Affinage

GRB14

Growth factor receptor-bound protein 14 · UniProt Q14449

Length
540 aa
Mass
61.0 kDa
Annotated
2026-04-28
52 papers in source corpus 33 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRB14 is a multidomain adaptor protein that functions as a tissue-specific negative regulator of receptor tyrosine kinase signaling, most prominently insulin receptor (IR) signaling. Its BPS/PIR domain acts as a pseudosubstrate inhibitor occupying the IR kinase substrate-binding groove, while its SH2 domain docks to IR activation-loop phosphotyrosines; together these interactions suppress IRS-1 phosphorylation and downstream Akt/ERK activation, as demonstrated by crystal structures, in vitro kinase assays, and improved glucose homeostasis in Grb14 knockout mice (PMID:16246733, PMID:11726652, PMID:14749734). Beyond IR, GRB14 inhibits FGFR1 signaling by competitively displacing PLCγ from pY766 via its SH2 domain (PMID:20932831), inhibits CEACAM3-mediated phagocytosis (PMID:22948154), and when phosphorylated on Tyr-347 by Src acts as an endogenous inhibitor of PTP1B in the retina (PMID:21791607). GRB14 activity is regulated by PKCζ-mediated phosphorylation (enhanced IR inhibition) (PMID:12242277), GSK-3 phosphorylation of BPS-domain serines (which opposes IR binding and is reversed by PP1) (PMID:24535599, PMID:31347216), binding to activated Ras through its integrated RA-PH structural unit (PMID:19648926), and interaction with p62/SQSTM1 to modulate the Nrf2–LXR lipogenic pathway in liver (PMID:27215388).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 Medium

    Identification of GRB14 as a new GRB7-family adaptor with PH, BPS, and SH2 domains that binds activated PDGF receptors established it as a candidate RTK-signaling adaptor.

    Evidence cDNA library cloning, GST-SH2 pulldown with PDGFR, serine phosphorylation analysis

    PMID:8647858

    Open questions at the time
    • No endogenous function demonstrated
    • PDGFR binding not confirmed by reciprocal IP
    • In vivo relevance unknown
  2. 1998 High

    Demonstration that Grb14 binds the insulin receptor in an insulin-dependent manner via two domains (PIR/BPS and SH2) and that overexpression suppresses IRS-1 phosphorylation, DNA synthesis, and glycogen synthesis established GRB14 as a negative regulator of insulin signaling.

    Evidence Yeast two-hybrid, co-IP with IR deletion/point mutants (Y1150/Y1151), overexpression in CHO cells

    PMID:9748281

    Open questions at the time
    • Mechanism of inhibition (competitive vs. pseudosubstrate) unresolved
    • In vivo relevance not tested
    • Contribution of individual domains not fully dissected
  3. 2000 High

    Extending the adaptor's scope beyond IR, binding to activated FGFR1 and inhibition of FGF-induced proliferation revealed GRB14 as a broader RTK-signaling inhibitor.

    Evidence Yeast two-hybrid, co-IP, domain deletion analysis, cell proliferation assay in FGFR1-expressing cells

    PMID:10713090

    Open questions at the time
    • Mechanism of FGFR inhibition not identified
    • Relative contribution of SH2 vs. upstream regions unclear
  4. 2001 High

    In vitro kinase assays showed the BPS/PIR domain alone inhibits IR kinase activity toward substrates without altering ATP Km, establishing an uncompetitive pseudosubstrate inhibition mechanism and linking this to delayed Akt/ERK activation in cells.

    Evidence In vitro IR kinase assay with purified BPS domain, CHO cell overexpression, phospho-specific Western blots

    PMID:11726652

    Open questions at the time
    • Structural basis of pseudosubstrate mechanism not yet solved
    • In vivo significance not demonstrated
  5. 2002 High

    Discovery of the PKCζ–ZIP–Grb14 trimeric complex and PKCζ-dependent phosphorylation of Grb14 that enhances its IR-inhibitory activity identified a regulatory input controlling GRB14 potency.

    Evidence Co-IP, in vitro/in vivo kinase assay, Xenopus oocyte insulin-maturation assay with epistasis analysis

    PMID:12242277

    Open questions at the time
    • Phosphorylation sites on Grb14 not mapped
    • Relevance in mammalian metabolic tissues not tested
  6. 2004 High

    Grb14 knockout mice showed improved glucose tolerance, lower insulin levels, and enhanced IRS-1/Akt signaling specifically in liver and muscle but not adipose, providing the first in vivo genetic evidence that GRB14 is a tissue-specific physiological brake on insulin action.

