Affinage

GRB7

Growth factor receptor-bound protein 7 · UniProt Q14451

Length
532 aa
Mass
59.7 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRB7 is a multi-domain adaptor protein that couples receptor tyrosine kinase (RTK) signaling to cell migration, translational regulation, and stress granule dynamics. Its C-terminal SH2 domain binds autophosphorylated RTKs—including HER2 (pY1139), ErbB3, FAK (pY397), PDGFR, c-Kit, EphB1, and Ret—while its PH domain engages D3/D5-phosphoinositides required for FAK-mediated phosphorylation and full pro-migratory activity, and its N-terminal RA-PH region mediates calcium-dependent calmodulin binding that regulates membrane association and nuclear translocation (PMID:7907978, PMID:10446223, PMID:12021278, PMID:15806159). At focal adhesions, FAK phosphorylates GRB7, enabling recruitment of SHC to activate RAS-ERK signaling and VAV2 to activate RAC1, thereby promoting integrin-dependent cell migration (PMID:10893408, PMID:23593540). GRB7 also functions as an RNA-binding translational repressor that blocks eIF4E loading onto target mRNAs until FAK-mediated hyperphosphorylation relieves repression, and it is an integral stress granule component whose FAK-triggered dissociation drives stress granule disassembly (PMID:17318180, PMID:18273060). GRB7 protein stability is negatively regulated by JNK phosphorylation at Ser194-Pro, which recruits Pin1 for proteasomal degradation, and in cancer GRB7 co-amplification with HER2 enhances HER2/AKT phosphorylation while also mediating MEK inhibitor resistance through interaction with PLK1 (PMID:27658202, PMID:22584052, PMID:34718347).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1994 High

    The initial question—what signaling proteins associate with the oncogenic receptor HER2—was answered by identifying GRB7 as a major SH2 domain-containing binding partner of phosphorylated HER2 in breast cancer cells, establishing GRB7 as an RTK-coupled adaptor protein.

    Evidence Expression cloning with phosphorylated EGFR C-terminus as probe; reciprocal co-immunoprecipitation from SKBR-3 cells

    PMID:7907978

    Open questions at the time
    • Downstream signaling consequences of GRB7-HER2 interaction unknown
    • Whether GRB7 binds other RTKs not yet tested
  2. 1996 High

    The question of whether GRB7 is a general RTK adaptor was resolved by demonstrating direct SH2-mediated binding to PDGFR (pY716/pY775), Ret, and SHPTP2, revealing broad receptor engagement rather than HER2 exclusivity.

    Evidence GST pulldown with autophosphorylated receptors; site-directed mutagenesis of receptor tyrosines; kinase-dead Ret mutant; co-immunoprecipitation

    PMID:8622870 PMID:8631863 PMID:8940081

    Open questions at the time
    • Functional consequences of these interactions not established
    • No downstream effectors identified
  3. 1997 High

    The structural basis for GRB7's preferential recognition of HER2 over other targets was clarified by mapping binding to pY1139 and identifying a single residue (Leu at βD6) in the SH2 domain as a key specificity determinant within the Grb7 family.

    Evidence Phosphopeptide competition and site-directed mutagenesis of SH2 domain

    PMID:9079677

    Open questions at the time
    • No three-dimensional structure yet available
    • Binding affinities not quantified by biophysical methods
  4. 1998 High

    GRB7 receptor engagement was extended to heregulin-activated ErbB3/ErbB4, with pY1180 and pY1243 on ErbB3 identified as binding sites—establishing GRB7 as a pan-ErbB family adaptor also recruited by ErbB3 and ErbB4.

    Evidence Co-immunoprecipitation from breast cancer cells; ErbB3 point mutants; phosphopeptide competition; GST pulldown

    PMID:9516479

    Open questions at the time
    • Downstream signaling from ErbB3/ErbB4-GRB7 complexes uncharacterized
  5. 1999 High

    The critical question of GRB7's cellular function was answered: GRB7 localizes to focal contacts via its SH2 domain, directly binds FAK at pY397, and overexpression enhances cell migration toward fibronectin while the isolated SH2 domain acts as a dominant negative—linking GRB7 to integrin-mediated cell migration.

    Evidence In vitro binding; co-immunoprecipitation; tetracycline-regulated expression; Boyden chamber migration assay; c-Kit pY936 mapping by mutagenesis

    PMID:10377264 PMID:10446223

    Open questions at the time
    • GRB7 phosphorylation sites not mapped
    • Mechanism by which GRB7 promotes migration (effectors downstream) not identified
  6. 2000 High

    Several lines of evidence established that FAK directly phosphorylates GRB7 at focal contacts in a cell-adhesion-dependent manner, and that SH2-mediated focal contact targeting is indispensable for migration; additionally, phospho-caveolin-1 and the GTPase Rnd1 were identified as GRB7 binding partners.

    Evidence FAK−/− fibroblasts; chimeric molecules; phospho-specific antibodies; GST pulldown from SKBR3; yeast two-hybrid for Rnd1

    PMID:10664463 PMID:10893408 PMID:11075810

    Open questions at the time
    • Specific phosphorylation sites on GRB7 not identified
    • Rnd1 interaction functional consequence unknown
  7. 2002 High

    GRB7's PH domain was shown to bind phosphoinositides (D3/D5), and this lipid interaction was required not for focal contact recruitment but for FAK-mediated phosphorylation and full pro-migratory function—revealing a two-step activation model requiring both SH2-mediated recruitment and PH-mediated lipid engagement.

    Evidence In vitro lipid-binding assay; PI3K inhibitor; FAK−/− cells; PH domain deletion mutants; migration assay

    PMID:12021278

    Open questions at the time
    • Specific lipid species in vivo not determined
    • No structure of PH domain available
  8. 2002 High

    The SH2 domain inhibitor peptide G7-18NATE was discovered by phage display, selectively disrupting GRB7-ErbB interactions while sparing Grb2 and Grb14—establishing proof-of-concept for therapeutic targeting of GRB7.

