Affinage

GRB2

Growth factor receptor-bound protein 2 · UniProt P62993

Round 2 corrected
Length
217 aa
Mass
25.2 kDa
Annotated
2026-04-28
130 papers in source corpus 53 papers cited in narrative 49 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRB2 is a non-enzymatic adaptor protein that serves as a central signaling hub coupling activated receptor tyrosine kinases to the Ras/MAPK cascade and other downstream effector pathways. Its SH2 domain binds phosphotyrosine motifs (pY-X-N-X) on receptors (EGFR Y1068, FAK Y925, Ret Y1096) and docking proteins (Shc, IRS-1, SHP2, FRS2), while its two flanking SH3 domains constitutively engage proline-rich sequences on SOS1, Gab1, p85-PI3K, WASp, PLD2, and Cbl, with phosphotyrosine binding to the SH2 domain allosterically potentiating SH3–SOS1 interaction (PMID:1322798, PMID:8479540, PMID:34232285). Beyond cytoplasmic Ras activation, GRB2 negatively regulates basal FGFR2 signaling by forming an inhibitory heterotetramer that is relieved upon receptor-mediated GRB2 tyrosine phosphorylation, competitively excludes PLCγ1 from FGFR2, recruits Cbl to drive receptor endocytosis, and in the nucleus stabilizes RAD51 at stalled replication forks to prevent MRE11-mediated degradation and cGAS–STING-dependent innate immune activation (PMID:22726438, PMID:24440983, PMID:17449471, PMID:38459011). Grb2-null mice are embryonic lethal due to failure of primitive endoderm specification via loss of MAPK-dependent Nanog repression, and Grb2 haploinsufficiency impairs T cell negative selection and pressure-overload cardiac hypertrophy through selective reduction of JNK/p38 activation (PMID:9865697, PMID:16678776, PMID:11135575, PMID:12639989).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    The identification of GRB2 as an SH2/SH3-containing adaptor that binds activated EGF and PDGF receptors and cooperates with Ras to stimulate DNA synthesis established the first molecular link between receptor tyrosine kinases and Ras signaling in mammalian cells.

    Evidence cDNA cloning, immunoblotting, microinjection in quiescent fibroblasts; co-IP showing Shc–GRB2 complex formation

    PMID:1322798 PMID:1465135

    Open questions at the time
    • Exact mechanism by which GRB2 activates Ras was unknown
    • Ras GEF partner not yet identified
  2. 1993 High

    Discovery that GRB2's SH3 domains constitutively bind the Ras GEF SOS1, and that EGF stimulation recruits the preformed GRB2–SOS1 complex to the receptor, resolved the biochemical mechanism by which receptor phosphotyrosine signals activate Ras.

    Evidence Co-immunoprecipitation and in vivo binding assays replicated across three independent laboratories simultaneously

    PMID:8479540 PMID:8479541 PMID:8493579

    Open questions at the time
    • Whether GRB2-SOS is the sole pathway to Ras activation downstream of RTKs
    • Structural basis of SH3–SOS interaction not yet determined
  3. 1994 High

    Mapping of GRB2's SH2 specificity (pY-X-N-X motif) and identification of direct binding sites on EGFR (Y1068), FAK (Y925), and indirect coupling via SHP2 to PDGFR defined the receptor-proximal logic by which GRB2 discriminates among upstream inputs.

    Evidence Phosphopeptide library screening, BIAcore affinity measurements, EGFR/FAK/PDGFR point mutant co-IPs

    PMID:7511210 PMID:7518560 PMID:7997267 PMID:8264620

    Open questions at the time
    • Full repertoire of GRB2 SH2-binding partners not established
    • In vivo relevance of affinity differences unknown
  4. 1995 Medium

    Identification of SH3-mediated constitutive interactions with p85-PI3K and β-dystroglycan revealed that GRB2 routes signals beyond the Ras/MAPK pathway to PI3K and the dystrophin complex.

    Evidence Yeast two-hybrid, GST pulldown with SH3 domain mutants, co-IP from skeletal muscle

    PMID:7744812 PMID:7759531

    Open questions at the time
    • Functional consequence of GRB2–dystroglycan interaction in muscle unknown
    • Whether GRB2–p85 and GRB2–SOS complexes coexist or are mutually exclusive in vivo
  5. 1996 High

    Discovery of ERK-mediated feedback phosphorylation of SOS causing GRB2–SOS complex dissociation, and constitutive SH3-mediated GRB2–Gab1 interaction bridging c-Met to Shp2, defined GRB2 as a node subject to negative feedback and capable of branching to multiple effectors.

    Evidence Kinase inhibitors, membrane-anchored GRB2 fusions, yeast two-hybrid domain mapping, MDCK morphogenesis assay

    PMID:10871282 PMID:8626428

    Open questions at the time
    • Quantitative contribution of feedback SOS dissociation to signal termination in vivo
    • Structural basis of Gab1 atypical PXXP motif recognition
  6. 1998 High

    Grb2-null mouse embryonic lethality and rescue by an SH2–SOS1 fusion protein provided definitive genetic proof that GRB2 functions as a non-enzymatic adaptor essential for Ras activation and endoderm specification in vivo.