    Evidence Grb14−/− mouse model with glucose tolerance tests, insulin signaling assays, ex vivo glucose uptake

    PMID:14749734

    Open questions at the time
    • Molecular basis for tissue specificity unclear
    • Compensation by Grb10 not addressed
    • Lipogenic consequences not explored
  7. 2004 High

    Identification of constitutive Grb14–PDK-1 binding through a distinct motif, which recruits PDK-1 to the IR and is required for full insulin-stimulated Akt activation, revealed a paradoxical positive-signaling role for an otherwise inhibitory adaptor.

    Evidence Co-IP, membrane translocation assay, dominant-negative disruption, Akt phosphorylation readout

    PMID:15210700

    Open questions at the time
    • Relative contribution of positive (PDK-1 recruitment) vs. negative (pseudosubstrate) roles not quantified
    • PDK-1 binding site not structurally characterized
  8. 2005 High

    The crystal structure of the BPS region bound to the IR kinase domain at atomic resolution confirmed the pseudosubstrate model: the BPS N-terminus occupies the substrate-binding groove, providing the structural basis for GRB14's inhibitory mechanism.

    Evidence X-ray crystallography of BPS–IR kinase complex and SH2 domain

    PMID:16246733

    Open questions at the time
    • Full-length Grb14–IR complex structure not available
    • Dynamics of engagement/disengagement not addressed
  9. 2006 High

    Real-time BRET in living cells showed that Grb14 recruitment to IR is rapid and dose-dependent, that Grb14 reduces IR–PTP1B interaction while selectively promoting dephosphorylation of Y972 (the IRS-1 docking site) and protecting activation-loop phosphotyrosines, mechanistically explaining site-selective signal attenuation.

    Evidence BRET donor/acceptor pairs in HEK cells, site-specific phospho-antibodies, co-IP

    PMID:16582879 PMID:16934761

    Open questions at the time
    • Insulin-induced Grb14 dimerization function unclear
    • Whether PTP1B modulation occurs in all IR-expressing tissues unknown
  10. 2008 High

    Hepatocyte Grb14 knockdown revealed a dual role: while enhancing proximal IR signaling, it abolished SREBP-1c maturation and lipogenic gene expression, showing GRB14 promotes a distal lipogenic step independently of its kinase-inhibitory function.

    Evidence siRNA knockdown in primary mouse hepatocytes with Akt/FOXO1 phosphorylation, SREBP-1c processing, and gluconeogenesis assays

    PMID:18339716

    Open questions at the time
    • Mechanism linking Grb14 to SREBP-1c maturation not identified
    • Whether this is direct or via intermediary pathway unknown
  11. 2009 High

    Crystal structure of the RA-PH integrated unit bound to GTP-loaded H-Ras established that GRB14 directly engages activated Ras, potentially serving as a timing mechanism linking Ras activity to insulin-signaling downregulation.

    Evidence X-ray crystallography at 2.4 Å, biochemical Ras-binding assays

    PMID:19648926

    Open questions at the time
    • Functional consequence of Ras binding on IR inhibition not tested in cells
    • Whether Ras binding recruits Grb14 to specific membrane microdomains unknown
  12. 2010 High

    Demonstration that Grb14 SH2 domain binds FGFR1 pY766 (the PLCγ docking site) in a trimeric complex, competitively trapping and inactivating PLCγ, provided the mechanism for GRB14's inhibition of FGFR signaling.

    Evidence BRET, co-IP, PLCγ phosphorylation Western blot, Xenopus oocyte maturation assay

    PMID:20932831

    Open questions at the time
    • In vivo physiological relevance for FGFR regulation not demonstrated
    • Whether GRB14 inhibits other FGFR family members unknown
  13. 2011 High

    Src-mediated phosphorylation of BPS Tyr-347 converts GRB14 into an endogenous PTP1B inhibitor, as shown by elevated retinal PTP1B activity in Grb14 KO mice; this added a gain-of-function dimension to the adaptor.