    Evidence Phage display; competition binding assays; cell lysate immunoprecipitation inhibition

    PMID:11809769

    Open questions at the time
    • In vivo efficacy not tested
    • Cellular permeability and pharmacokinetics unknown
  9. 2003 High

    NMR structure of the GRB7 SH2 domain in complex with ErbB2 pY1139 peptide provided atomic-level understanding of the binding mode, showing the phosphopeptide adopts a β-turn conformation.

    Evidence Solution NMR spectroscopy

    PMID:12975581

    Open questions at the time
    • Full-length GRB7 structure not available
    • Autoinhibition mechanism not structurally characterized
  10. 2005 High

    Calmodulin was identified as a calcium-dependent regulator of GRB7, binding to an amphiphilic helix at residues 243–256 in the RA-PH region; CaM competes with phosphoinositide binding and regulates GRB7 membrane association, adding a calcium-sensing layer to GRB7 signaling.

    Evidence CaM-affinity chromatography; FRET between EYFP-GRB7 and ECFP-CaM in living cells; deletion mutants; CaM inhibitory peptides

    PMID:15806159

    Open questions at the time
    • Physiological conditions triggering CaM-GRB7 interaction in vivo not defined
    • Effect on downstream signaling pathways unknown
  11. 2007 High

    A fundamentally new function was discovered: GRB7 is an RNA-binding protein that represses translation by binding the 5′-UTR of KOR mRNA and blocking eIF4E recruitment; FAK-mediated hyperphosphorylation of two C-terminal tyrosines relieves repression—linking Netrin-1/FAK signaling to translational control through GRB7.

    Evidence RNA-binding assay; in vitro translation assay; FAK phosphorylation assay; domain deletion and mutagenesis

    PMID:17318180

    Open questions at the time
    • Full spectrum of GRB7-regulated mRNAs unknown
    • Structural basis for RNA recognition not determined
  12. 2007 High

    Crystal structure of the GRB7 SH2 domain (2.1 Å) revealed dimerization at micromolar affinity, and showed G7-18NATE binds at the ligand-binding surface while disrupting the dimer interface—establishing dimerization as a regulatable property of GRB7.

    Evidence X-ray crystallography; analytical ultracentrifugation; ITC; NMR titration

    PMID:17894853

    Open questions at the time
    • Biological significance of dimerization in signaling not established
    • Full-length structure still unavailable
  13. 2008 High

    GRB7 was shown to be an integral component of stress granules, directly interacting with HuR and required for SG formation; FAK hyperphosphorylation upon stress termination dissociates GRB7 from HuR and drives SG disassembly—unifying GRB7's RNA-binding and FAK-regulated functions in the stress response.

    Evidence Co-immunoprecipitation; stress granule immunofluorescence; dominant-negative mutants; siRNA knockdown

    PMID:18273060

    Open questions at the time
    • Whether SG role is independent of translational repression unclear
    • Phosphorylation sites mediating HuR release not mapped
  14. 2010 Medium

    GRB7 was placed in an RTK-Ras-ERK signaling axis: EGF-induced GRB7 phosphorylation promotes RAS-GTP loading and ERK activation, and GRB7 overexpression enhances HER2 phosphorylation and AKT activation in breast cancer—establishing GRB7 as an amplifier of RTK signaling.

    Evidence Co-immunoprecipitation; RasGTP pulldown; siRNA knockdown; xenograft tumor model; phospho-signaling immunoblotting

    PMID:17916906 PMID:20622016

    Open questions at the time
    • Mechanism by which GRB7 enhances HER2 phosphorylation not established
    • Whether GRB7 acts catalytically or as a scaffold unresolved
  15. 2012 Medium

    CaM was found to regulate GRB7 nuclear translocation through overlapping NLS and CaM-binding domains; CaM antagonism enhanced nuclear GRB7, while SH2 domain dimerization was quantified (KD ~11 μM) and a monomeric mutant (F511R) was engineered, establishing intramolecular and intermolecular regulatory mechanisms.

    Evidence Confocal microscopy with CaM antagonist W-7; deletion mutants; sedimentation equilibrium ultracentrifugation; ITC

    PMID:22673522 PMID:22811067

    Open questions at the time
    • Nuclear function of GRB7 uncharacterized
    • How autoinhibition and dimerization are coordinated unclear
  16. 2013 Medium

    A bifurcation model was established in HER2+ cells: GRB7 recruits SHC to activate RAS-ERK for proliferation, and separately, FAK-phosphorylated GRB7 recruits VAV2 to activate RAC1 for migration; CaM binding to GRB7 was shown to be required for normal cell migration and ECM attachment.

    Evidence Co-IP with RasGTP and Rac1-GTP pulldown after fibronectin stimulation; siRNA; CaM antagonists W-7/W-13 with deletion mutants; wound healing assay

    PMID:23593540 PMID:23743201

    Open questions at the time
    • Direct VAV2-GRB7 binding interface not mapped
    • How CaM and FAK phosphorylation are coordinated not resolved
  17. 2016 Medium

    A new negative regulatory mechanism was uncovered: JNK phosphorylates GRB7 at Ser194-Pro, enabling Pin1 WW domain binding and prolyl isomerization that targets GRB7 for proteasomal degradation, affecting G2-M progression.

    Evidence Co-immunoprecipitation; MG-132 proteasome inhibitor; Pin1 WW domain binding assay; JNK inhibitor; Ser194 mutagenesis; cell cycle analysis

    PMID:27658202

    Open questions at the time
    • E3 ubiquitin ligase responsible not identified
    • Physiological triggers of JNK-mediated GRB7 degradation unclear
  18. 2017 High

    Crystal structures of bicyclic peptide G7-B4 with the GRB7 SH2 domain, combined with SH2 domain microarray profiling across 79 domains, confirmed exquisite selectivity of the inhibitor scaffold and identified Arg462 and βD6-Leu as key specificity determinants.

