Affinage

GRB14

Growth factor receptor-bound protein 14 · UniProt Q14449

Length
540 aa
Mass
61.0 kDa
Annotated
2026-06-10
52 papers in source corpus 34 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRB14 is a multi-domain adaptor protein that functions principally as a tissue-specific negative regulator of insulin receptor (IR) signaling, binding the activated IR in an insulin-dependent manner and dampening downstream IRS-1 phosphorylation, glycogen synthesis, and DNA synthesis (PMID:9748281, PMID:14749734). Its inhibitory core is the BPS/PIR domain, which acts as a pseudosubstrate inhibitor occupying the IR kinase substrate-binding groove while the SH2 domain anchors to receptor phosphotyrosines, as resolved by the BPS–IR kinase domain crystal structure (PMID:16246733); biochemically the BPS domain alone inhibits IR substrate phosphorylation uncompetitively, and although intrinsically unstructured it retains full activity (PMID:11726652, PMID:14623073). Once bound, Grb14 selectively protects IR kinase-loop phosphotyrosines from PTP1B while favoring dephosphorylation of Y972, reducing IRS-1 recruitment and ERK activation (PMID:16582879), and is itself recruited and dimerized on the activated receptor dimer in real time (PMID:16934761, PMID:18657188). Recruitment is gated by phosphorylation: GSK-3 phosphorylates BPS serines Ser358/362/366 to prevent premature IR association, while PP1 dephosphorylates these sites to permit high-affinity binding (PMID:24535599, PMID:28130417, PMID:31347216), and PKCζ (via the ZIP adaptor) phosphorylates Grb14 to enhance its inhibitory activity (PMID:12242277). Grb14 carries a dual role, additionally recruiting PDK-1 to facilitate insulin-dependent Akt activation (PMID:15210700) and, in liver, sequestering p62 to permit SREBP-1c– and LXR-driven lipogenesis (PMID:18339716, PMID:27215388). Beyond insulin signaling, Grb14 binds activated Ras through an integrated RA–PH unit (PMID:19648926, PMID:23967305), restricts FGFR1–PLCγ signaling (PMID:10713090, PMID:20932831), inhibits PTP1B when Grb14-Y347 is phosphorylated by Src in retina (PMID:21791607), gates the photoreceptor CNG channel via its RA domain (PMID:22180090, PMID:24273167), and negatively regulates CEACAM3-mediated bacterial phagocytosis through its SH2 domain (PMID:22948154).

Mechanistic history

Synthesis pass · year-by-year structured walk · 33 steps
  1. 1996 Medium

    Established Grb14 as a phosphotyrosine-binding adaptor coupled to receptor tyrosine kinase signaling, the first clue to its function.

    Evidence GST-SH2 domain pulldown against activated PDGF receptors and in vivo serine phosphorylation labeling

    PMID:8647858

    Open questions at the time
    • No functional consequence of PDGFR binding tested
    • Identity of the PDGF-regulated serine kinase unknown
  2. 1998 High

    Defined Grb14 as an inhibitory regulator of insulin signaling that binds the IR via its PIR domain, reframing it as a negative feedback adaptor rather than a positive coupler.

    Evidence Yeast two-hybrid, Co-IP, deletion-mutant binding, and CHO-IR cell metabolic readouts

    PMID:9748281

    Open questions at the time
    • Did not resolve the catalytic mechanism of inhibition
    • Tissue relevance not yet established
  3. 2001 High

    Showed the BPS/PIR domain alone uncompetitively inhibits IR substrate phosphorylation and protects the IR from phosphatases, separating substrate occlusion from receptor anchoring.

    Evidence In vitro kinase assays with deletion mutants and CHO-IR cell signaling readouts

    PMID:11726652

    Open questions at the time
    • Structural basis of substrate-groove occlusion not yet visualized
    • Which phosphatase is antagonized unspecified at this stage
  4. 2001 Medium

    Identified tankyrase 2 as an N-terminal binding partner, hinting at additional Grb14 interactions beyond the IR.

    Evidence Yeast two-hybrid, reciprocal Co-IP, and microsomal fractionation

    PMID:11278563

    Open questions at the time
    • Functional consequence of tankyrase 2 binding not established
    • No link to insulin signaling demonstrated
  5. 2002 High

    Placed Grb14 in a PKCζ–ZIP heterotrimeric complex and showed phosphorylation by PKCζ enhances its IR inhibition, adding a kinase input that tunes inhibitory strength.

    Evidence Co-IP, in vitro kinase assay, in vivo 32P labeling, and Xenopus oocyte maturation assay

    PMID:12242277

    Open questions at the time
    • Phosphorylated residues on Grb14 not mapped here
    • Physiological relevance in metabolic tissues untested
  6. 2003 Medium

    Demonstrated the inhibitory PIR domain is intrinsically unstructured yet fully active, indicating function does not require a stable fold.