    Evidence In vitro PTP1B assay, Y347 mutagenesis, Grb14 KO mouse retina, Src kinase activity measurement

    PMID:21791607

    Open questions at the time
    • Whether pY347-mediated PTP1B inhibition occurs outside the retina not tested
    • Structural basis of pY347–PTP1B interaction unknown
  14. 2012 High

    SH2 domain microarray and functional assays identified CEACAM3 as a GRB14 binding partner, with Grb14 rapidly recruited to bacteria-host contact sites to inhibit phagocytosis, extending GRB14 function to innate immunity.

    Evidence SH2 microarray, FRET-FLIM, RNAi knockdown and overexpression, phagocytosis assay

    PMID:22948154

    Open questions at the time
    • Mechanism of phagocytosis inhibition beyond SH2 binding not resolved
    • In vivo infection model not tested
  15. 2014 Medium

    Identification of GSK-3 as a kinase that phosphorylates BPS serines 358/362/366 to disrupt Grb14–IR complex formation, with PP1 serving as the opposing phosphatase, established a phosphorylation toggle controlling GRB14's access to its primary target.

    Evidence In vitro kinase/phosphatase assays, Ala/Glu substitutions, co-IP, SPR (Kd ~8 nM abolished by phosphomimetics)

    PMID:24535599 PMID:28130417 PMID:31347216

    Open questions at the time
    • Physiological contexts triggering GSK-3/PP1 regulation of Grb14 not defined
    • Whether priming at S370 is constitutive or regulated unknown
    • Single-lab findings
  16. 2015 High

    Identification of the Chfr ubiquitin ligase as an insulin-stimulated Grb14 partner that potentiates cell-cycle arrest by degrading Aurora A and Plk established a pathway by which GRB14 links insulin signaling to mitotic checkpoint control.

    Evidence Co-IP, Xenopus G2/M oocyte assay, mutagenesis of Chfr T39 and Grb14 T220, mammalian cell knockdown/overexpression

    PMID:25578860

    Open questions at the time
    • In vivo relevance for tumor suppression not shown
    • Whether Chfr–Grb14 interaction is direct or bridged unclear
  17. 2016 High

    Liver-specific Grb14 knockdown revealed that GRB14 sequesters p62/SQSTM1, and its loss releases p62 to activate Nrf2, which represses LXR-driven lipogenesis, resolving the molecular link between GRB14 and hepatic de novo lipogenesis.

    Evidence In vivo hepatic siRNA/shRNA, co-IP of Grb14–p62, Nrf2/LXR reporter assays, metabolic phenotyping in insulin-resistant mice