    Evidence Mouse gene knockout, ES cell chimera analysis, SH2-SOS1 fusion rescue

    PMID:9865697

    Open questions at the time
    • Which specific RTK or docking protein upstream of GRB2 drives endoderm specification
    • Whether SH3-dependent partners other than SOS contribute to the embryonic phenotype
  7. 2001 High

    Solution NMR/SAXS showing GRB2 domain flexibility, and Grb2 haploinsufficiency selectively impairing JNK/p38 but not ERK in thymocytes, revealed that GRB2 is not a rigid scaffold and that its dosage differentially gates MAPK pathway branches.

    Evidence NMR and SAXS biophysical analysis; Grb2+/- mouse with kinase activation assays and thymic selection phenotype

    PMID:11135575 PMID:11178911

    Open questions at the time
    • How GRB2 flexibility modulates partner selectivity in cells
    • Molecular basis of dose-dependent pathway selectivity between ERK and JNK/p38
  8. 2006 High

    Demonstration that all ICM cells in Grb2-null embryos express Nanog and lack Gata6, and that GRB2-MEK signaling represses Nanog transcription, established GRB2 as the receptor-proximal gatekeeper of ES cell pluripotency versus primitive endoderm fate.

    Evidence Grb2-null embryo immunofluorescence, Grb2-deficient ES cells with MEK inhibitor/constitutively active MEK epistasis

    PMID:16678776 PMID:16908534

    Open questions at the time
    • Identity of the upstream ligand/receptor activating GRB2 in preimplantation embryos (later attributed to FGF4/FGFR)
    • Whether non-Ras GRB2 effectors contribute to Nanog repression
  9. 2007 High

    GRB2 was shown to be required for clathrin-dependent c-Met endocytosis by recruiting Cbl ubiquitin ligase, and SH2 domain-swapped dimer structures revealed that GRB2 dimerization reduces phosphopeptide affinity, suggesting a regulatory role for oligomeric state.

    Evidence siRNA, dominant-negative GRB2, GRB2–Cbl chimera rescue of endocytosis; X-ray crystallography and ITC of dimer vs. monomer

    PMID:17449471 PMID:17466257

    Open questions at the time
    • Whether GRB2 dimerization occurs at physiological concentrations in vivo
    • Generality of GRB2-dependent Cbl recruitment to other RTKs
  10. 2012 High

    Reconstitution of a GRB2 dimer–FGFR2 dimer heterotetramer that restrains basal receptor phosphorylation, relieved by FGFR2-mediated tyrosine phosphorylation of GRB2, established GRB2 as a negative regulator of RTK signaling — an unexpected inversion of its canonical positive adaptor role.

    Evidence Biochemical reconstitution, mass spectrometry, receptor phosphorylation and mutagenesis assays

    PMID:22726438

    Open questions at the time
    • Whether inhibitory GRB2 tetramers form with other FGFRs or RTKs
    • Structural details of the heterotetramer at atomic resolution
  11. 2014 Medium

    Three mechanistic dimensions of GRB2 were expanded: competitive exclusion of PLCγ1 from FGFR2 C-terminus by GRB2 controls basal phospholipase activity and invasion; SUMOylation at K56 enhances SOS1 binding and ERK output; and GRB2 promotes ARF1/ARF6 GTPase activation downstream of EGFR.

    Evidence In vitro competition binding and calcium/invasion assays; in vivo/in vitro SUMOylation with K56R mutant rescue and xenograft; co-IP with GTPase activation assays

    PMID:24407288 PMID:24440983 PMID:24775912

    Open questions at the time
    • Enzymes responsible for GRB2 K56 SUMOylation and deSUMOylation not identified
    • Direct versus indirect role of GRB2 in ARF activation
    • Whether PLCγ1 competition is relevant beyond FGFR2
  12. 2021 High

    NMR-based demonstration of intramolecular allostery — pY-peptide binding to the SH2 domain potentiates SH3–SOS1 interaction via sequential nSH3-then-cSH3 engagement — provided a biophysical mechanism for signal amplification within the GRB2 molecule itself.

    Evidence NMR, fluorescence polarization, analytical ultracentrifugation with domain mutants

    PMID:34232285

    Open questions at the time
    • Whether allostery operates at endogenous GRB2 concentrations in cells
    • Contribution of allostery to signaling dynamics in vivo not tested
  13. 2023 Medium

    Identification of RNF173 as an E3 ligase that ubiquitinates GRB2 for proteasomal degradation, suppressing RAF/MEK/ERK signaling, provided the first defined ubiquitin ligase targeting GRB2 and complemented earlier evidence of PSMD14-dependent stabilization.

    Evidence Ubiquitination assays, RNF173 knockdown/overexpression, in vivo HCC tumor models

    PMID:31634528 PMID:37626338

    Open questions at the time
    • Specific ubiquitination sites on GRB2 not mapped
    • Whether RNF173 regulation of GRB2 extends beyond hepatocellular carcinoma
  14. 2024 High

    Discovery that nuclear GRB2 stabilizes RAD51 on stalled replication forks by inhibiting RAD51's ATPase, preventing MRE11-mediated fork degradation and cytoplasmic DNA leakage that activates cGAS-STING innate immunity, established a replication-stress function for GRB2 entirely independent of its RTK adaptor role.