    Evidence NMR of 15N-labeled recombinant PIR and Xenopus oocyte assay

    PMID:14623073

    Open questions at the time
    • Conformation when bound to IR not resolved
    • No partner-induced folding shown
  7. 2004 High

    Genetic ablation in mice proved Grb14 is a physiological, tissue-specific repressor of IR–IRS-1 signaling controlling glucose homeostasis.

    Evidence Knockout mouse with glucose/insulin tolerance tests, ex vivo metabolic assays, and signaling western blots

    PMID:14749734

    Open questions at the time
    • Tissue-specific limiting factors not identified
    • Did not explain how liver IRS-1 phosphorylation rises despite lower IR autophosphorylation
  8. 2004 High

    Revealed a dual role by which Grb14 constitutively recruits PDK-1 to facilitate Akt activation, complicating its purely inhibitory image.

    Evidence Directed proteomics pulldown, Co-IP, point mutagenesis, fractionation, and Akt activity assay

    PMID:15210700

    Open questions at the time
    • Balance between IR inhibition and Akt facilitation not quantified
    • PDK-1 binding motif structural detail limited
  9. 2004 Medium

    Linked Grb14 abundance to insulin resistance, showing hormonal regulation of its expression across diabetic models.

    Evidence Western blot, RT-PCR, and 3T3-F442A adipocyte treatment assays in ob/ob, GK rat, and human diabetic tissue

    PMID:15059968

    Open questions at the time
    • Causal direction between Grb14 levels and insulin resistance not established
    • Transcriptional regulators of Grb14 unidentified
  10. 2004 Medium

    Biophysical characterization detected a transiently structured stretch (399–407) in the disordered PIR, suggesting partner-induced ordering.

    Evidence SAXS, circular dichroism with TFE, and sequence analysis

    PMID:15465854

    Open questions at the time
    • Functional consequence of the transient structure untested
    • Binding partner triggering the transition unknown
  11. 2005 High

    The BPS–IR kinase domain crystal structure resolved the pseudosubstrate inhibition mechanism, providing the structural basis for substrate-groove occlusion plus SH2 anchoring.

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

    PMID:16246733

    Open questions at the time
    • Full-length Grb14 conformation on the IR dimer not crystallized
    • Regulatory phosphorylation not captured in structure
  12. 2005 Medium

    Extended Grb14's inhibitory reach to estrogen- and insulin-driven proliferation in breast cancer cells, tying it to mitogenic control.

    Evidence MCF-7 overexpression, cell cycle analysis, and ERK1/2 phospho western blots

    PMID:15372466

    Open questions at the time
    • Domain requirements for the antiproliferative effect not dissected
    • Overexpression-only evidence without loss-of-function
  13. 2005 Medium

    Identified phosphorylation-independent binding of the IRS-1 PTB domain to a Grb14 NPXY motif, proposing IRS-1 sequestration in retina.

    Evidence Yeast two-hybrid retinal screen, in vitro pulldown, and Co-IP from retinal lysates

    PMID:15924411

    Open questions at the time
    • Functional sequestration of IRS-1 inferred but not directly tested
    • Retinal relevance of the complex not validated in vivo here
  14. 2000 High

    Showed Grb14 binds activated FGFR1 with receptor specificity and inhibits FGF-2-induced proliferation, broadening its RTK targets beyond the IR.

    Evidence Yeast two-hybrid, Co-IP, in vitro binding, proliferation assay, and SH2 point mutagenesis

    PMID:10713090

    Open questions at the time
    • Molecular mechanism of FGFR1 inhibition not yet defined
    • In vivo relevance untested
  15. 2006 High

    Real-time imaging defined how Grb14 reshapes IR phosphorylation—protecting kinase-loop tyrosines from PTP1B while favoring Y972 dephosphorylation—to selectively curtail IRS-1 recruitment.

    Evidence BRET in living HEK cells, site-specific phosphotyrosine antibodies, and Co-IP

    PMID:16582879

    Open questions at the time
    • Structural basis of site-selective phosphatase protection unresolved
    • Generality across tissues not addressed
  16. 2006 Medium

    Demonstrated insulin-induced Grb14 dimerization, consistent with two molecules binding the activated IR dimer.

    Evidence BRET saturation experiments, Co-IP, and site-specific phospho-antibodies

    PMID:16934761

    Open questions at the time
    • Dimerization interface not mapped
    • Functional necessity of dimerization untested
  17. 2008 High

    Captured insulin-driven redistribution of endogenous Grb14 to the IR in rat liver and confirmed negative feedback by showing its removal raises IR kinase activity.