    PMID:27215388

    Open questions at the time
    • Direct binding interface between Grb14 and p62 not mapped
    • Interaction of this pathway with SREBP-1c maturation defect from 2008 study not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structural model of GRB14 bound to the intact IR, the precise mechanism linking GRB14 to SREBP-1c maturation, the physiological significance of Ras binding via the RA domain in metabolic tissues, and the in vivo relevance of GRB14 in innate immune phagocytosis remain unresolved.
  • No full-length Grb14–IR structure
  • SREBP-1c connection mechanistically unexplained
  • Ras–RA domain function not tested in metabolic models
  • CEACAM3 inhibition not validated in infection models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 2
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1430728 Metabolism 3 R-HSA-1640170 Cell Cycle 2
Partners
CHFRFGFR1INSRPDPK1PLCG1PRKCZSQSTM1TNKS2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 GRB14 was identified as a novel member of the GRB7 gene family containing a PH domain, a BPS/PIR region, and a C-terminal SH2 domain. The GST-Grb14 SH2 domain fusion protein exhibited strong binding to activated PDGF receptors in vitro, and Grb14 was phosphorylated on serine residues in a PDGF-regulated manner. cDNA library screening, GST pulldown, co-immunoprecipitation, Western blot The Journal of biological chemistry Medium 8647858
1998 Rat Grb14 binds to the insulin receptor (IR) in an insulin-dependent manner via two domains: the SH2 domain and a region between PH and SH2 domains (PIR/BPS), with PIR being the major binding domain. The interaction requires IR tyrosines Y1150/Y1151. Grb14 overexpression decreases insulin-stimulated IRS-1 tyrosine phosphorylation, DNA synthesis, and glycogen synthesis without altering IR autophosphorylation. Yeast two-hybrid, co-immunoprecipitation, in vitro binding with deletion mutants, cell-based overexpression assays The Journal of biological chemistry High 9748281
2000 Grb14 binds activated FGFR1 in a kinase-activity-dependent manner, requiring the FGFR1 C-tail tyrosines and juxtamembrane domain. The SH2 domain of Grb14 mediates binding but regions upstream of SH2 confer specificity for FGFR1 over PDGFR. Grb14 overexpression inhibits FGF-2-induced cell proliferation, whereas an SH2-binding-deficient mutant enhances it. Yeast two-hybrid, co-immunoprecipitation, in vitro binding assay, cell proliferation assay, domain deletion analysis The Journal of biological chemistry High 10713090
2001 Tankyrase 2, a poly(ADP-ribose) polymerase, was identified as a binding partner of Grb14 via yeast two-hybrid screening. The interaction is mediated by the N-terminal 110 amino acids of Grb14 and ankyrin repeats 10-19 of tankyrase 2. Both proteins co-localize in the low-density microsome fraction and co-immunoprecipitate in vivo. Yeast two-hybrid, co-immunoprecipitation, subcellular fractionation, deletion mapping The Journal of biological chemistry Medium 11278563
2001 Grb14 directly inhibits IR substrate phosphorylation in vitro, acting as an uncompetitive inhibitor for IR substrate without altering Km for ATP. The PIR/BPS domain alone mediates this inhibitory effect. Grb14 binding protects IR kinase-loop phosphotyrosines from phosphatases but delays downstream Akt and ERK1/2 activation. In vitro kinase assay, domain deletion analysis, CHO cell overexpression, Western blot The Journal of biological chemistry High 11726652
2002 ZIP (PKCζ interacting protein) binds Grb14 through its ZZ zinc finger domain interacting with the PIR region of Grb14, forming a PKCζ-ZIP-Grb14 heterotrimeric complex. PKCζ phosphorylates Grb14 in vitro and in vivo, and this phosphorylation increases Grb14's inhibitory effect on IR tyrosine kinase activity. In Xenopus oocytes, ZIP potentiates Grb14-mediated inhibition of insulin-induced maturation in a PKCζ- and phosphorylation-dependent manner. Co-immunoprecipitation, in vitro kinase assay, in vivo radiolabeling, Xenopus oocyte functional assay, domain deletion mapping Molecular and cellular biology High 12242277