    Evidence RAD51 ATPase assay, DNA fiber fork protection assay, cGAS-STING activation, syngeneic ovarian cancer mouse model with PARP inhibitor

    PMID:38459011

    Open questions at the time
    • How GRB2 is directed to the nucleus during replication stress
    • Whether the RAD51-stabilization function depends on GRB2 SH2 or SH3 domains
    • Generality of GRB2–PARP inhibitor synthetic lethality across tumor types

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how GRB2 partitions among its many simultaneous SH3-bound partners in a single cell, the structural basis of the inhibitory FGFR2–GRB2 heterotetramer, the enzymology controlling GRB2 SUMOylation/ubiquitination dynamics, and whether the nuclear replication-fork protection role is generalizable beyond ovarian cancer.
  • No quantitative model of competitive partner allocation in vivo
  • Atomic-resolution structure of FGFR2–GRB2 heterotetramer lacking
  • Regulatory enzymes for GRB2 SUMOylation unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 4 GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-73894 DNA Repair 2
Partners
CBLEGFRFGFR2FRS2GAB1RAD51SHC1SOS1
Complex memberships
FGFR2-GRB2 heterotetramerGRB2-SOS1PLD2-GRB2-WASp

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 GRB2 was identified as a 25 kDa protein containing one SH2 domain and two flanking SH3 domains. Its SH2 domain binds tyrosine-phosphorylated EGF and PDGF receptors, and microinjection of GRB2 together with H-Ras stimulated DNA synthesis in quiescent fibroblasts, establishing GRB2 as a link between receptor tyrosine kinases and Ras signaling. cDNA cloning, immunoblotting, microinjection assay Cell High 1322798
1992 Tyrosine-phosphorylated Shc proteins form a specific complex with GRB2/Sem-5 via GRB2's SH2 domain, coupling tyrosine kinases to the Ras signaling pathway through a Shc-GRB2 complex. Co-immunoprecipitation, in vitro binding assays Nature High 1465135
1993 The SH3 domains of GRB2 bind to the proline-rich carboxy-terminal tail of mSos1 (a Ras guanine nucleotide exchange factor). EGF stimulation induces binding of the GRB2-mSos1 complex to the autophosphorylated EGF receptor, thereby linking receptor tyrosine kinases to Ras activation. Co-immunoprecipitation, in vivo binding assays Nature High 8479540 8479541 8493579
1993 GRB2 forms a stable complex with tyrosine-phosphorylated IRS-1 and Shc upon insulin stimulation, with the SH2 domain recognizing a YV/IN motif on these substrates. GRB2 overexpression enhanced ERK activation in an SH2- and SH3-dependent manner, and dominant-negative Ras blocked this effect, establishing GRB2 as the link between the insulin receptor and Ras/ERK signaling via IRS-1 and Shc. Co-immunoprecipitation, overexpression with SH2/SH3 point mutants, dominant-negative Ras epistasis The EMBO journal / Science High 8316835 8491186
1994 GRB2 directly binds the EGF receptor via its SH2 domain at phosphotyrosine Y1068 (primary site) and Y1086 (minor site), while Y1173 is an indirect binding site mediated through Shc. Dissociation constants were measured by BIAcore real-time interaction analysis. Co-immunoprecipitation with EGFR point mutants, phosphopeptide competition, dephosphorylation protection assay, BIAcore affinity measurements Molecular and cellular biology High 7518560
1994 GRB2's SH2 domain binds phosphotyrosine with the optimal recognition motif pTyr-X-N-X (hydrophilic-hydrophilic-hydrophobic), distinct from other SH2 domains, as determined by degenerate phosphopeptide library screening. Degenerate phosphopeptide library, peptide binding assays Molecular and cellular biology High 7511210
1994 Fibronectin-mediated integrin engagement promotes GRB2 SH2-domain binding to FAK phosphorylated at Tyr925 (YENV motif), linking integrins to the Ras/MAPK pathway. Mutation of Tyr925 to phenylalanine blocks GRB2 SH2 binding to FAK in vitro. Co-immunoprecipitation in vivo, in vitro SH2 binding with FAK mutants, MAPK activation assay Nature High 7997267
1994 GRB2 does not bind the PDGF receptor directly; instead, upon PDGF stimulation, GRB2 binds the tyrosine-phosphorylated phosphatase Syp/SHPTP2 (a ~70 kDa protein) which is recruited to the PDGF receptor at Tyr1009. Syp thus acts as an adaptor linking the PDGF receptor to the GRB2-Sos complex. Co-immunoprecipitation, PDGF receptor tyrosine mutants, direct binding assays with GST fusions Molecular and cellular biology High 8264620
1994 GRB2 and Sos1 form a constitutive complex; M-CSF stimulation of Fms receptor leads to Fms association with GRB2 and Sos1 through Shc or the myeloid-specific p150 protein, providing a mechanism for Ras activation downstream of Fms in myeloid cells. Co-immunoprecipitation, Fms SH2 domain binding Molecular and cellular biology Medium 7520523
