2, inhibits EGF-induced Ras signaling, and when microinjected into fibroblasts, induces apoptosis. cDNA cloning, transfection/reporter assay, microinjection into fibroblasts Science Medium 8178156
1994 In rat liver in vivo, EGF induces rapid EGFR internalization into endosomes coincident with Shc tyrosine phosphorylation and formation of a Shc–Grb2–mSOS complex predominantly in endosomes, linking endosomal EGFR to Ras/Raf-1 activation. In vivo EGF/insulin administration, subcellular fractionation, co-immunoprecipitation, SDS-PAGE mobility shift for Raf-1 The EMBO journal Medium 7925272
1995 Cbl associates constitutively with Grb2 via Grb2's N-terminal SH3 domain in resting Jurkat T cells; after TCR–CD3 activation, Cbl binds the Grb2 SH2 domain, and a Cbl-associated PI3-kinase activity is distinct from the Sos-Grb2 complex. Co-immunoprecipitation, GST-Grb2 fusion protein binding, PI3-kinase activity assay Molecular and cellular biology Medium 7791764
1996 ERK (but not JNK) pathway activation is responsible for feedback phosphorylation of SOS and subsequent dissociation of the Grb2–SOS complex, limiting Ras activation; MEK inhibitor PD98059 blocks SOS phosphorylation and complex disassembly. Dominant-negative Ras expression, MEK inhibitor treatment, SOS phosphorylation and Grb2-SOS co-immunoprecipitation in CHO cells and 3T3-L1 adipocytes The Journal of biological chemistry High 8626428
1996 Grb2 was identified as a Grb2-associated binder-1 (Gab1) binding protein via its SH3 domains; Gab1 acts as a docking protein downstream of EGFR and insulin receptor and its overexpression enhances cell growth and causes transformation. Recombinant Grb2 affinity purification, cDNA isolation, receptor substrate assay, overexpression transformation assay Nature Medium 8596638
1996 Tpr-Met transformation of fibroblasts requires signaling downstream of Grb2 (and Shc); a Tpr-Met mutant selectively lacking Grb2 binding shows reduced transforming activity, while PI3K, PLCγ, and SHP2 pathways alone are insufficient. Site-directed mutagenesis of Tpr-Met, focus formation assay, co-immunoprecipitation The Journal of biological chemistry Medium 8662733
1998 Grb2 null embryos fail to form primitive endoderm/epiblast; rescue by a Sos1 fusion protein bearing the Grb2 SH2 domain demonstrates Grb2 acts as a genetic adaptor in the Ras pathway; Grb2 is rate-limiting for polyomavirus middle-T-induced mammary carcinomas. Gene knockout in mouse, chimera analysis, transgenic rescue with SH2-Sos1 fusion protein, tumor induction assay Cell High 9865697
1999 Pyk2-induced ERK activation is mediated through Grb2/Sos: a Grb2 mutant lacking the N-terminal SH3 domain or the C-terminal Sos-binding region strongly reduces ERK but not JNK activation downstream of Pyk2. Dominant-negative Grb2 mutant expression, ERK/JNK activation assays The Journal of biological chemistry Medium 10329689
2000 Live-cell FRET microscopy demonstrated that EGFR–CFP and Grb2–YFP directly interact in membrane ruffles and endosomes upon EGF stimulation, establishing that RTK–Grb2 signaling occurs in the endosomal compartment. FRET microscopy (CFP/YFP fusion proteins) in living cells Current biology : CB High 11084343
2000 Gab1 associates constitutively with Grb2 via both a classical PXXP SH3-binding motif and a novel PX(V/I)(D/N)RXXKP Grb2-SH3 consensus motif; association with Shp2 (but not PI3K, CRKL, or Shc) through Gab1 is essential for c-Met/Gab1-dependent branching morphogenesis. Reverse yeast two-hybrid, mutagenesis, modified yeast two-hybrid phosphorylation-dependent interaction assay, MDCK branching morphogenesis assay The Journal of cell biology High 10871282
2001 Grb2 haploinsufficiency selectively reduces TCR-induced JNK and p38 (but not ERK) activation in thymocytes, thereby impairing negative but not positive selection of T cells. Grb2+/- mouse analysis, MAPK activation assays, thymocyte selection assays Nature immunology High 11135575
2001 Grb2 hypomorphic mutation (E89K) reducing SH2 phosphotyrosine binding causes defects in placental morphogenesis and neural crest survival with reduced ERK/MAPK activation and Gab1 phosphorylation in fibroblasts, revealing dose-dependent functions in tissue morphogenesis. Hypomorphic knock-in mouse (E89K allele), compound heterozygote with null, fibroblast ERK activation and Gab1 phosphorylation assays Current biology : CB High 11369229