2003 The PIR domain of Grb14 is an intrinsically unstructured protein by NMR analysis, yet retains biological activity as demonstrated by inhibition of insulin-induced meiosis reinitiation in Xenopus oocytes. NMR spectroscopy, Xenopus oocyte functional assay FEBS letters Medium 14623073
2003 Grb14 (but not Grb10) inhibits FGF receptor-induced maturation in Xenopus oocytes by binding to the receptor and inhibiting the Ras-dependent pathway. The PIR and SH2 domains of Grb14 have different roles in FGFR signaling inhibition compared to its paralogs. Xenopus oocyte maturation assay, co-immunoprecipitation FEBS letters Medium 12885405
2004 Grb14 knockout mice display improved glucose tolerance, lower circulating insulin, enhanced glycogen synthesis in liver and skeletal muscle, and increased insulin-induced IRS-1 and PKB phosphorylation in a tissue-specific manner (liver and skeletal muscle, but not adipose), demonstrating that Grb14 is a tissue-specific negative regulator of insulin signaling in vivo. Gene knockout mouse model, glucose tolerance test, insulin signaling assays (phosphorylation of IR, IRS-1, PKB), ex vivo glucose uptake The EMBO journal High 14749734
2004 The PIR domain of Grb14 is natively unfolded in solution (SAXS and CD analyses), with a potentially structured short stretch around residues 399-407 that may undergo structural transition upon binding to a partner. Small-angle X-ray scattering (SAXS), circular dichroism, NMR Biophysical journal Medium 15465854
2004 Grb14 binds PDK-1 constitutively through a PDK-1 binding motif on Grb14 (distinct from SH2 domain). This interaction facilitates insulin-triggered membrane translocation of PDK-1 to activated IR and promotes Akt phosphorylation. Disruption of the Grb14-PDK-1 interaction significantly decreases insulin-dependent Akt activation. Directed proteomics, co-immunoprecipitation, membrane translocation assay, dominant-negative overexpression, Akt activation assay The Journal of biological chemistry High 15210700
2005 Crystal structure of the Grb14 BPS region in complex with the insulin receptor tyrosine kinase domain reveals that the N-terminal portion of BPS acts as a pseudosubstrate inhibitor binding in the substrate peptide-binding groove of the kinase. Together with the SH2 domain crystal structure, a model for dual-domain engagement of IR by Grb14 is presented. X-ray crystallography (crystal structure of BPS-IR kinase domain complex and SH2 domain) Molecular cell High 16246733
2005 Grb14 overexpression inhibits insulin- and estrogen-induced cell cycle progression in MCF-7 breast cancer cells, associated with decreased ERK1/2 activation. Estradiol represses insulin-induced Grb14 expression, while anti-estrogen ICI 182780 increases Grb14 levels. Cell overexpression, cell cycle analysis, ERK1/2 phosphorylation assay, hormonal treatment Journal of cellular physiology Medium 15372466
2005 Grb14 contains an FXNPXY motif, and the PTB domain of IRS-1 binds to this NPXY motif of Grb14 in a phosphorylation-independent manner. Grb14-IRS-1 complexes are detected in retinal tissue lysates, suggesting Grb14 acts as a dominant negative for IRS-1 functions in the retina. Yeast two-hybrid (retinal cDNA library screen), GST pulldown, co-immunoprecipitation from retinal tissue Biochemistry Medium 15924411
2006 Real-time BRET analysis in living HEK cells shows that Grb14 is rapidly and dose-dependently recruited to the activated IR upon insulin stimulation. Grb14 reduces IR-PTP1B interaction (BRET), protects kinase-loop tyrosines from PTP1B dephosphorylation, while promoting dephosphorylation of Y972, thereby decreasing IRS-1 binding to IR and attenuating ERK pathway activation. Insulin also induces Grb14 dimerization. BRET (bioluminescence resonance energy transfer) in living cells, co-immunoprecipitation, site-specific phosphotyrosine antibodies EMBO reports High 16582879 16934761
2008 In rat liver, Grb14 localizes predominantly to microsomal and cytosolic fractions at baseline and translocates to the plasma membrane and Golgi/endosome fractions upon insulin stimulation, co-localizing with phosphorylated IR. KCl removal of Grb14 from fractions increases IR tyrosine kinase activity, demonstrating endogenous Grb14 exerts negative feedback on liver IR activity in vivo. Subcellular fractionation, co-immunoprecipitation, in vitro phosphatase assay, KCl extraction, in vivo rat liver model The FEBS journal High 18657188