    Evidence X-ray crystallography; SPR; SH2 domain microarray (79 domains); mutagenesis

    PMID:27257138 PMID:29083893

    Open questions at the time
    • No in vivo pharmacological data for optimized inhibitors
    • Whether disrupting SH2 interactions is sufficient for anti-tumor effect in vivo unknown
  19. 2021 Medium

    An unbiased CRISPR screen revealed GRB7 as a driver of MEK inhibitor resistance in KRAS-mutant CRC; mass spectrometry identified PLK1 as the predominant GRB7-associated kinase, and combined PLK1 + MEK inhibition synergistically suppressed CRC growth—expanding GRB7 function into drug resistance and implicating PLK1 as a key effector.

    Evidence Genome-wide CRISPR/Cas9 screen; GRB7 IP-mass spectrometry; combination drug treatment in vitro and xenograft

    PMID:34718347

    Open questions at the time
    • Direct GRB7-PLK1 binding mode not characterized
    • Whether PLK1 phosphorylates GRB7 not tested
    • Mechanism linking GRB7-PLK1 to FAK/STAT3/AKT/4EBP1 not fully delineated
  20. 2024 Medium

    GRB7 was shown to interact with Notch1 to activate Wnt/β-catenin and EMT in HER2+ breast cancer, and TCF12 was identified as a direct transcriptional activator of the GRB7 promoter—revealing upstream transcriptional regulation and a new downstream pathway.

    Evidence ChIP-PCR; luciferase reporter assay; co-immunoprecipitation; xenograft model; RNA sequencing

    PMID:39113057

    Open questions at the time
    • Direct vs. indirect nature of GRB7-Notch1 interaction not established
    • TCF12-GRB7 axis not validated in non-breast contexts

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length GRB7 three-dimensional structure (needed to understand autoinhibition), the complete repertoire of GRB7-regulated mRNAs, the E3 ligase mediating Pin1-triggered degradation, the mechanism by which GRB7 enhances HER2 phosphorylation, and the nuclear functions of GRB7.
  • Full-length structure not determined
  • Nuclear function not characterized
  • Complete mRNA target repertoire unknown
  • E3 ubiquitin ligase for GRB7 degradation not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0003723 RNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1643685 Disease 3
Partners
CALM1ELAVL1ERBB2FAKFLNAPLK1SHC1VAV2