1994 A GRB2 isoform lacking functional SH2 domain (Grb3-3) retains functional SH3 domains, cannot bind phosphorylated EGFR, inhibits EGF-induced Ras signaling as a dominant negative, and induces apoptosis upon microinjection into fibroblasts. cDNA cloning, reporter gene assay, microinjection-induced apoptosis Science Medium 8178156
1994 EGF stimulation in rat liver parenchyma leads to rapid compartmentalization of SHC, GRB2, and mSOS predominantly in endosomes, where the tyrosine-phosphorylated SHC-GRB2-mSOS complex forms and drives sustained Raf-1 activation. Insulin stimulation does not trigger this pathway in the same cells. Subcellular fractionation in vivo, co-immunoprecipitation, Raf-1 gel-shift assay The EMBO journal Medium 7925272
1995 GRB2 directly interacts with beta-dystroglycan via SH3 domain binding to beta-dystroglycan's C-terminal proline-rich domains. Loss-of-function GRB2 mutants (P49L and G203R) in SH3 domains abolish this interaction, and endogenous GRB2 co-immunoprecipitates with alpha/beta-dystroglycan in skeletal muscle and brain. In vitro protein binding, affinity chromatography, co-immunoprecipitation with SH3 domain mutants The Journal of biological chemistry Medium 7744812
1995 GRB2 directly associates with p85 (the regulatory subunit of PI3-kinase) via SH3 domain interactions with p85 proline-rich motifs. This interaction occurs constitutively, is independent of growth factor stimulation, and is exclusive of Sos binding, suggesting that GRB2 can route signaling to PI3-kinase independently of Ras. Yeast two-hybrid, GST pulldown reconstitution, peptide competition The Journal of biological chemistry Medium 7759531
1995 Cbl is co-immunoprecipitated with GRB2 in unstimulated Jurkat T cells via GRB2's N-terminal SH3 domain. Upon TCR activation, Cbl undergoes tyrosine phosphorylation and shifts binding to GRB2's SH2 domain, while losing constitutive SH3-mediated binding. The Cbl-GRB2 complex is distinct from the Sos-GRB2 complex. Co-immunoprecipitation, GST fusion binding assays, T cell activation Molecular and cellular biology Medium 7791764
1996 ERK (but not JNK) pathway activation is responsible for feedback serine/threonine phosphorylation of SOS and dissociation of the GRB2-SOS complex. Plasma membrane targeting of GRB2-SOS (via EGFR) prevents this feedback uncoupling, whereas a GRB2 SH2 mutant unable to associate with the membrane fails to protect the GRB2-SOS complex. Kinase activation assays with specific inhibitors (PD98059), dominant-interfering Ras, membrane-anchored GRB2 fusion proteins, SH2 mutants The Journal of biological chemistry High 8626428 8626525
1996 GRB2 SH3 domain mediates constitutive interaction with Gab1 at two sites: a classical PXXP motif and a novel PX(V/I)(D/N)RXXKP motif. GRB2 bridges Gab1 to c-Met-signaling complexes; the Gab1-GRB2 interaction couples c-Met activation to downstream branching morphogenesis via Shp2. Reverse yeast two-hybrid domain mapping, modified yeast two-hybrid for phosphorylation-dependent interactions, MDCK branching morphogenesis assay The Journal of cell biology Medium 10871282
1997 FRS2, a lipid-anchored (myristylated) docking protein, is tyrosine phosphorylated upon FGF or NGF stimulation and recruits the GRB2/Sos complex to the plasma membrane. Myristylation is essential for FRS2 membrane localization, tyrosine phosphorylation, GRB2/Sos recruitment, and MAPK activation, linking FGF/NGF receptors to the Ras/MAPK pathway. Protein purification, cDNA cloning, co-immunoprecipitation, myristylation mutants, MAPK activation assay Cell High 9182757
1998 GRB2 is genetically required for endoderm differentiation and epiblast formation during mouse embryogenesis. A Sos1 fusion protein with GRB2's SH2 domain rescues Grb2-null defects, providing genetic evidence that GRB2 functions as an adaptor (not an enzyme) coupling SH2 phosphotyrosine binding to SH3-mediated Sos1 activation in a mammalian Ras signaling pathway. Mouse gene knockout, embryonic stem cell analysis, chimera analysis, rescue with SH2-Sos1 fusion protein Cell High 9865697
1998 GRB2 binds the Ret tyrosine kinase long isoform (Ret/ptc2) at phosphotyrosine Y620 (corresponding to Y1096 on proto-Ret). Mutation of Y620 to F reduces GRB2 co-immunoprecipitation and significantly diminishes transforming activity, demonstrating that GRB2 binding to Ret is required for efficient transformation. Phosphopeptide inhibition, site-directed mutagenesis, co-immunoprecipitation, transformation assay Oncogene Medium 9764818