2008 In primary hepatocytes with Grb14 knockdown, insulin-induced Akt phosphorylation and inhibition of gluconeogenesis are increased, but insulin-stimulated SREBP-1c maturation is completely blunted, blocking lipogenic gene expression and glycogen synthesis. This reveals a dual role for Grb14 in liver: inhibiting IR kinase activity and promoting a distal step (SREBP-1c maturation) required for lipogenic insulin action. RNAi knockdown in primary mouse hepatocytes, insulin signaling assays (Akt, GSK3, FOXO1 phosphorylation), gene expression analysis, glucose production measurement Endocrinology High 18339716
2009 Crystal structure of the Grb14 RA and PH domains at 2.4-Å resolution shows these domains form an integrated structural unit. Biochemical studies demonstrate that Grb14 binds to activated Ras (GTP-loaded), which may serve as a timing mechanism for downregulation of insulin signaling. The RA-PH unit can simultaneously engage small GTPases and phosphoinositide lipids. X-ray crystallography (RA-PH structure in complex with H-Ras G12V at 2.4-Å), biochemical binding assays Nature structural & molecular biology High 19648926
2009 Dual knockout of Grb10 and Grb14 in mice does not further increase IRS-1 phosphorylation and Akt activation beyond single knockouts, suggesting context-dependent limiting mechanisms including IR hypophosphorylation and decreased IRS-1 expression. Double KO mice are protected from high-fat diet-induced glucose intolerance whereas single KOs are not, suggesting additional glucose homeostasis regulatory mechanisms beyond IRS-1/Akt. Compound gene knockout mice, glucose tolerance test, insulin signaling assays, high-fat diet challenge Molecular endocrinology High 19541746
2009 Molecular determinants of Grb14-IR interaction include Grb14-L404 interacting with IR-L1038 (IR αC-helix) and Grb14-R385 interacting with IR-K1168 (activation loop), with L404 likely contributing to specificity for IR over other Grb7 family members. Grb14 S370 phosphorylation status controls its biological activity, and insulin-induced Grb14-PDK1 interaction is required for maximal inhibition of insulin signaling. Site-directed mutagenesis, co-immunoprecipitation, BRET, Xenopus oocyte assay, MEF functional complementation assay Molecular endocrinology High 19359342
2010 Grb14 inhibits FGFR signaling by being recruited to FGFR1 in a trimeric complex containing PLCγ. Grb14 binds to FGFR1 pY766 (the PLCγ docking site) via its SH2 domain, competitively trapping and inactivating PLCγ, and altering FGF-induced PLCγ phosphorylation and activation. BRET in living cells, Xenopus oocyte maturation assay, co-immunoprecipitation, Western blot for PLCγ phosphorylation FEBS letters High 20932831
2010 Tie2 receptor tyrosine kinase phosphorylates Grb14 on tyrosine residues in a manner requiring kinase-competent Tie2 and intact Tie2 tyrosines Y1100 and Y1106. A complete Grb14 SH2 domain is required for this phosphorylation. Grb14 tyrosine phosphorylation also occurs in primary endothelial cells treated with COMP-Ang1. Co-immunoprecipitation, Western blot with phosphotyrosine antibodies, kinase assay, dominant-negative Tie2 mutant, primary endothelial cells Cell communication and signaling Medium 20973951
2011 Phosphorylation of Tyr-347 in the BPS domain of Grb14 (by Src kinase, activated downstream of rhodopsin) enables Grb14 to competitively inhibit PTP1B activity. Ablation of Grb14 in mouse retina results in significantly elevated PTP1B activity in vivo, demonstrating that phosphorylated Grb14 is an endogenous inhibitor of retinal PTP1B. In vitro PTP1B activity assay, site-directed mutagenesis (Y347), Grb14 KO mouse retina assay, Src kinase activity measurement Molecular and cellular biology High 21791607
2011 In thyroid cancer cells, Grb14 knockdown reduces RET receptor phosphorylation and downstream Akt and STAT3 activation while facilitating IR signaling, whereas Grb14 overexpression facilitates RET activation and STAT3/Akt phosphorylation. This reveals a novel role for Grb14 in promoting RET-mediated thyroid cancer progression. Stable shRNA knockdown, overexpression, in vitro proliferation/invasion assays, in vivo xenograft mouse model, phosphorylation assays Oncogene High 22158039