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 GRB7 binds tightly to HER2/ErbB2 through its SH2 domain in breast cancer cells; a large fraction of tyrosine-phosphorylated HER2 in SKBR-3 cells is bound to GRB7. GRB7 can also bind tyrosine-phosphorylated SHC. Expression cloning using phosphorylated EGFR C-terminus as probe; co-immunoprecipitation from cell lysates The EMBO journal High 7907978
1996 GRB7 SH2 domain directly binds to autophosphorylated PDGF beta-receptor at Tyr-716 and Tyr-775 in vitro and in vivo; GRB7 also associates with Shc after PDGF alpha- or beta-receptor activation. GST pulldown with autophosphorylated PDGF receptor; site-directed mutagenesis of receptor tyrosines; co-immunoprecipitation; phosphopeptide competition The Journal of biological chemistry High 8940081
1996 GRB7 SH2 domain directly associates with the Ret receptor tyrosine kinase in vitro and in vivo in an autophosphorylation-dependent manner; a kinase-defective Ret mutant cannot bind GRB7. In vitro binding assay; co-immunoprecipitation; kinase-dead Ret mutant The Journal of biological chemistry High 8631863
1996 GRB7 SH2 domain interacts with tyrosine-phosphorylated SHPTP2 at Tyr-580 in the C-terminal tail of SHPTP2, as detected by modified two-hybrid system and confirmed by in vitro binding under phosphorylation conditions. Yeast two-hybrid with exogenous tyrosine kinase; in vitro binding assay; deletion/mutation mapping Oncogene Medium 8622870
1997 The Grb7 SH2 domain binds preferentially to Tyr-1139 of ErbB2; a single residue at position betaD6 (Leu in Grb7 vs. Gln in Grb14) is a key determinant of high-affinity ErbB2 binding specificity within the Grb7 family. Phosphopeptide competition; site-directed mutagenesis of SH2 domain; in vitro binding assays The Journal of biological chemistry High 9079677
1998 Grb7 is recruited by heregulin-activated ErbB3 and ErbB4 via its SH2 domain; Tyr-1180 (major) and Tyr-1243 (minor) of ErbB3 are the binding sites; Arg at position +3 relative to the phosphotyrosine acts as a selectivity determinant favoring Grb7 over Grb2. Co-immunoprecipitation from breast cancer cell lines; ErbB3 point mutants; phosphopeptide competition; GST pulldown The Journal of biological chemistry High 9516479
1999 The Grb7 SH2 domain directly interacts with FAK at its major autophosphorylation site Tyr-397 in vitro and in vivo; this interaction is cell adhesion-dependent (integrin signaling context); overexpression of Grb7 enhances cell migration toward fibronectin whereas its SH2 domain alone inhibits migration. In vitro binding assay; co-immunoprecipitation; tetracycline-regulated expression; Boyden chamber migration assay The Journal of biological chemistry High 10446223
1999 Grb7 binds to c-Kit/stem cell factor receptor (SCFR) at autophosphorylated Tyr-936 in the C-terminal tail via its SH2 domain; Grb2 binds both Tyr-703 and Tyr-936, whereas Grb7 binding is selective for Tyr-936. In vivo autophosphorylation mapping; SH2 domain binding experiments; site-directed mutagenesis of c-Kit The Biochemical journal High 10377264
1999 Sequence analysis identified a Ras-associating (RA)-like domain in the N-terminal region of Grb7/Grb10/Grb14 family proteins, suggesting direct interaction potential with Ras-like GTPases. Computational sequence analysis (BLAST, HCA, HMM profiling) with structural comparison Biochemical and biophysical research communications Low 10334925
2000 Grb7 localizes partially to focal contacts via its SH2 domain; SH2 domain deletion eliminates focal contact localization and abolishes Grb7-stimulated cell migration; FAK phosphorylates Grb7 in a kinase-activity-dependent and cell-adhesion-dependent manner, and Grb7 is a physiological substrate of FAK (phosphorylation reduced in FAK-/- cells). Deletion mutants and chimeric molecules; focal contacts localization by microscopy; FAK-/- fibroblasts; tetracycline-regulated expression; migration assay The Journal of biological chemistry High 10893408
2000 Tyrosine-phosphorylated caveolin-1 (at Tyr-14, phosphorylated by c-Src) binds to Grb7 via its SH2 domain both in vitro and in vivo; this interaction augments anchorage-independent growth and EGF-stimulated cell migration. In vitro GST pulldown; co-immunoprecipitation; monoclonal antibody specific for pTyr-14 caveolin-1; functional migration and growth assays Molecular endocrinology High 11075810
2000 Grb7 interacts with the Rho family GTPase Rnd1 (constitutively GTP-bound); the interaction involves the switch II loop of Rnd1 and the SH2 domain of Grb7; confirmed by two-hybrid, in vitro binding, and pulldown from SKBR3 cells. Yeast two-hybrid; in vitro binding; GST pulldown from breast cancer cell line FEBS letters Medium 10664463
2000 Grb7 binds activated insulin receptors (via both SH2 domain and PIR/phosphotyrosine-interacting region) but is not a substrate of the insulin receptor tyrosine kinase; it preferentially associates with the insulin receptor over EGFR, FGF receptor, and Ret. Yeast two-hybrid; GST pulldown; co-immunoprecipitation; domain deletion analysis Oncogene Medium 10803466
2001 Targeting Grb7 (as Grb7-FAT chimera) to focal contacts stimulates cell migration but not cell cycle progression; distinct FAK signaling complexes regulate cell migration (Grb7) vs. cell cycle progression (Grb2). Chimeric fusion proteins (FAT sequence fused to signaling molecules); cell migration assay; cell cycle analysis FEBS letters Medium 11418135
2002 The SH2 domain of Grb7 interacts with EphB1 receptor at Tyr-928 (primary site); EphB1 autophosphorylation is required for the interaction; EphB1 phosphorylates Grb7; co-expression of Grb7 with EphB1 enhances fibroblast motility while the Grb7 SH2 domain alone inhibits EphB1-stimulated migration. Yeast two-hybrid; co-immunoprecipitation; site-directed mutagenesis of EphB1; cell motility assay; EphB1 ligand (ephrinB1) stimulation The Journal of biological chemistry High 12223469
2002 The Grb7 PH domain binds phosphoinositides (with preference for D3- and D5-phosphoinositides) both in vitro and in intact cells; PH domain-phosphoinositide interaction is required for FAK-mediated phosphorylation of Grb7 (though not for Grb7-FAK interaction or focal contact recruitment) and contributes to Grb7-stimulated cell migration; PI 3-kinase activity regulates this interaction. Lipid-binding assay in vitro; intact cell phosphoinositide binding; deletion mutants; PI3K inhibitor; FAK-/- cells; migration assay The Journal of biological chemistry High 12021278