2001 Grb2 is required for actin-based motility of vaccinia virus; Grb2 is recruited to viral particles via phosphorylation of Tyr-132 of vaccinia A36R and depends on the polyproline-rich region of N-WASP; Grb2 acts cooperatively with Nck to stabilize/activate the actin-nucleating complex. Live-cell imaging, viral actin tail counting, site-directed mutagenesis of A36R tyrosines Current biology : CB Medium 12007418
2002 Grb2 redistributes from cytoplasm to plasma membrane within 1 min of EGF stimulation in an SH2-dependent manner and co-internalizes with EGFR via a clathrin-independent macropinocytic pathway; SH3 domain mutations prevent inward movement of macropinosomes, implicating the Grb2 SH3 domain in coupling to internalization effectors. Live-cell fluorescence imaging of GFP-tagged Grb2/EGFR, SH3 domain mutants, transferrin internalization control, AP-180 C-terminus expression Journal of cell science Medium 11956311
2003 Grb2 negatively regulates EGF-stimulated Stat3 tyrosine phosphorylation and transcriptional activity by competitively binding EGFR at Y-1086/Y-1068, thereby preventing Stat3 recruitment; this inhibition requires the Grb2 SH2 domain but not SH3 domains. Transient Grb2 overexpression, RNA interference knockdown, Stat3 phosphorylation and reporter assays, SH2 domain mutant analysis The Biochemical journal Medium 14498832
2003 Grb2 haploinsufficiency in mice blocks cardiac p38 MAPK and JNK activation induced by pressure overload, prevents cardiac hypertrophy and fibrosis; downstream, DN-p38α and DN-p38β transgenic mice show fibrosis resistance without preventing hypertrophy, placing Grb2 upstream of p38 in this pathway. Grb2+/- mice with aortic banding, MAPK activation assays, dominant-negative p38 transgenic mice The Journal of clinical investigation Medium 12639989
2006 In embryos lacking Grb2 (Grb2 null), Gata6 expression is lost and all ICM cells express Nanog, indicating that Grb2-Ras-MAPK signaling is required for Gata6 expression and epiblast/primitive endoderm lineage segregation. Grb2 null mouse embryo analysis, immunofluorescence for Nanog and Gata6, lineage tracing Developmental cell High 16678776
2006 The Grb2/Mek pathway represses Nanog transcription in ES cells: Grb2 deficiency or MEK inhibitor PD98059 prevents Nanog repression induced by sodium vanadate or ES cell aggregation; constitutively active MEK alone induces Nanog repression and primitive endoderm differentiation. Grb2-deficient ES cells, MEK inhibitor, constitutively active MEK transfection, Nanog reporter Molecular and cellular biology Medium 16908534
2001 Solution NMR and SAXS reveal Grb2 is a flexible protein in which the C-terminal SH3 domain is connected to the SH2 domain via a flexible linker; Grb2 adapts the relative orientation of its two SH3 domains to bivalently bind target proline-rich peptides, in contrast to a compact crystal structure. NMR solution structure, small-angle X-ray scattering, peptide binding experiments Journal of molecular biology High 11178911
2009 Grb2 binds directly to FGFR2 through its C-terminal SH3 domain via the proline-rich C-terminus of the receptor (last 10 amino acids critical); this SH3-mediated binding (phosphorylation-independent) provides resistance to Shp2-mediated receptor dephosphorylation. Deletion mutants of FGFR2, synthetic peptide binding assays, co-immunoprecipitation, FGFR2-Grb2 interaction mapping Cellular signalling Medium 19735729
2011 B-cell-specific Grb2 knockout causes a block in mature follicular B-cell differentiation, enhanced BCR-induced Ca2+ signaling, impaired Akt/PI3K activation, and defective germinal center formation and IgG memory responses. B-cell-specific Grb2 conditional knockout mouse, B-cell development and signaling assays, immunization experiments The EMBO journal High 21427701
2011 Grb2 ablation in B cells disrupts lymphotoxin-β expression and splenic follicular architecture; Grb2 connects CXCR5 signaling to lymphotoxin-β upregulation (but not chemotaxis), acting as a nonredundant regulator of germinal center reactions. B-cell-specific Grb2 knockout mouse, lymphotoxin-β expression assays, CXCL13 stimulation, splenic architecture analysis Proceedings of the National Academy of Sciences of the United States of America Medium 21508326