2011 Grb14 RA domain mediates closure of the photoreceptor-specific CNG channel (CNGA1) through electrostatic interactions; three Glu residues (180-182) in Grb14 interact electrostatically with Arg559 in the cGMP binding pocket of CNGA1, and Lys140 of Grb14 also contributes. Grb14 competes with cGMP for the CNGA1 binding pocket. This activity is specific to Grb14 and not shared by Grb7 or Grb10. In vitro binding assay, site-directed mutagenesis of electrostatic residues, channel activity assay Protein & cell Medium 22180090
2012 Grb14 SH2 domain binds the ITAM-like sequence in the cytoplasmic domain of CEACAM3 (identified by SH2 domain microarray). Grb14 is rapidly recruited to sites of bacteria-host cell contact, and both Grb14 knockdown and overexpression indicate an inhibitory role for Grb14 in CEACAM3-mediated bacterial phagocytosis. SH2 domain microarray, co-immunoprecipitation, FRET-FLIM in intact cells, RNAi knockdown, overexpression, phagocytosis assay The Journal of biological chemistry High 22948154
2013 Crystal structure of Grb14 RA-PH domains in complex with GTP-loaded H-Ras(G12V) at 2.4-Å resolution reveals the integrated RA-PH structural unit binds simultaneously to activated Ras and phosphoinositide lipids. Binding mode of Grb14 RA domain to H-Ras is similar to RalGDS and Raf1 RA domains but with distinct features. X-ray crystallography (RA-PH domains in complex with H-Ras G12V) PloS one High 23967305
2014 GSK-3 phosphorylates Ser358, Ser362, and Ser366 in the BPS domain of Grb14 (requiring a priming phospho-Ser370), and this phosphorylation suppresses Grb14-IR complex formation. Pharmacological inhibition or knockdown of GSK-3 facilitates Grb14-IR binding, and Ala substitutions at these serines enhance Grb14-IR association. In vitro kinase assay with phosphopeptides, proximity ligation assay, pharmacological GSK-3 inhibition, siRNA knockdown, co-immunoprecipitation Journal of biochemistry Medium 24535599
2015 The ubiquitin ligase Chfr binds to the T220 residue of Grb14 in an insulin-stimulated manner and potentiates Grb14's inhibitory effect on insulin-induced cell division. Chfr ligase activity and phosphorylation of its T39 residue (an Akt substrate) are required for this function. Insulin-stimulated Chfr binding to Grb14 activates Chfr ligase activity, leading to Aurora A and Polo-like kinase degradation, blocking cell division. Co-immunoprecipitation, Xenopus oocyte G2/M transition assay, targeted mutagenesis, mammalian cell line overexpression/knockdown Cellular signalling High 25578860
2016 Liver-specific Grb14 knockdown in mice enhances insulin signaling but also releases p62/SQSTM1 (a Grb14 binding partner), which activates the Nrf2 transcription factor, which in turn represses LXR and thereby inhibits de novo lipogenesis. This reveals Grb14 as a signaling node at the crossroads of the IR and p62-Nrf2-LXR pathways regulating both glucose homeostasis and hepatic lipid synthesis. In vivo siRNA/shRNA liver knockdown, mouse metabolic phenotyping, co-immunoprecipitation (Grb14-p62), gene expression analysis, Nrf2/LXR reporter assays Molecular and cellular biology High 27215388
2017 GSK-3-mediated phosphorylation of N-terminal BPS domain serines (Ser358, Ser362, Ser366) in human Grb14 negatively regulates Grb14-IR complex formation; surface plasmon resonance shows Kd of 8 nM for Grb14-IR, which is abolished by Glu substitutions at these serines. The BPS domain alone does not show this differential, indicating additional domain contributions. In vitro kinase assay, co-immunoprecipitation, yeast two-hybrid, surface plasmon resonance Journal of biochemistry Medium 28130417
2019 Protein phosphatase 1 (PP1) dephosphorylates Ser358 and Ser362 in the N-terminal BPS domain of human Grb14, and this dephosphorylation facilitates Grb14-IR complex formation as demonstrated by co-immunoprecipitation with phosphomimetic substitutions. In vitro phosphatase assay with synthetic phosphopeptides, co-immunoprecipitation Journal of peptide science Medium 31347216