2002 Novel non-phosphorylated peptides with a YXN motif bind selectively to the Grb7 SH2 domain (not Grb2 or Grb14 SH2); the cyclic structure is required for binding; the peptide G7-18 inhibits Grb7 association with ErbB family RTKs (particularly ErbB3) in cell lysates in a dose-dependent manner. Phage display random peptide libraries; competition binding assays; cell lysate immunoprecipitation inhibition The Journal of biological chemistry High 11809769
2003 Solution NMR structure of the human Grb7 SH2 domain in complex with the ErbB2 pY1139 phosphopeptide; the erbB2 peptide binds in a beta-turn conformation; structural basis for recognition specificity characterized. NMR spectroscopy; solution structure determination Journal of biomolecular NMR High 12975581
2003 Grb7 binds to the immunoglobulin superfamily receptor G6f via the Grb7 SH2 domain in a phosphorylation-dependent manner (pY281 of G6f); antibody cross-linking of G6f activates MAP kinase signaling. GST pulldown; immunoprecipitation; MAP kinase activation assay with MEK inhibitors The Biochemical journal Medium 12852788
2003 Grb7 (but not Grb10) inhibits FGF receptor-induced maturation in Xenopus oocytes; this correlates with Grb7 binding to the receptor and inhibition of the Ras-dependent pathway; PIR and SH2 domains of Grb7 are differentially involved in FGFR signaling inhibition. Xenopus oocyte maturation assay; injection of Grb7 protein; domain deletion analysis FEBS letters Medium 12885405
2005 Grb7 and its variant GRB7V are calmodulin (CaM)-binding proteins; the CaM-binding domain maps to an amphiphilic helix at residues 243-256 in the proximal PH domain region; CaM competes with phosphoinositide binding to Grb7; CaM regulates intracellular mobilization of Grb7 and its membrane association; ErbB2 activation by heregulin decreases membrane-associated Grb7 in a CaM-dependent manner. CaM-affinity chromatography; biotinylated CaM overlay; deletion mutants; phosphoinositide competition; cell-permeable CaM inhibitory peptides; FRET between EYFP-Grb7 and ECFP-CaM in living cells Oncogene High 15806159
2007 Grb7 is an RNA-binding protein that serves as a molecular adaptor linking Netrin-1/FAK signaling to translational regulation; Grb7 binds the first stem loop of kappa opioid receptor (KOR) mRNA 5'-UTR and blocks eIF4E recruitment, repressing translation; FAK-mediated hyperphosphorylation of two C-terminal tyrosines of Grb7 reduces its RNA-binding and translation-repressive activity. RNA-binding assay; in vitro translation assay; FAK phosphorylation assay; co-immunoprecipitation; domain deletion and mutagenesis The EMBO journal High 17318180
2007 Crystal structure of the Grb7 SH2 domain solved to 2.1 Å resolution; the SH2 domain dimerizes with KD in the μM range (both for full-length Grb7 and SH2 domain alone); G7-18NATE cyclic peptide binds Grb7-SH2 with KD ~35.7 μM and disrupts both the ligand-binding surface and the dimer interface. X-ray crystallography (2.1 Å); analytical ultracentrifugation; ITC; NMR spectroscopy titration BMC structural biology High 17894853
2008 Grb7 is an integral component of stress granules (SGs) and directly interacts with HuR; Grb7 is required for SG formation in response to stress; upon stress termination, FAK hyperphosphorylates Grb7, causing loss of HuR interaction and Grb7 dissociation from SG components, thereby driving SG disassembly; dominant-negative hypophospho-mutants of FAK and Grb7 attenuate SG disassembly. Co-immunoprecipitation; stress granule immunofluorescence; dominant-negative mutants; FAK kinase assay; siRNA knockdown The EMBO journal High 18273060
2009 Grb7 interacts with the transcriptional regulator FHL2 via its RA and PH domains (not the SH2 domain); this interaction occurs in mammalian cells and requires Grb7 to be tyrosine phosphorylated; NMR evidence supports a model of Grb7 autoinhibition via intramolecular domain association. Yeast two-hybrid; co-immunoprecipitation; immunofluorescence; NMR Journal of molecular recognition Medium 18853468
2010 EGF-induced Grb7 tyrosine phosphorylation/activation recruits and activates Ras GTPases, subsequently promotes ERK1/2 phosphorylation, and drives tumor growth; Grb7 forms a signaling complex with EGFR and Ras. Co-immunoprecipitation; RasGTP pulldown assay; siRNA knockdown; xenograft tumor model; Western blot The Journal of biological chemistry Medium 20622016
2010 GRB7 overexpression facilitates HER2/Neu tyrosine phosphorylation and activates downstream PLC-γ1/PKC and AKT pathways; conversely, GRB7 knockdown decreases HER2 tyrosine phosphorylation and AKT phosphorylation in breast cancer cells. Overexpression and siRNA knockdown; immunoblotting for phospho-HER2, phospho-AKT, phospho-PLC-γ1, MARCKS phosphorylation; xenograft tumor growth Carcinogenesis Medium 17916906
2010 Grb7 upregulation following lapatinib (HER2/PI3K inhibitor) treatment is driven by relief of Akt-mediated transcriptional repression of GRB7; constitutively active Akt prevents Grb7 upregulation; Grb7 removal by siRNA reduces breast cancer cell viability and enhances lapatinib activity. Retroviral transgenesis of constitutively active Akt; siRNA; quantitative PCR; Western blot; xenograft model PloS one Medium 20126311
2011 GRB7 inhibition reduces cell motility and invasion in triple-negative breast cancer cell lines and promotes apoptosis in 3D culture. siRNA knockdown; Boyden chamber migration/invasion assay; 3D culture apoptosis assay Breast cancer research and treatment Medium 22005836
2011 Full-length Grb7 can exist in a head-to-tail conformational state; Grb7 RA-PH domains bind the Grb7 SH2 domain with micromolar affinity (by ITC), suggesting intramolecular autoinhibition; Grb7 also interacts with Hax-1 (a cytoskeletal/anti-apoptotic protein) via RA and PH domains. Yeast two-hybrid; co-immunoprecipitation; ITC (intramolecular RA-PH vs SH2 binding) Journal of molecular recognition Medium 20665473