2011 After EGF stimulation, RhoU physically associates with activated EGFR in a Grb2-dependent manner through proline-rich motifs in RhoU's N-terminus; mutation of these motifs or GRB2 siRNA knockdown abrogates RhoU-EGFR interaction and EGF-stimulated RhoU GTP loading, linking GRB2 to Rho GTPase activation and cell migration. Co-immunoprecipitation, RhoU proline-rich motif mutagenesis, GRB2 RNAi, RhoU-GTP loading assay Molecular biology of the cell Medium 21508312
2012 Dimeric Grb2 binds to the C-termini of two FGFR2 molecules to form a heterotetramer; this complex allows low-level transphosphorylation but sterically hinders C-terminal phosphorylation and downstream protein recruitment. FGFR2 phosphorylates Grb2 tyrosines, promoting Grb2 dissociation and enabling full receptor activation. Biochemical reconstitution, structural/biophysical characterization of Grb2 dimer-FGFR2 complex, FGFR2 phosphorylation assays, signaling protein recruitment assays Cell High 22726438
2012 TIGIT engagement phosphorylates Tyr225 in its ITT-like motif, which recruits Grb2 via its SH2 domain; Grb2 then recruits SHIP1 to terminate PI3K and MAPK signaling, suppressing NK cell granule polarization and cytotoxicity. Co-immunoprecipitation, mutagenesis of Tyr225 and Asn227, SHIP1 knockdown, NK cell killing assays Cell death and differentiation Medium 23154388
2013 Grb2 controls FGFR2 phosphorylation homeostasis by inhibiting both FGFR2 kinase activity and Shp2 phosphatase activity when bound to the receptor; FGFR2 phosphorylates Grb2 to release it, upregulating both activities; Shp2 subsequently dephosphorylates Grb2 to restore the inhibitory complex. FLIM-FRET in live cells, in vitro kinase/phosphatase activity assays, Grb2 phosphorylation analysis The Journal of cell biology High 23420874
2013 In live HeLa cells, Grb2-YFP is co-internalized with EGFR into endosomes with a stoichiometry of approximately 2 Grb2 molecules per EGF-Rh; Grb2 remains associated with EGFR in endosomes, correlating with sustained ERK1/2 activation. Spinning disk confocal live imaging, quantitative fluorescence ratio analysis, Grb2-YFP knock-in replacement Journal of cell science Medium 24259669
2014 In non-stimulated cells, the C-terminal SH3 domain of Grb2 and the SH3 domain of PLCγ1 compete for the same proline-rich C-terminus of FGFR2 in a phosphorylation-independent manner; reduced Grb2 permits PLCγ1 access, elevating phospholipase activity, PIP2 turnover, Ca2+ levels, and cell invasiveness. Competition binding assays, phospholipase activity assays, intracellular Ca2+ measurements, invasion assays, Grb2 depletion experiments Nature structural & molecular biology High 24440983
2014 Grb2 is SUMOylated by SUMO1 at Lys-56 in the linker between the N-terminal SH3 and SH2 domains; SUMOylation enhances formation of the Grb2–Sos1 complex, increasing Ras/MEK/ERK activation; the K56R mutant fails to rescue ERK activity, cell motility, or tumorigenesis when Grb2 is knocked down. In vivo SUMOylation Ni-NTA pulldown, E. coli-based in vitro SUMOylation, co-immunoprecipitation, ERK activation assays, xenograft tumor model Molecular cancer Medium 24775912
2014 GRB2 SH2 domain binds phosphorylated Tyr-638 of protein-tyrosine phosphatase ε (cyt-PTPe); GRB2 is required for cyt-PTPe-mediated Src activation in osteoclasts; GRB2 overexpression increases activating phosphorylation of Src and cyt-PTPe, while GRB2 knockdown reduces podosomal organization and osteoclast differentiation. SH2 domain screen (73 domains), co-immunoprecipitation, GRB2 shRNA knockdown and gene inactivation, Src phosphorylation assays in OCLs The Journal of biological chemistry Medium 25381250
2015 Grb2 exists in a constitutive monomer–dimer equilibrium; only monomeric Grb2 binds SOS and upregulates MAP kinase signaling; phosphorylation of Tyr-160 on Grb2 (or SH2 ligand binding) causes dimer dissociation; pY160-Grb2 is detectable in malignant prostate, colon, and breast cancers. Biochemical dimerization assays, SOS binding assays, ERK activation readout, phospho-specific detection in cancer tissues Nature communications High 26103942