2000 Activated EGFR-CFP interacts with GRB2-YFP in membrane ruffles and endosomes as measured by FRET microscopy in living cells, directly demonstrating that EGFR-GRB2 signaling complexes persist in the endosomal compartment. Live-cell FRET microscopy (CFP/YFP fusion proteins) Current biology High 11084343
2001 Grb2 null mutation in mice causes embryonic lethality due to failure of endoderm differentiation. A hypomorphic SH2 mutation (E89K) in mouse Grb2 causes defects in placental morphogenesis, neural crest survival, and palate formation, with marked reduction in ERK/MAPK activation and Gab1 tyrosine phosphorylation in fibroblasts, establishing dose-dependent and SH2-mediated functions for GRB2 in tissue morphogenesis. Allelic series mouse genetics, compound heterozygote analysis, ERK activation assay, Gab1 phosphorylation Current biology High 11369229
2001 NMR and small-angle X-ray scattering reveal that GRB2 is a flexible protein in solution, with the C-terminal SH3 domain connected to the SH2 domain via a flexible linker, contrasting with the compact crystal structure. GRB2 adapts the relative position and orientation of both SH3 domains to bind bivalently to proline-rich target sequences. Solution NMR, small-angle X-ray scattering, peptide binding experiments Journal of molecular biology High 11178911
2001 GRB2 haploinsufficiency (Grb2+/- mice) selectively impairs TCR-induced JNK and p38 (but not ERK) activation in thymocytes, leading to defective negative but not positive selection. This establishes GRB2 as a quantitative regulator of MAPK pathway selection in T cell development. Grb2 heterozygous mouse model, kinase activation assays, thymic selection analysis Nature immunology High 11135575
2002 H. pylori CagA protein binds GRB2 in vitro and in vivo in a phosphorylation-independent manner via its EPIYA (PY) region, activating the Ras/MEK/ERK pathway and inducing cell scattering and proliferation. Co-immunoprecipitation in vivo and in vitro, ERK activation assay, cell morphology and proliferation assays Molecular cell Medium 12419219
2002 GRB2 and Ras traffic together to endosomes upon EGF stimulation. GTP-bound (active) Ras is localized at the plasma membrane (ruffles/cell edges) and in endosomes containing EGFR, as measured by FRET between CFP-Ras and YFP-Raf-RBD, demonstrating that endosomes are sites of active Ras signaling. Live-cell fluorescence imaging, FRET microscopy with fluorescent fusion proteins Molecular biology of the cell High 12006650
2002 GRB2 SH3 domains are required for macropinocytic internalization of EGFR. GRB2-YFP rapidly redistributes from cytoplasm to plasma membrane after EGF stimulation in an SH2-dependent manner; the SH3 domains then couple EGFR-containing membranes to effectors required for clathrin-independent macropinocytic internalization. Live-cell imaging with GFP-tagged GRB2 SH2/SH3 domain mutants, transferrin uptake assay, AP-180 C-terminus inhibition Journal of cell science Medium 11956311
2003 GRB2 haploinsufficiency in mice inhibits cardiac p38 MAPK and JNK activation and blocks pressure overload-induced cardiac hypertrophy and fibrosis. This establishes GRB2 as required upstream of p38/JNK signaling in the mechanosensing pathway driving cardiac hypertrophy. Grb2+/- mouse model, pressure overload surgery, MAPK activation assays, histology The Journal of clinical investigation High 12639989
2003 p27Kip1 (CDKN1B) binds GRB2 in the cytoplasm upon mitogen stimulation and blocks GRB2 association with SOS. Cells lacking p27 maintain GRB2-SOS complexes for longer after mitogen stimulation, and p27 inhibits Ras activation by targeting GRB2, a function separable from its CDK inhibitory activity. Yeast two-hybrid, co-immunoprecipitation, mitogen stimulation time-courses, transient transfection Ras activation assay Molecular and cellular biology Medium 12748278
2006 In the absence of Grb2, all inner cell mass (ICM) cells at E3.5 express Nanog and lack Gata6, demonstrating that Grb2-Ras-MAPK signaling is required for Gata6 expression and the specification of primitive endoderm (PE) progenitors in the early mouse embryo. Grb2-null mouse embryo analysis, immunofluorescence for Nanog/Gata6, lineage tracing Developmental cell High 16678776
2006 The GRB2/MEK pathway represses Nanog transcription in embryonic stem cells. Grb2 deficiency or MEK inhibitor PD98059 abolishes sodium vanadate-induced Nanog repression and primitive endoderm differentiation; a constitutively active MEK mutant induces Nanog repression, placing GRB2 upstream of MEK in controlling ES cell pluripotency. Grb2-deficient ES cells, MEK inhibitor, constitutively active MEK transfection, reporter gene assays Molecular and cellular biology High 16908534