2011 Crystal structure of the G7-18NATE cyclic peptide in complex with the Grb7 SH2 domain determined; key contacts involve peptide residues F2, G4, F9, and YDN motif; additional phage display identified analogues with micromolar affinity retaining the same contact residues. X-ray crystallography; phage display; ITC Journal of molecular biology High 21802427
2012 GRB7 overexpression or knockdown in ovarian cancer cells modulates ERK phosphorylation and FOXM1 levels in an ordered cascade (GRB7→ERK→FOXM1); FOXM1 overexpression cannot alter GRB7 or ERK levels, establishing GRB7 is upstream; GRB7 promotes cell migration/invasion through JNK signaling while proliferation involves ERK. Western blot; enforced expression and siRNA knockdown; specific kinase inhibitors (U0126, PD98059); FOXM1 inhibitor; cell migration/invasion assay; xenograft model PloS one Medium 23285101
2012 Grb7 SH2 domain dimerizes (KD ~11 μM); mutation of Phe511 to Arg produces a monomeric SH2 domain; phosphorylation-mimic mutation Y80E in the SH2 domain impairs dimerization and alters thermodynamic characteristics of phosphotyrosine peptide binding. Sedimentation equilibrium ultracentrifugation; size-exclusion chromatography; site-directed mutagenesis; ITC; circular dichroism Journal of molecular recognition / European biophysics journal High 15841400 22811067
2012 GRB7 is identified as a context-dependent oncogene in the 17q12-21 amplicon; GRB7 overexpression enhances ERBB2 phosphorylation and AKT phosphorylation in an ERBB2-dependent context. Retrovirus-mediated gene transfer; expression screening; Western blot for phospho-ERBB2 and phospho-AKT FEBS letters Medium 22584052
2012 Calmodulin regulates Grb7 nuclear translocation; a nuclear localization signal (NLS) overlaps the CaM-binding domain of Grb7; deletion of the CaM-binding domain prevents nuclear localization; CaM antagonist W-7 enhances Grb7 nuclear presence. Confocal microscopy; deletion mutants; CaM antagonist W-7 treatment; cellular fractionation FEBS letters Medium 22673522
2013 In HER2+ breast cancer cells, GRB7 recruits SHC into the HER2-GRB7 signaling complex leading to RAS-GTP activation (proliferation); following integrin engagement, GRB7 is phosphorylated at tyrosine by FAK (pY397-dependent), and the FAK-GRB7 complex activates RAC1-GTP through recruitment of VAV2 (migration); GRB7 directly binds VAV2 after fibronectin engagement. Co-immunoprecipitation; RasGTP and Rac1-GTP pulldown assays; siRNA knockdown; fibronectin-stimulated adhesion; proliferation and migration assays American journal of cancer research Medium 23593540
2013 Deletion of the calmodulin-binding domain of Grb7 impairs cell migration, cell attachment to extracellular matrix, and actin cytoskeleton reorganization; cell-permeable CaM antagonists (W-7, W-13) inhibit migration of cells expressing wild-type Grb7 but not Grb7Δ, confirming CaM binding to Grb7 is required for normal Grb7-mediated migration. Deletion mutant expression; wound healing and Boyden chamber migration assay; CaM antagonists; cell attachment assay; actin staining Biochemical and biophysical research communications Medium 23743201
2013 Grb7 interacts with Filamin-a (actin-crosslinking cytoskeletal protein) via the Grb7 RA-PH domains and Filamin-a immunoglobulin-like repeat domains 16-19; Grb7 and Filamin-a co-localize in membrane ruffles upon EGF stimulation. Yeast two-hybrid; Co-immunoprecipitation; in vitro binding; immunofluorescence microscopy Journal of molecular recognition Medium 24089360
2016 Pin1 negatively regulates Grb7 stability: JNK phosphorylates Grb7 on the Ser194-Pro motif, facilitating binding to Pin1's WW domain; Pin1's peptidyl-prolyl isomerase activity then promotes Grb7 degradation via the ubiquitin-proteasome pathway; Pin1-mediated Grb7 degradation affects G2-M cell cycle progression. Co-immunoprecipitation; ubiquitin-proteasome inhibitor (MG-132); Pin1 WW domain binding assay; cell cycle analysis; JNK inhibitor; mutagenesis of Ser194 PloS one Medium 27658202
2017 X-ray crystal structure of bicyclic peptide inhibitor G7-B4 in complex with the Grb7-SH2 domain determined; Arg462 in the BC loop is a key specificity determinant for G7-18NATE; Leu at the βD6 position is required for Grb7-SH2 binding; the closed staple linkage is essential for target interaction. X-ray crystallography; surface plasmon resonance (SPR); SH2 domain microarray (79 SH2 domains); mutagenesis Scientific reports / Journal of medicinal chemistry High 27257138 29083893
2020 Calmodulin directly interacts with full-length Grb7 in a calcium-dependent manner; interaction is mediated through the RA-PH domain of Grb7 (not the SH2 domain); measured by surface plasmon resonance. SPR with purified full-length Grb7, RA-PH domain, and SH2 domain International journal of molecular sciences High 32079204
2021 Genome-wide CRISPR/Cas9 screen identified GRB7 as a driver of MEK inhibitor resistance in KRAS-mutant colorectal cancer; mass spectrometry of GRB7 immunoprecipitates identified PLK1 as the predominant interacting kinase; PLK1 inhibition suppresses FAK, STAT3, AKT, and 4EBP1 signaling downstream of RTK; combined PLK1 + MEK inhibition synergistically inhibits CRC cell proliferation and induces apoptosis. Genome-wide CRISPR/Cas9 screen; mass spectrometry of GRB7 immunoprecipitates; gain- and loss-of-function assays; combination drug treatment in vitro and in vivo xenograft Oncogene Medium 34718347
2016 Grb7 and Hax1 co-localize partially to mitochondria in EGF-treated SKBR3 cells; Grb7 can affect Caspase3 cleavage of Hax1 isoform 1 in vitro; Grb7 expression slows Caspase3-mediated Hax1 cleavage in apoptotic cells and increases cell viability in apoptotic HeLa cells. Co-immunoprecipitation; immunofluorescence; in vitro Caspase3 cleavage assay; cell viability assay Journal of molecular recognition Low 26869103
2024 GRB7 interacts with Notch1 to activate Wnt/β-catenin pathways and promote EMT progression in HER2+ breast cancer; TCF12 transcription factor directly binds the GRB7 gene promoter (by ChIP) and promotes its transcription. RNA sequencing; ChIP-PCR; luciferase reporter assay; co-immunoprecipitation; xenograft model; siRNA knockdown Journal of translational medicine Medium 39113057