2015 GRB2 nucleates LAT signaling microclusters in T cells; GRB2-deficient human CD4+ T cells have impaired LAT cluster formation, reduced MAP kinase activation, diminished Ca2+ flux, and reduced IL-2/IFN-γ production; a GRB2 N-terminal SH3 domain mutant fails to rescue, indicating SH3 domain-mediated protein cluster assembly is required. GRB2 knockdown in human T cells, LAT microcluster imaging, Ca2+ flux, cytokine ELISA, SH3 mutant add-back Frontiers in immunology Medium 25870599
2019 PSMD14 deubiquitinase stabilizes GRB2 by removing ubiquitin modifications, preventing its proteasomal degradation; PSMD14 inhibition decreases GRB2 protein levels and suppresses HCC proliferation, migration, and invasion. Co-immunoprecipitation, ubiquitination assay, PSMD14 knockdown/overexpression, pharmacological inhibition with OPA Cancer letters Medium 31634528
2019 Grb2 interacts with PTEN and its loss reduces nuclear PTEN localization and Rad51 expression; Grb2 knockdown causes micronuclei formation under oxidative stress, and nuclear-localized PTEN (T398A mutant) rescues Rad51 expression and genomic stability, placing Grb2 in a PTEN–Rad51 axis for DNA damage response. Co-immunoprecipitation, GRB2 knockdown, PTEN nuclear localization assay, Rad51 expression assay, micronuclei quantification Cell death & disease Medium 31320611
2021 GRB2 forms a biophysically validated complex with MRE11 (GM complex); GRB2 SH2 domain targets GM complex to γH2AX at DSBs; ubiquitination of GRB2 K109 by E3 ligase RBBP6 releases MRE11 to promote HDR; GRB2 KO increases MRE11-XRCC1 complex and Alt-EJ; GRB2 separation-of-function mutant causes HDR deficiency and synthetic lethality with PARP inhibitor. Biophysical binding assays, immunoprecipitation, ubiquitination mapping, RBBP6 depletion, GRB2 KO and reconstitution with separation-of-function mutant, DSB repair assays, PARP inhibitor sensitivity Science advances High 34348893
2021 Monomeric Grb2 forms a bidentate interaction with both the N-terminal SH2 and catalytic domains of Shp2, releasing Shp2 from its auto-inhibited conformation to activate phosphatase activity independent of Shp2 phosphorylation; dimeric Grb2 does not activate Shp2. In vitro phosphatase activity assays, binding assays distinguishing monomer vs. dimer, NMR/biophysical characterization of interaction interfaces Communications biology High 33795832
2021 Intramolecular allostery in GRB2: HER2 phosphopeptide binding to the SH2 domain potentiates SH3 domain interactions with SOS1 (allosteric mechanism); the SH2 domain blocks cSH3 in basal state enabling nSH3 to engage SOS1 first (avidity-based mechanism); the allosteric effect between SH2 and SH3 domains is directional. Biochemical binding assays, structural analysis of GRB2 domain interactions, phosphotyrosine peptide competition The Biochemical journal Medium 34232285
2023 E3 ubiquitin ligase RNF173 ubiquitinates and promotes degradation of GRB2, suppressing RAF/MEK/ERK signaling; RNF173 knockdown impairs GRB2 ubiquitination, elevates GRB2 protein levels, and promotes HCC invasion and metastasis. Ubiquitination assay, mass spectrometry, co-immunoprecipitation, RNF173 knockdown/overexpression, in vitro/in vivo tumor assays Cell communication and signaling : CCS Medium 37626338
2024 Nuclear GRB2 protects DNA at stalled replication forks by binding and inhibiting RAD51 ATPase activity, stabilizing RAD51 on forks and preventing MRE11-mediated fork degradation in the BRCA2 replication fork protection axis; GRB2 depletion combined with PARP inhibitor releases fork-derived DNA into the cytoplasm, activating cGAS-STING and anti-tumor immunity. GRB2 depletion, RAD51 ATPase inhibition assay, replication fork protection assay (fiber assay), cGAS-STING pathway activation, syngeneic ovarian cancer mouse model Nature communications High 38459011
2003 p27Kip1 binds GRB2 and blocks its association with SOS; endogenous p27 translocates from nucleus to cytoplasm upon mitogen stimulation where it competes with SOS for GRB2 binding, reducing Ras activation; the CDK-inhibitory and GRB2-inhibitory functions of p27 are separable. Yeast two-hybrid, co-immunoprecipitation, transfection-based Ras activation assay Molecular and cellular biology Medium 12748278