    Evidence Rat liver subcellular fractionation, Co-IP, and in vitro IR kinase assay after KCl extraction

    PMID:18657188

    Open questions at the time
    • Trafficking determinants directing Grb14 to membrane/Golgi/endosome unclear
    • Link between localization and inhibition mechanism not resolved
  18. 2008 Medium

    Uncovered the liver dual role: Grb14 inhibits IR but is required for insulin-induced SREBP-1c maturation and lipogenic gene expression.

    Evidence RNAi in primary mouse hepatocytes with signaling and gene-expression readouts

    PMID:18339716

    Open questions at the time
    • Molecular link from Grb14 to SREBP-1c not yet defined at this stage
    • How lipogenesis persists despite improved Akt unexplained
  19. 2009 High

    Structural and biochemical work defined the RA–PH tandem as an integrated unit that binds GTP-loaded Ras, proposing Ras-dependent timing of insulin signaling downregulation.

    Evidence X-ray crystallography of RA-PH (Grb10) and biochemical Ras-binding assay for Grb14

    PMID:19648926

    Open questions at the time
    • Functional consequence of Grb14–Ras binding in cells not tested
    • Crystal structure was of Grb10 RA-PH, not Grb14
  20. 2009 High

    Compound Grb10/Grb14 knockout established genetic epistasis and showed combined loss protects against diet-induced glucose intolerance, revealing limiting compensatory mechanisms.

    Evidence Double-knockout mice with tolerance tests and IR/IRS-1/Akt signaling readouts

    PMID:19541746

    Open questions at the time
    • Identity of the limiting factors (IR hypophosphorylation, IRS-1 levels) not mechanistically resolved
    • Tissue contributions to protection unseparated
  21. 2009 High

    Mutagenesis pinpointed the Grb14–IR contact residues conferring specificity and confirmed the PDK-1 interaction is required alongside IR binding for maximal inhibition.

    Evidence Mutagenesis, Co-IP, BRET, Xenopus oocyte assay, and Grb14 KO MEF complementation

    PMID:19359342

    Open questions at the time
    • How S370 phosphorylation status mechanistically gates activity not fully resolved
    • Structural model of full assembly incomplete
  22. 2010 Medium

    Defined the FGFR1 inhibition mechanism: Grb14 binds FGFR1 pY766 within a PLCγ-containing trimeric complex to trap and inactivate PLCγ.

    Evidence BRET, Xenopus oocyte FGF-maturation assay, and FGFR pY766 mutagenesis

    PMID:20932831

    Open questions at the time
    • Conformational trapping model not structurally confirmed
    • Physiological role in FGF biology untested
  23. 2011 High

    Identified Grb14 as a phosphorylation-regulated inhibitor of PTP1B in retina, with Tyr-347 phosphorylation by rhodopsin-activated Src enabling competitive PTP1B inhibition.

    Evidence In vitro PTP1B activity assay, Y347 mutagenesis, retinal Grb14 KO mice, and in vivo phosphorylation assays

    PMID:21791607

    Open questions at the time
    • How Y347 phosphorylation reconciles with IR-protective role unclear
    • Retinal substrate landscape of derepressed PTP1B not mapped
  24. 2011 Medium

    Revealed a non-adaptor channel-gating function: Grb14's RA domain electrostatically competes with cGMP to close the photoreceptor CNGA1 channel, with isoform specificity.

    Evidence In vitro binding, CNG channel electrophysiology, and RA-domain mutagenesis

    PMID:22180090

    Open questions at the time
    • In vivo channel regulation not yet shown here
    • Structural detail of the RA–CNGA1 interface limited
  25. 2011 Medium

    Showed Grb14 can act as a positive driver of oncogenic RET signaling in thyroid cancer, promoting Akt/STAT3 activation, invasion, and metastasis.

    Evidence Stable shRNA knockdown, overexpression, invasion assay, and orthotopic mouse xenograft

    PMID:22158039

    Open questions at the time
    • Direct Grb14–RET binding not structurally defined
    • Mechanism distinguishing RET facilitation from IR inhibition unresolved
  26. 2012 High

    Defined Grb14 as a negative regulator of CEACAM3-mediated bacterial phagocytosis via SH2 binding to the receptor's ITAM-like motif.

    Evidence SH2 domain microarray, Co-IP, FRET-FLIM, RNAi, overexpression, and phagocytosis assay

    PMID:22948154

    Open questions at the time
    • Downstream signaling blocked by Grb14 at CEACAM3 not detailed
    • Why both knockdown and overexpression reduce phagocytosis unexplained mechanistically
  27. 2013 High

    High-resolution crystal structure of Grb14 RA–PH bound to GTP-loaded H-Ras showed the integrated unit can simultaneously engage Ras and phosphoinositides.