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette. Molecular endocrinology (Baltimore, Md.) 291 11075810
1994 The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. The EMBO journal 220 7907978
1999 Association of focal adhesion kinase with Grb7 and its role in cell migration. The Journal of biological chemistry 197 10446223
2001 The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions. Oncogene 153 11607834
1996 Cloning and characterization of GRB14, a novel member of the GRB7 gene family. The Journal of biological chemistry 117 8647858
1998 The Grb7 family of signalling proteins. Cellular signalling 109 9794242
1999 Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor. The Biochemical journal 98 10377264
2000 Role of Grb7 targeting to focal contacts and its phosphorylation by focal adhesion kinase in regulation of cell migration. The Journal of biological chemistry 93 10893408
1996 Use of the two hybrid system to detect the association of the protein-tyrosine-phosphatase, SHPTP2, with another SH2-containing protein, Grb7. Oncogene 89 8622870
2005 Expression of HER2 and the coamplified genes GRB7 and MLN64 in human breast cancer: quantitative real-time reverse transcription-PCR as a diagnostic alternative to immunohistochemistry and fluorescence in situ hybridization. Clinical cancer research : an official journal of the American Association for Cancer Research 88 16322295
2001 Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts. FEBS letters 85 11418135
1997 Coexpression of Grb7 with epidermal growth factor receptor or Her2/erbB2 in human advanced esophageal carcinoma. Cancer research 84 8988034
2004 Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon. International journal of oncology 83 15010812
2002 Identification of novel non-phosphorylated ligands, which bind selectively to the SH2 domain of Grb7. The Journal of biological chemistry 83 11809769
2008 Regulation of stress granule dynamics by Grb7 and FAK signalling pathway. The EMBO journal 82 18273060
1998 Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3. The Journal of biological chemistry 81 9516479
1996 Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7. The Journal of biological chemistry 77 8631863
2006 Specific peptide ligand for Grb7 signal transduction protein and pancreatic cancer metastasis. Journal of the National Cancer Institute 76 16595785
2002 EphB1 associates with Grb7 and regulates cell migration. The Journal of biological chemistry 76 12223469
1998 A novel variant of human Grb7 is associated with invasive esophageal carcinoma. The Journal of clinical investigation 72 9710451
2003 MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. International journal of oncology 71 12739007
1997 Structural determinants of the interaction between the erbB2 receptor and the Src homology 2 domain of Grb7. The Journal of biological chemistry 69 9079677
2004 Grb7 in intracellular signaling and its role in cell regulation. Frontiers in bioscience : a journal and virtual library 67 14766359
2018 Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways. Theranostics 66 29290818
1996 Grb7 is a downstream signaling component of platelet-derived growth factor alpha- and beta-receptors. The Journal of biological chemistry 66 8940081
2007 Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells. British journal of cancer 62 17426702
2021 Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer. Oncogene 60 34718347
2011 GRB7 is required for triple-negative breast cancer cell invasion and survival. Breast cancer research and treatment 52 22005836
2002 Association of Grb7 with phosphoinositides and its role in the regulation of cell migration. The Journal of biological chemistry 51 12021278
2007 GRB-7 facilitates HER-2/Neu-mediated signal transduction and tumor formation. Carcinogenesis 48 17916906
2000 Grb7 signal transduction protein mediates metastatic progression of esophageal carcinoma. Journal of cellular physiology 48 10797316
2012 Targeting GRB7/ERK/FOXM1 signaling pathway impairs aggressiveness of ovarian cancer cells. PloS one 47 23285101
2000 Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2. Oncogene 47 10803466
2019 Grb7, a Critical Mediator of EGFR/ErbB Signaling, in Cancer Development and as a Potential Therapeutic Target. Cells 46 31083325
2010 EGF-induced Grb7 recruits and promotes Ras activity essential for the tumorigenicity of Sk-Br3 breast cancer cells. The Journal of biological chemistry 46 20622016
2007 The adaptor Grb7 links netrin-1 signaling to regulation of mRNA translation. The EMBO journal 45 17318180
1999 Sequence analysis identifies a ras-associating (RA)-like domain in the N-termini of band 4.1/JEF domains and in the Grb7/10/14 adapter family. Biochemical and biophysical research communications 45 10334925
1997 Molecular cloning of human GRB-7 co-amplified with CAB1 and c-ERBB-2 in primary gastric cancer. Biochemical and biophysical research communications 41 9125150
2010 GRB7 protein over-expression and clinical outcome in breast cancer. Breast cancer research and treatment 40 20635137
2010 Differential functions of growth factor receptor-bound protein 7 (GRB7) and its variant GRB7v in ovarian carcinogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 39 20388850
2004 Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma. International journal of cancer 39 15386389
2007 Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation. BMC structural biology 38 17894853
2010 Grb7 upregulation is a molecular adaptation to HER2 signaling inhibition due to removal of Akt-mediated gene repression. PloS one 36 20126311
2013 Dissecting GRB7-mediated signals for proliferation and migration in HER2 overexpressing breast tumor cells: GTP-ase rules. American journal of cancer research 35 23593540
2003 Grb7-based molecular therapeutics in cancer. Expert reviews in molecular medicine 34 14585167
2017 GRB7 Expression and Correlation With HER2 Amplification in Invasive Breast Carcinoma. Applied immunohistochemistry & molecular morphology : AIMM 30 26945445
2020 Aquaporin-1 facilitates proliferation and invasion of gastric cancer cells via GRB7-mediated ERK and Ras activation. Animal cells and systems 29 33209198
2005 The adaptor Grb7 is a novel calmodulin-binding protein: functional implications of the interaction of calmodulin with Grb7. Oncogene 29 15806159
2003 Solution structure of the human Grb7-SH2 domain/erbB2 peptide complex and structural basis for Grb7 binding to ErbB2. Journal of biomolecular NMR 27 12975581
2004 Grb7 expression and cellular migration in chronic lymphocytic leukemia: a comparative study of early and advanced stage disease. Leukemia 26 15470489
2008 Genomic organization and control of the grb7 gene family. Current genomics 25 19424485
2005 Grb7-SH2 domain dimerisation is affected by a single point mutation. European biophysics journal : EBJ 25 15841400
2000 Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family. FEBS letters 24 10664463
2012 Expression screening of 17q12-21 amplicon reveals GRB7 as an ERBB2-dependent oncogene. FEBS letters 23 22584052