2007 GRB2 is required for clathrin-dependent endocytosis of cMet. siRNA depletion of GRB2, dominant-negative GRB2, or point mutations blocking GRB2 binding to the cMet multisubstrate docking site all impair cMet internalization. A GRB2-Cbl chimera rescues internalization in GRB2-depleted cells, indicating GRB2 recruits Cbl ubiquitin ligase activity to cMet for endocytosis. siRNA knockdown, dominant-negative overexpression, cMet point mutants, rescue with Cbl-GRB2 chimera, endocytosis assays The Journal of biological chemistry High 17449471
2007 The Grb2-SH2 domain forms a domain-swapped dimer with 4- to 13-fold reduced affinity for a Shc-derived phosphopeptide compared to monomer. Crystal structures reveal that residues V122, V123, and R142 influence W121 conformation, which governs ligand specificity. Isothermal titration calorimetry, X-ray crystallography, NMR Archives of biochemistry and biophysics High 17466257
2009 GRB2 recruits to FGFR2 through a phosphorylation-independent interaction between GRB2's C-terminal SH3 domain and the proline-rich C-terminus of FGFR2. Deletion of the last 10 amino acids of FGFR2 abrogates GRB2 binding, and this interaction provides resistance to Shp2-mediated receptor dephosphorylation. Domain deletion mutants, synthetic peptide binding (affinity measurements), FLIM-FRET, Shp2 dephosphorylation assay Cellular signalling Medium 19735729
2009 Gasp (Themis) constitutively associates with GRB2 via GRB2's N-terminal SH3 domain in DP thymocytes. Loss of Gasp severely impairs positive selection of both CD4 and CD8 T cells, suggesting GRB2-Gasp acts as a thymocyte-specific adaptor complex in Ras signaling during positive selection. Co-immunoprecipitation, knockout mouse phenotypic analysis, flow cytometry Proceedings of the National Academy of Sciences of the United States of America Medium 19805304
2010 GRB2 localizes specifically to degradative structures (podosomes) in Src-transformed fibroblasts and PMA-stimulated endothelial cells, but not to invadopodia in metastatic mammary carcinoma cells, distinguishing these two types of actin-rich structures by their upstream N-WASp/WASp activators. Immunofluorescence localization in multiple cell types, comparison of GRB2 vs. Nck1 distribution European journal of cell biology Medium 20850195
2011 GRB2 forms a heterotrimer with PLD2 and WASp, with GRB2 bridging PLD2 (via SH2 domain binding to PLD2 Y169) and WASp (via SH3 domains binding WASp poly-proline region). This PLD2-GRB2-WASp complex localizes to phagocytic cups and is required for actin polymerization and phagocytosis in macrophages. Co-immunoprecipitation, PLD2 and GRB2 mutants, RNAi knockdown, phagocytosis assay, immunofluorescence Molecular and cellular biology Medium 21930784
2012 Dimeric GRB2 binds to the C-termini of two FGFR2 molecules, forming a heterotetramer. This complex allows low-level transphosphorylation but sterically blocks C-terminal phosphorylation and recruitment of downstream signaling proteins. Upon FGFR2 stimulation, FGFR2 phosphorylates tyrosine residues on GRB2, promoting dissociation and enabling full downstream signaling. GRB2 thus acts as a negative regulator of basal FGFR2 activity. Biochemical reconstitution, structural analysis, mass spectrometry, receptor phosphorylation assays, mutagenesis Cell High 22726438
2012 TIGIT/PVR engagement leads to phosphorylation of Tyr225 in TIGIT's ITT-like motif, which recruits GRB2 via its SH2 domain. GRB2 in turn recruits SHIP1, which terminates PI3K and MAPK signaling and suppresses NK cell granule polarization and cytotoxicity. Tyr225 or Asn227 mutation restores cytotoxicity, and SHIP1 silencing abolishes TIGIT-mediated killing inhibition. Mutagenesis of TIGIT ITT-like motif, co-immunoprecipitation, SHIP1 siRNA knockdown, NK cell cytotoxicity assay Cell death and differentiation High 23154388
2013 Live-cell quantitative imaging reveals an average of two GRB2-YFP molecules co-localized per EGF-receptor in endosomes. GRB2 association with EGFR persists in endosomes during trafficking and correlates with sustained ERK1/2 activation, supporting endosomal EGFR signaling as a significant contributor to this pathway. Quantitative spinning disk confocal microscopy, endogenous GRB2 replacement with GRB2-YFP, single-endosome quantification Journal of cell science Medium 24259669