2006 Dok-3 binds Grb2 via the Grb2 SH2 domain upon Dok-3 tyrosine phosphorylation, sequestering Grb2-Sos from Shc and inhibiting Ras-Erk activation downstream of Src; a Dok-3 Tyr/Phe double mutant (Dok-3-FF) fails to inhibit Ras and Erk. Co-immunoprecipitation, mutagenesis, Ras/Erk activation assays, Shc-Grb2-Sos recruitment assay Genes to cells : devoted to molecular & cellular mechanisms Medium 16436051

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 1559 1322798
1994 Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1477 7997267
1993 Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 925 8479541
2006 Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Developmental cell 707 16678776
1996 A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature 592 8596638
1993 Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature 571 8386805
1994 A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Molecular and cellular biology 454 8264620
1994 Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Molecular and cellular biology 409 7518560
1998 Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 305 9865697
2000 Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. The Journal of cell biology 295 10871282
1994 Compartmentalization of SHC, GRB2 and mSOS, and hyperphosphorylation of Raf-1 by EGF but not insulin in liver parenchyma. The EMBO journal 294 7925272
2012 Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell death and differentiation 263 23154388
2000 Interaction of EGF receptor and grb2 in living cells visualized by fluorescence resonance energy transfer (FRET) microscopy. Current biology : CB 246 11084343
1995 Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells. Molecular and cellular biology 224 7791764
2003 The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. The Journal of clinical investigation 179 12639989
1999 Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades. The Journal of biological chemistry 178 10329689
2008 Grb2 signaling in cell motility and cancer. Expert opinion on therapeutic targets 172 18620523
1994 The GRB2/Sem-5 adaptor protein. FEBS letters 171 8307166
1996 SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. The Journal of biological chemistry 144 8626428
2012 Inhibition of basal FGF receptor signaling by dimeric Grb2. Cell 136 22726438
2001 Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Nature immunology 134 11135575
1995 The Grb2 adaptor. FEBS letters 130 7641883
1994 Shc, Grb2, Sos1, and a 150-kilodalton tyrosine-phosphorylated protein form complexes with Fms in hematopoietic cells. Molecular and cellular biology 126 7520523
2002 Grb2 and Nck act cooperatively to promote actin-based motility of vaccinia virus. Current biology : CB 125 12007418
2002 Role of Grb2 in EGF-stimulated EGFR internalization. Journal of cell science 116 11956311
1996 Pathways downstream of Shc and Grb2 are required for cell transformation by the tpr-Met oncoprotein. The Journal of biological chemistry 110 8662733
2006 The Grb2/Mek pathway represses Nanog in murine embryonic stem cells. Molecular and cellular biology 103 16908534
1995 Direct association of Grb2 with the p85 subunit of phosphatidylinositol 3-kinase. The Journal of biological chemistry 101 7759531
2001 GRB2: a pivotal protein in signal transduction. Seminars in oncology 99 11706405
1994 Cloning of a Grb2 isoform with apoptotic properties. Science (New York, N.Y.) 98 8178156
2019 Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2. Cancer letters 93 31634528
1994 Overexpression of the Grb2 gene in human breast cancer cell lines. Oncogene 89 8058337
2007 Amyloid precursor protein and Presenilin1 interact with the adaptor GRB2 and modulate ERK 1,2 signaling. The Journal of biological chemistry 80 17314098
1998 Grb2 binding to the different isoforms of Ret tyrosine kinase. Oncogene 78 9764818
2012 Grb2, a double-edged sword of receptor tyrosine kinase signaling. Science signaling 72 23131845
1999 Selective GRB2 SH2 inhibitors as anti-Ras therapy. International journal of cancer 72 10471533
2000 Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. The Journal of experimental medicine 68 10993915