2017 Discovery, Development, and Cellular Delivery of Potent and Selective Bicyclic Peptide Inhibitors of Grb7 Cancer Target. Journal of medicinal chemistry 22 29083893
2020 Upregulated GRB7 promotes proliferation and tumorigenesis of Bladder Cancer via Phospho-AKT Pathway. International journal of biological sciences 20 33162827
2011 Structural basis of binding by cyclic nonphosphorylated peptide antagonists of Grb7 implicated in breast cancer progression. Journal of molecular biology 20 21802427
2019 Epigenetically altered miR‑193a‑3p promotes HER2 positive breast cancer aggressiveness by targeting GRB7. International journal of molecular medicine 19 31017268
2011 Relationship between quantitative GRB7 RNA expression and recurrence after adjuvant anthracycline chemotherapy in triple-negative breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 19 21933890
2003 Inhibition of FGF receptor signalling in Xenopus oocytes: differential effect of Grb7, Grb10 and Grb14. FEBS letters 19 12885405
2015 Cyclic Peptides Incorporating Phosphotyrosine Mimetics as Potent and Specific Inhibitors of the Grb7 Breast Cancer Target. Journal of medicinal chemistry 17 26359549
2014 Context-dependent role of Grb7 in HER2+ve and triple-negative breast cancer cell lines. Breast cancer research and treatment 17 24464577
2013 Targeting the calmodulin-regulated ErbB/Grb7 signaling axis in cancer therapy. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 17 23958188
2009 The cell migration protein Grb7 associates with transcriptional regulator FHL2 in a Grb7 phosphorylation-dependent manner. Journal of molecular recognition : JMR 17 18853468
2020 GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma. The Journal of pathology 16 32737994
2017 Shortened Penetratin Cell-Penetrating Peptide Is Insufficient for Cytosolic Delivery of a Grb7 Targeting Peptide. ACS omega 16 29152602
2016 Unexpected involvement of staple leads to redesign of selective bicyclic peptide inhibitor of Grb7. Scientific reports 16 27257138
2013 Nuclear magnetic resonance imaging of tumour growth and neovasculature performance in vivo reveals Grb7 as a novel antiangiogenic target. NMR in biomedicine 16 23348935
2012 Calmodulin regulates the translocation of Grb7 into the nucleus. FEBS letters 16 22673522
2007 Calorimetric investigation of phosphorylated and non-phosphorylated peptide ligand binding to the human Grb7-SH2 domain. Journal of molecular recognition : JMR 16 17705331
2003 Adaptor signalling proteins Grb2 and Grb7 are recruited by human G6f, a novel member of the immunoglobulin superfamily encoded in the MHC. The Biochemical journal 16 12852788
2012 Interaction of the non-phosphorylated peptide G7-18NATE with Grb7-SH2 domain requires phosphate for enhanced affinity and specificity. Journal of molecular recognition : JMR 15 22213451
2007 NMR analysis of G7-18NATE, a nonphosphorylated cyclic peptide inhibitor of the Grb7 adapter protein. Biopolymers 14 17206629
2017 Grb7 is over-expressed in cervical cancer and facilitate invasion and inhibit apoptosis in cervical cancer cells. Pathology, research and practice 13 28780081
2005 Backbone nuclear relaxation characteristics and calorimetric investigation of the human Grb7-SH2/erbB2 peptide complex. Protein science : a publication of the Protein Society 13 15930003
2013 Deletion of the calmodulin-binding domain of Grb7 impairs cell attachment to the extracellular matrix and migration. Biochemical and biophysical research communications 12 23743201
2013 Grb7 and Filamin-a associate and are colocalized to cell membrane ruffles upon EGF stimulation. Journal of molecular recognition : JMR 12 24089360
2011 Grb7 binds to Hax-1 and undergoes an intramolecular domain association that offers a model for Grb7 regulation. Journal of molecular recognition : JMR 12 20665473
1998 Expression of Grb7 growth factor receptor signaling protein in kidney development and in adult kidney. The American journal of physiology 12 9815134
2012 The discovery of phenylbenzamide derivatives as Grb7-based antitumor agents. ChemMedChem 11 23355456
2008 Development of binding assays for the SH2 domain of Grb7 and Grb2 using fluorescence polarization. Journal of biomolecular screening 11 18216394
2023 GRB7 plays a promoting role in the progression of gastric cancer. BMC cancer 10 38129809
2016 Grb7 and Hax1 may colocalize partially to mitochondria in EGF-treated SKBR3 cells and their interaction can affect Caspase3 cleavage of Hax1. Journal of molecular recognition : JMR 10 26869103
2013 Design and testing of bicyclic inhibitors of Grb7--are two cycles better than one? Biopolymers 10 23505041
2012 Dimerization in the Grb7 protein. Journal of molecular recognition : JMR 10 22811067
2023 Up-regulated GRB7 protein in gastric cancer cells correlates with clinical properties and increases proliferation and stem cell properties. Frontiers in oncology 9 36686796
2016 Grb7 Protein Stability Modulated by Pin1 in Association with Cell Cycle Progression. PloS one 9 27658202
2024 TCF12-regulated GRB7 facilitates the HER2+ breast cancer progression by activating Notch1 signaling pathway. Journal of translational medicine 8 39113057
2019 GRB7 dependent proliferation of basal-like, HER-2 positive human breast cancer cell lines is mediated in part by HER-1 signaling. Molecular carcinogenesis 8 30604896
2017 Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target. Frontiers in molecular biosciences 8 29018805
2012 Novel nonphosphorylated peptides with conserved sequences selectively bind to Grb7 SH2 domain with affinity comparable to its phosphorylated ligand. PloS one 8 22253820
2022 Association of genetic ancestry with HER2, GRB7 AND estrogen receptor expression among Colombian women with breast cancer. Frontiers in oncology 7 36620598
2020 Grb7-derived calmodulin-binding peptides inhibit proliferation, migration and invasiveness of tumor cells while they enhance attachment to the substrate. Heliyon 7 32420488
2010 The intertwining of structure and function: proposed helix-swapping of the SH2 domain of Grb7, a regulatory protein implicated in cancer progression and inflammation. Critical reviews in immunology 7 20370637
2020 Direct Interaction between Calmodulin and the Grb7 RA-PH Domain. International journal of molecular sciences 6 32079204
2012 Conservation and divergence of Grb7 family of Ras-binding domains. Protein & cell 6 22271596
2010 Preparation and crystallization of the Grb7 SH2 domain in complex with the G7-18NATE nonphosphorylated cyclic inhibitor peptide. Acta crystallographica. Section F, Structural biology and crystallization communications 6 21139214
2007 Transduced PEP-1-Grb7 fusion protein suppressed LPS-induced COX-2 expression. Journal of biochemistry and molecular biology 6 17394768
2019 Evaluation of Cyclic Peptide Inhibitors of the Grb7 Breast Cancer Target: Small Change in Cargo Results in Large Change in Cellular Activity. Molecules (Basel, Switzerland) 5 31627265
2014 Preparation of crystals for characterizing the Grb7 SH2 domain before and after complex formation with a bicyclic peptide antagonist. Acta crystallographica. Section F, Structural biology communications 5 24637751