2014 In the absence of ligand stimulation, GRB2 C-terminal SH3 domain competes with PLCγ1 SH3 domain for a proline-rich site at the FGFR2 C-terminus. Reduction in GRB2 concentration permits constitutive PLCγ1 recruitment, upregulating phospholipase activity, PIP2 turnover, calcium levels, and cell invasiveness independently of receptor stimulation. In vitro competition binding assays, PLCγ1 activity measurements, calcium imaging, invasion assays in low-GRB2 cancer cells Nature structural & molecular biology High 24440983
2014 GRB2 is SUMOylated by SUMO1 at lysine K56 (in the linker between N-SH3 and SH2 domains). SUMOylation at K56 enhances formation of the GRB2-Sos1 complex, increasing Ras/MEK/ERK activation. GRB2-K56R mutant cannot rescue ERK activity, cell motility, or tumorigenesis in GRB2 knockdown cells. In vivo SUMOylation assay (Ni2+-NTA pulldown), in vitro E. coli-based SUMOylation assay, co-immunoprecipitation, GRB2 knockdown/re-expression, xenograft tumor model Molecular cancer Medium 24775912
2014 GRB2 promotes ARF1 and ARF6 activation downstream of EGFR in breast cancer cells. GRB2 is required for recruitment of ARF1 to the EGFR. Conversely, p66Shc blocks GRB2-mediated ARF1 recruitment and ARF1 activation. GRB2 is also required for ARF6 activation and receptor recruitment. Co-immunoprecipitation, GTPase activation assays, siRNA knockdown, EGF stimulation The Journal of biological chemistry Medium 24407288
2014 EGF-stimulated EGFR clusters (containing on average 4 EGFR molecules) preferentially recruit GRB2. Modeling indicates that ~94% of EGFR tetramers are associated with GRB2, while monomers and dimers show much less GRB2 association, implicating EGFR tetramers as the predominant GRB2-binding signaling unit. Image correlation spectroscopy, FLIM-FRET, quantitative modeling Biochemistry Medium 24697349
2019 PSMD14, a deubiquitinating enzyme, directly stabilizes GRB2 protein by inhibiting its ubiquitin-mediated proteasomal degradation. PSMD14 knockdown reduces GRB2 protein levels, and pharmacological PSMD14 inhibition suppresses GRB2-dependent HCC malignant behaviors in vitro and in vivo. Co-immunoprecipitation, knockdown/overexpression experiments, ubiquitination assay, in vitro and in vivo tumor models Cancer letters Medium 31634528
2019 GRB2 binds PTEN and is required for PTEN's nuclear translocation upon oxidative stress. Loss of GRB2 reduces nuclear PTEN, decreasing RAD51 expression and leading to micronuclei formation, indicating GRB2 is required for genome stability in the DNA damage response via a PTEN-RAD51 axis. Co-immunoprecipitation, GRB2 knockdown/overexpression, nuclear fractionation, PTEN mutant rescue, micronuclei counting Cell death & disease Medium 31320611
2021 GRB2 displays intramolecular allostery: phosphotyrosine peptide (HER2 pY) binding to the SH2 domain potentiates GRB2 SH3 domain interactions with SOS1. The SH2 domain blocks the C-terminal SH3 domain (cSH3), enabling nSH3 to bind SOS1 first before cSH3 follows. This allosteric mechanism is unidirectional between cSH3 and other domains. NMR, fluorescence polarization, analytical ultracentrifugation, pull-down assays with domain mutants The Biochemical journal High 34232285
2022 BCR-ABL recruits GRB2 via the pBCR 176FpYVNV180 motif binding specifically to GRB2's SH2 domain. The specificity pocket in SH2-GRB2 is governed by N179 in pBCR and W121 in SH2-GRB2. The optimal binding motif for SH2-GRB2 is E/D-pY-E/V-N-I/L. Computational modeling of pBCR-SH2GRB2 complexes, comparison of multiple pY-peptide-SH2 complexes Biophysical journal Low 35651316
2023 RNF173 (a MARCH family E3 ubiquitin ligase) ubiquitinates GRB2, promoting its degradation and suppressing RAF/MEK/ERK signaling in hepatocellular carcinoma. RNF173 knockdown impairs GRB2 ubiquitination and degradation, leading to RAF/MEK/ERK pathway activation and enhanced invasion/metastasis. RNA sequencing, mass spectrometry, co-immunoprecipitation, ubiquitination assay, RNF173 knockdown/overexpression, in vitro and in vivo tumor models Cell communication and signaling Medium 37626338
2024 Nuclear GRB2 protects stalled replication forks from MRE11-mediated degradation by binding RAD51 and inhibiting its ATPase activity, stabilizing RAD51 on stalled forks. GRB2 depletion causes DNA fragments to enter the cytoplasm and activate the cGAS-STING innate immune pathway, triggering pro-inflammatory cytokine production. In a syngeneic ovarian cancer model, GRB2 depletion combined with PARP inhibition reduced tumor burden and enabled high survival. RAD51 ATPase assay, replication fork protection assay (fiber assay), co-immunoprecipitation, cGAS-STING activation measurement, syngeneic mouse cancer model Nature communications High 38459011