1997 Differential requirement of Grb2 and PI3-kinase in HGF/SF-induced cell motility and tubulogenesis. Journal of cellular physiology 68 9365521
2013 Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity. The Journal of cell biology 67 23420874
2015 Grb2 monomer-dimer equilibrium determines normal versus oncogenic function. Nature communications 65 26103942
2009 Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes. Proceedings of the National Academy of Sciences of the United States of America 65 19805304
2005 The multiple function of Grb2 associated binder (Gab) adaptor/scaffolding protein in immune cell signaling. Immunology letters 64 16386802
2018 The Role of Grb2 in Cancer and Peptides as Grb2 Antagonists. Protein and peptide letters 59 29173143
2001 Solution structure of Grb2 reveals extensive flexibility necessary for target recognition. Journal of molecular biology 58 11178911
2011 Grb2 regulates B-cell maturation, B-cell memory responses and inhibits B-cell Ca2+ signalling. The EMBO journal 56 21427701
2006 Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy. Anti-cancer drugs 56 16317285
2014 SUMOylation of Grb2 enhances the ERK activity by increasing its binding with Sos1. Molecular cancer 55 24775912
2003 p27Kip1 inhibition of GRB2-SOS formation can regulate Ras activation. Molecular and cellular biology 55 12748278
2006 Grb2 and Gads exhibit different interactions with CD28 and play distinct roles in CD28-mediated costimulation. Journal of immunology (Baltimore, Md. : 1950) 52 16818765
1999 Effect of potent and selective inhibitors of the Grb2 SH2 domain on cell motility. The Journal of biological chemistry 52 10438507
2018 The PEAK1-PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer. Cancer letters 49 30472186
2016 miR-411-5p inhibits proliferation and metastasis of breast cancer cell via targeting GRB2. Biochemical and biophysical research communications 49 27264952
2019 LncRNA PCFL promotes cardiac fibrosis via miR-378/GRB2 pathway following myocardial infarction. Journal of molecular and cellular cardiology 47 31220469
2013 Live-cell fluorescence imaging reveals high stoichiometry of Grb2 binding to the EGF receptor sustained during endocytosis. Journal of cell science 46 24259669
2010 Nck1 and Grb2 localization patterns can distinguish invadopodia from podosomes. European journal of cell biology 46 20850195
2001 Gene dosage-dependent functions for phosphotyrosine-Grb2 signaling during mammalian tissue morphogenesis. Current biology : CB 44 11369229
2001 ShcA and Grb2 mediate polyoma middle T antigen-induced endothelial transformation and Gab1 tyrosine phosphorylation. The EMBO journal 43 11707404
2014 The kinase LMTK3 promotes invasion in breast cancer through GRB2-mediated induction of integrin β₁. Science signaling 42 24939894
2009 Grb2, a simple adapter with complex roles in lymphocyte development, function, and signaling. Immunological reviews 42 19909362
2003 Grb2 regulates Stat3 activation negatively in epidermal growth factor signalling. The Biochemical journal 42 14498832
2011 Growth-factor receptor-bound protein-2 (Grb2) signaling in B cells controls lymphoid follicle organization and germinal center reaction. Proceedings of the National Academy of Sciences of the United States of America 40 21508326
2001 Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner. Biochemical and biophysical research communications 40 11394904
2000 Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells. Oncogene 40 11175341
2014 Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion. Nature structural & molecular biology 39 24440983
2006 Potential disease targets for drugs that disrupt protein-- protein interactions of Grb2 and Crk family adaptors. Current pharmaceutical design 37 16472145
2009 Direct binding of Grb2 SH3 domain to FGFR2 regulates SHP2 function. Cellular signalling 36 19735729
2009 The B-lymphoid Grb2 interaction code. Immunological reviews 36 19909361
2016 Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability. Science signaling 35 27188442
2014 Recruitment of the adaptor protein Grb2 to EGFR tetramers. Biochemistry 35 24697349