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Grb10 and Grb14: enigmatic regulators of insulin action--and more? The Biochemical journal 138 15901248
1996 Cloning and characterization of GRB14, a novel member of the GRB7 gene family. The Journal of biological chemistry 117 8647858
2006 GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle. Physiological genomics 112 16849634
2004 Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice. The EMBO journal 112 14749734
2001 Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14. The Journal of biological chemistry 110 11278563
2005 Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Molecular cell 98 16246733
2001 Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14. The Journal of biological chemistry 97 11726652
1998 Identification of the rat adapter Grb14 as an inhibitor of insulin actions. The Journal of biological chemistry 93 9748281
2009 Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Nature structural & molecular biology 64 19648926
2000 Association of fibroblast growth factor receptor 1 with the adaptor protein Grb14. Characterization of a new receptor binding partner. The Journal of biological chemistry 60 10713090
2021 Identification of low-dose radiation-induced exosomal circ-METRN and miR-4709-3p/GRB14/PDGFRα pathway as a key regulatory mechanism in Glioblastoma progression and radioresistance: Functional validation and clinical theranostic significance. International journal of biological sciences 58 33867829
2004 Increased adipose tissue expression of Grb14 in several models of insulin resistance. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 55 15059968
2013 Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased β-cell function whereas risk alleles near ANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort. The Journal of clinical endocrinology and metabolism 51 23457408
2004 SAXS study of the PIR domain from the Grb14 molecular adaptor: a natively unfolded protein with a transient structure primer? Biophysical journal 46 15465854
2009 Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. Molecular endocrinology (Baltimore, Md.) 45 19541746
2002 The adapter protein ZIP binds Grb14 and regulates its inhibitory action on insulin signaling by recruiting protein kinase Czeta. Molecular and cellular biology 41 12242277
2006 Interaction with Grb14 results in site-specific regulation of tyrosine phosphorylation of the insulin receptor. EMBO reports 36 16582879
2011 Phosphorylated Grb14 is an endogenous inhibitor of retinal protein tyrosine phosphatase 1B, and light-dependent activation of Src phosphorylates Grb14. Molecular and cellular biology 32 21791607
2004 Regulation and functional roles of Grb14. Frontiers in bioscience : a journal and virtual library 32 14977573
2004 The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1. The Journal of biological chemistry 32 15210700
2009 Molecular determinants of Grb14-mediated inhibition of insulin signaling. Molecular endocrinology (Baltimore, Md.) 29 19359342
2005 Hormonal regulation of the Grb14 signal modulator and its role in cell cycle progression of MCF-7 human breast cancer cells. Journal of cellular physiology 27 15372466
2013 Structural basis for the interaction of the adaptor protein grb14 with activated ras. PloS one 25 23967305
2016 Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance. Molecular and cellular biology 23 27215388
2006 Interaction between the insulin receptor and Grb14: a dynamic study in living cells using BRET. Biochemical pharmacology 23 16934761
2003 The PIR domain of Grb14 is an intrinsically unstructured protein: implication in insulin signaling. FEBS letters 22 14623073
2005 Identification of a NPXY motif in growth factor receptor-bound protein 14 (Grb14) and its interaction with the phosphotyrosine-binding (PTB) domain of IRS-1. Biochemistry 20 15924411
2011 The insulin resistance Grb14 adaptor protein promotes thyroid cancer ret signaling and progression. Oncogene 19 22158039
2010 Grb14 inhibits FGF receptor signaling through the regulation of PLCγ recruitment and activation. FEBS letters 19 20932831
2008 Dual effect of the adapter growth factor receptor-bound protein 14 (grb14) on insulin action in primary hepatocytes. Endocrinology 19 18339716
2003 Inhibition of FGF receptor signalling in Xenopus oocytes: differential effect of Grb7, Grb10 and Grb14. FEBS letters 19 12885405
2020 Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction. Scientific reports 18 32099031
2008 Compartmentalization and in vivo insulin-induced translocation of the insulin-signaling inhibitor Grb14 in rat liver. The FEBS journal 12 18657188
2005 FGF receptor phosphotyrosine 766 is a target for Grb14 to inhibit MDA-MB-231 human breast cancer cell signaling. Anticancer research 12 16309174
2023 Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium. medRxiv : the preprint server for health sciences 11 37461624
2013 Modulation of mouse rod photoreceptor responses by Grb14 protein. The Journal of biological chemistry 11 24273167
2013 Spatial and temporal aspects and the interplay of Grb14 and protein tyrosine phosphatase-1B on the insulin receptor phosphorylation. Cell communication and signaling : CCS 8 24350791
2012 Grb14 is a negative regulator of CEACAM3-mediated phagocytosis of pathogenic bacteria. The Journal of biological chemistry 7 22948154
2012 Grb14 mRNA levels during follicular deviation in cattle are higher in granulosa cells of subordinate compared to dominant follicles. Reproduction in domestic animals = Zuchthygiene 7 23020213
2010 Tyrosine phosphorylation of Grb14 by Tie2. Cell communication and signaling : CCS 7 20973951
2022 Metabolic Effects of the Waist-To-Hip Ratio Associated Locus GRB14/COBLL1 Are Related to GRB14 Expression in Adipose Tissue. International journal of molecular sciences 6 35955692
2017 Identification of insulin-sensitizing molecules acting by disrupting the interaction between the Insulin Receptor and Grb14. Scientific reports 6 29203791
2017 Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor. Journal of biochemistry 5 28130417
2014 Phosphorylation of Grb14 BPS domain by GSK-3 correlates with complex forming of Grb14 and insulin receptor. Journal of biochemistry 5 24535599
2024 Grb7, Grb10 and Grb14, encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism. BMC biology 4 39343875
2015 Insulin-induced cell division is controlled by the adaptor Grb14 in a Chfr-dependent manner. Cellular signalling 4 25578860
2011 Mechanism involved in the modulation of photoreceptor-specific cyclic nucleotidegated channel by the tyrosine kinase adapter protein Grb14. Protein & cell 4 22180090
2004 Solution structure of the human Grb14-SH2 domain and comparison with the structures of the human Grb7-SH2/erbB2 peptide complex and human Grb10-SH2 domain. Protein science : a publication of the Protein Society 3 15322292
2002 Assignment of backbone 1H, 13C, and 15N resonances of the SH2 domain of human Grb14. Journal of biomolecular NMR 2 12522317
2019 Dephosphorylation of clustered phosphoserine residues in human Grb14 by protein phosphatase 1 and its effect on insulin receptor complex formation. Journal of peptide science : an official publication of the European Peptide Society 1 31347216
2023 Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor. Molecules (Basel, Switzerland) 0 38202781
2014 [Control of insulin signalisation and action by the Grb14 protein]. Biologie aujourd'hui 0 25190572