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
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2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1994 Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1476 7997267
2011 Systematic and quantitative assessment of the ubiquitin-modified proteome. Molecular cell 1334 21906983
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 1200 26627737
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2000 FAK integrates growth-factor and integrin signals to promote cell migration. Nature cell biology 1078 10806474
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1999 Signaling through focal adhesion kinase. Progress in biophysics and molecular biology 1008 10354709
1998 LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 1003 9489702
1993 The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature 987 8479540
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1992 Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 953 1465135
1993 Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 925 8479541
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1994 Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav. Molecular and cellular biology 840 7511210
2010 Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular systems biology 775 20160708
1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science (New York, N.Y.) 772 8493579
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Molecular & cellular proteomics : MCP 749 21890473
1997 A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 738 9182757
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2006 Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Developmental cell 702 16678776
1993 The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. The EMBO journal 689 8491186
1998 The structural basis of the activation of Ras by Sos. Nature 684 9690470
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
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2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
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1994 A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Molecular and cellular biology 453 8264620
1994 Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Molecular and cellular biology 408 7518560
1998 Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 305 9865697
2002 Grb2 is a key mediator of helicobacter pylori CagA protein activities. Molecular cell 299 12419219
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 261 23154388
2000 Interaction of EGF receptor and grb2 in living cells visualized by fluorescence resonance energy transfer (FRET) microscopy. Current biology : CB 245 11084343
1995 SH3 domain-mediated interaction of dystroglycan and Grb2. The Journal of biological chemistry 237 7744812
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 178 12639989
2008 Grb2 signaling in cell motility and cancer. Expert opinion on therapeutic targets 171 18620523
1994 The GRB2/Sem-5 adaptor protein. FEBS letters 171 8307166
2002 Coordinated traffic of Grb2 and Ras during epidermal growth factor receptor endocytosis visualized in living cells. Molecular biology of the cell 170 12006650
1996 SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. The Journal of biological chemistry 143 8626428
1996 Interactions of Cbl with two adapter proteins, Grb2 and Crk, upon T cell activation. The Journal of biological chemistry 138 8626404
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2002 Role of Grb2 in EGF-stimulated EGFR internalization. Journal of cell science 115 11956311
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2006 The Grb2/Mek pathway represses Nanog in murine embryonic stem cells. Molecular and cellular biology 102 16908534
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2001 GRB2: a pivotal protein in signal transduction. Seminars in oncology 99 11706405
1994 Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling. The Journal of biological chemistry 99 7983051
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 90 31634528
1994 Overexpression of the Grb2 gene in human breast cancer cell lines. Oncogene 89 8058337
1998 Grb2 binding to the different isoforms of Ret tyrosine kinase. Oncogene 77 9764818
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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 64 19805304
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1999 Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis. Oncogene 64 10022119
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
2018 miR-378a-3p sensitizes ovarian cancer cells to cisplatin through targeting MAPK1/GRB2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 56 30257357
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
1999 Effect of potent and selective inhibitors of the Grb2 SH2 domain on cell motility. The Journal of biological chemistry 52 10438507
2006 Grb2 and Gads exhibit different interactions with CD28 and play distinct roles in CD28-mediated costimulation. Journal of immunology (Baltimore, Md. : 1950) 51 16818765
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
2010 Nck1 and Grb2 localization patterns can distinguish invadopodia from podosomes. European journal of cell biology 46 20850195
2013 Ataxin-2 modulates the levels of Grb2 and SRC but not ras signaling. Journal of molecular neuroscience : MN 45 23335000
2013 Live-cell fluorescence imaging reveals high stoichiometry of Grb2 binding to the EGF receptor sustained during endocytosis. Journal of cell science 45 24259669
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
2009 Grb2, a simple adapter with complex roles in lymphocyte development, function, and signaling. Immunological reviews 42 19909362
2014 The adaptor proteins p66Shc and Grb2 regulate the activation of the GTPases ARF1 and ARF6 in invasive breast cancer cells. The Journal of biological chemistry 41 24407288
2014 The kinase LMTK3 promotes invasion in breast cancer through GRB2-mediated induction of integrin β₁. Science signaling 41 24939894
2007 Specific Grb2-mediated interactions regulate clathrin-dependent endocytosis of the cMet-tyrosine kinase. The Journal of biological chemistry 40 17449471
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
2018 MiR-433-3p Inhibits Proliferation and Invasion of Esophageal Squamous Cell Carcinoma by Targeting GRB2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 39 29730656
2014 Competition between Grb2 and Plcγ1 for FGFR2 regulates basal phospholipase activity and invasion. Nature structural & molecular biology 39 24440983
2011 The mechanism of cell membrane ruffling relies on a phospholipase D2 (PLD2), Grb2 and Rac2 association. Cellular signalling 39 21419846
1998 Interleukin 5 signals through Shc and Grb2 in human eosinophils. American journal of respiratory cell and molecular biology 39 9448048
1996 Epidermal growth factor receptor targeting prevents uncoupling of the Grb2-SOS complex. The Journal of biological chemistry 39 8626525
1994 Analysis of the role of the Shc and Grb2 proteins in signal transduction by the v-ErbB protein. Molecular and cellular biology 37 7909355
2017 MiR-200a modulates TGF-β1-induced endothelial-to-mesenchymal shift via suppression of GRB2 in HAECs. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 28846982
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
2014 Recruitment of the adaptor protein Grb2 to EGFR tetramers. Biochemistry 35 24697349
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2011 Overexpression of Grb2-associated binder 2 in human lung cancer. International journal of biological sciences 34 21552417
2011 A novel phospholipase D2-Grb2-WASp heterotrimer regulates leukocyte phagocytosis in a two-step mechanism. Molecular and cellular biology 34 21930784
2000 Significance of the Grb2 and son of sevenless (Sos) proteins in human bladder cancer cell lines. IUBMB life 34 10995035
2019 Bridging the Gap: Modulatory Roles of the Grb2-Family Adaptor, Gads, in Cellular and Allergic Immune Responses. Frontiers in immunology 32 31402911
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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
2024 GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer. Nature communications 29 38459011
2024 The Configuration of GRB2 in Protein Interaction and Signal Transduction. Biomolecules 29 38540680
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 A role for Grb2-associated binder-1 in growth hormone signaling. Endocrinology 27 12446613
2004 Role of the Grb2-associated binder 1/SHP-2 interaction in cell growth and transformation. Cancer research 26 15026337
2019 Grb2 binds to PTEN and regulates its nuclear translocation to maintain the genomic stability in DNA damage response. Cell death & disease 25 31320611
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
2022 The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia. Biophysical journal 22 35651316
2011 Grb2-associated binding (Gab) proteins in hematopoietic and immune cell biology. American journal of blood research 22 22163099
2023 RNF173 suppresses RAF/MEK/ERK signaling to regulate invasion and metastasis via GRB2 ubiquitination in Hepatocellular Carcinoma. Cell communication and signaling : CCS 21 37626338
2017 Quantifying the Interaction between EGFR Dimers and Grb2 in Live Cells. Biophysical journal 21 28734476
2013 MicroRNA-200a regulates Grb2 and suppresses differentiation of mouse embryonic stem cells into endoderm and mesoderm. PloS one 21 23874841
1994 Mapping GRB2, a signal transduction gene in the human and the mouse. Genomics 21 7806216
2008 Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor. Journal of biomolecular NMR 20 18830565
2010 Grb2-mediated alteration in the trafficking of AbetaPP: insights from Grb2-AICD interaction. Journal of Alzheimer's disease : JAD 19 20164575
2016 c-CBL regulates melanoma proliferation, migration, invasion and the FAK-SRC-GRB2 nexus. Oncotarget 18 27472394