2000 Recent advances in the design and synthesis of SH2 inhibitors of Src, Grb2 and ZAP-70. Current medicinal chemistry 35 10911019
2024 The Configuration of GRB2 in Protein Interaction and Signal Transduction. Biomolecules 34 38540680
2021 GRB2 enforces homology-directed repair initiation by MRE11. Science advances 34 34348893
2019 Bridging the Gap: Modulatory Roles of the Grb2-Family Adaptor, Gads, in Cellular and Allergic Immune Responses. Frontiers in immunology 33 31402911
2006 Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein-tyrosine kinases. Genes to cells : devoted to molecular & cellular mechanisms 33 16436051
2024 GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer. Nature communications 32 38459011
2011 GRB2 couples RhoU to epidermal growth factor receptor signaling and cell migration. Molecular biology of the cell 32 21508312
1997 Anti-synapsin monoclonal antibodies: epitope mapping and inhibitory effects on phosphorylation and Grb2 binding. Brain research. Molecular brain research 32 9450672
2021 Targeting M2 Macrophages Alleviates Airway Inflammation and Remodeling in Asthmatic Mice via miR-378a-3p/GRB2 Pathway. Frontiers in molecular biosciences 31 34589519
2016 mir-329 restricts tumor growth by targeting grb2 in pancreatic cancer. Oncotarget 31 26885689
2011 The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (and a surprise discovery: PLD2 is a GEF). Cellular signalling 31 21740967
2007 Structural and energetic aspects of Grb2-SH2 domain-swapping. Archives of biochemistry and biophysics 30 17466257
1997 Inhibition of Grb2 and Crkl proteins results in growth inhibition of Philadelphia chromosome positive leukemic cells. Biochemical and biophysical research communications 29 9199202
2002 Preferential binding of Grb2 or phosphatidylinositol 3-kinase to the met receptor has opposite effects on HGF-induced myoblast proliferation. Experimental cell research 28 11900489
2018 Grb2 and GRAP connect the B cell antigen receptor to Erk MAP kinase activation in human B cells. Scientific reports 27 29523808
2002 A role for Grb2-associated binder-1 in growth hormone signaling. Endocrinology 27 12446613
2019 Grb2 binds to PTEN and regulates its nuclear translocation to maintain the genomic stability in DNA damage response. Cell death & disease 26 31320611
2004 Role of the Grb2-associated binder 1/SHP-2 interaction in cell growth and transformation. Cancer research 26 15026337
2021 Grb2 binding induces phosphorylation-independent activation of Shp2. Communications biology 25 33795832
2015 GRB2 Nucleates T Cell Receptor-Mediated LAT Clusters That Control PLC-γ1 Activation and Cytokine Production. Frontiers in immunology 25 25870599
2014 Adaptor protein GRB2 promotes Src tyrosine kinase activation and podosomal organization by protein-tyrosine phosphatase ϵ in osteoclasts. The Journal of biological chemistry 25 25381250
1998 SLP-76-Cbl-Grb2-Shc interactions in FcgammaRI signaling. Blood 25 9716598
2021 The intramolecular allostery of GRB2 governing its interaction with SOS1 is modulated by phosphotyrosine ligands. The Biochemical journal 24 34232285
2023 RNF173 suppresses RAF/MEK/ERK signaling to regulate invasion and metastasis via GRB2 ubiquitination in Hepatocellular Carcinoma. Cell communication and signaling : CCS 23 37626338
2022 The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia. Biophysical journal 23 35651316
2017 Quantifying the Interaction between EGFR Dimers and Grb2 in Live Cells. Biophysical journal 23 28734476
2013 MicroRNA-200a regulates Grb2 and suppresses differentiation of mouse embryonic stem cells into endoderm and mesoderm. PloS one 22 23874841
2014 Grb2-associated binder 1 is essential for cardioprotection against ischemia/reperfusion injury. Basic research in cardiology 20 24951957
2007 Grb2 is required for atherosclerotic lesion formation. Arteriosclerosis, thrombosis, and vascular biology 20 17363695
2010 Grb2-mediated alteration in the trafficking of AbetaPP: insights from Grb2-AICD interaction. Journal of Alzheimer's disease : JAD 19 20164575
2024 Ginsenoside Rg3 Restores Mitochondrial Cardiolipin Homeostasis via GRB2 to Prevent Parkinson's Disease. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 39159293

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