    Evidence X-ray crystallography at 2.4 Å of the Grb14 RA-PH–H-Ras G12V complex

    PMID:23967305

    Open questions at the time
    • Cellular function of simultaneous Ras/lipid engagement not tested
    • Coupling to IR inhibition timing not demonstrated structurally
  28. 2013 Medium

    Single-rod electrophysiology showed Grb14 modulates both CNG channel sensitivity and PDE6 inactivation rate, defining a physiological role in phototransduction.

    Evidence Suction-electrode recordings from single Grb14 KO vs WT mouse rods in dark- and light-adapted states

    PMID:24273167

    Open questions at the time
    • Molecular basis of PDE6 inactivation effect unresolved
    • Whether channel and PDE6 effects share a mechanism unclear
  29. 2013 Medium

    Showed the BPS phosphorylation state switches Grb14 between IR-promoting (PTP1B-inhibiting) and IR-inhibiting modes in retinal neurons, with relevance to diabetic retinopathy.

    Evidence Co-IP, proximity ligation assay, phospho-specific analysis, and Ins2Akita diabetic mouse retina

    PMID:24350791

    Open questions at the time
    • Switch mechanism relies partly on inference from prior studies
    • Kinase/phosphatase setting the retinal phospho-state not fully defined
  30. 2014 High

    Identified GSK-3 as the kinase phosphorylating BPS serines Ser358/362/366 to block premature Grb14–IR complex formation, defining an upstream gating input.

    Evidence In vitro kinase assay, proximity ligation assay, GSK-3 inhibition/knockdown, and S-to-A mutagenesis

    PMID:24535599

    Open questions at the time
    • How insulin lowers GSK-3 activity to permit binding not detailed here
    • The opposing phosphatase not yet identified at this stage
  31. 2015 High

    Connected Grb14 to cell-cycle control by showing insulin-dependent Chfr binding activates the E3 ligase to degrade Aurora A and PLK, blocking insulin-driven division.

    Evidence Co-IP, Xenopus oocyte G2/M assay, mutagenesis of Grb14 T220 and Chfr T39/RING, and mammalian proliferation assays

    PMID:25578860

    Open questions at the time
    • Physiological context of Grb14–Chfr-driven division control unclear
    • Tissue specificity of the effect untested
  32. 2016 High

    Resolved the liver lipogenic dual role mechanistically: Grb14 sequesters p62, and its loss releases p62 to activate Nrf2 and repress LXR, silencing de novo lipogenesis.

    Evidence Liver-specific AAV shRNA in lean and obese mice with lipogenesis assays, gene expression, and Grb14–p62 Co-IP

    PMID:27215388

    Open questions at the time
    • Structural basis of Grb14–p62 binding undefined
    • How IR engagement is coupled to p62 release unresolved
  33. 2017 High

    Quantified the phospho-gated affinity switch and identified PP1 as the phosphatase that, by dephosphorylating Ser358/362, licenses high-affinity Grb14–IR binding.

    Evidence In vitro kinase assay, surface plasmon resonance, yeast two-hybrid, Co-IP, and phosphopeptide phosphatase assay

    PMID:28130417 PMID:31347216

    Open questions at the time
    • How insulin coordinates GSK-3 inactivation with PP1 activation in vivo unclear
    • Spatiotemporal control of the phospho-switch at the membrane undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Grb14's many context-specific roles—IR inhibition vs Akt/RET facilitation, lipogenic regulation, channel gating, and immune phagocytosis—are coordinated within a single full-length protein in vivo remains unresolved.
  • No full-length Grb14 structure on an intact receptor
  • Tissue-specific determinants selecting inhibitory vs facilitatory output unknown
  • Integration of RA/Ras, BPS/IR, and SH2 inputs into a unified regulatory logic not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-9709957 Sensory Perception 2
Partners
CEACAM3CHFRFGFR1HRASINSRPDPK1PTP1BSQSTM1
Complex memberships
PKCζ–ZIP–Grb14 complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 GRB14 SH2 domain binds to activated PDGF receptors in vitro; GRB14 is phosphorylated on serine residues in response to PDGF stimulation, identifying it as a target for a PDGF-regulated serine kinase. GST-SH2 domain pulldown, in vivo serine phosphorylation labeling The Journal of biological chemistry Medium 8647858
1998 Rat Grb14 binds the insulin receptor in an insulin-dependent manner in vivo; the PIR domain (between PH and SH2) is the primary IR-binding domain, while the SH2 domain contributes secondarily. Binding requires IR tyrosines Y1150/Y1151. Overexpression of Grb14 in CHO-IR cells decreases insulin-stimulated IRS-1 tyrosine phosphorylation and reduces glycogen and DNA synthesis, establishing Grb14 as an inhibitory regulator of insulin signaling. Yeast two-hybrid, co-immunoprecipitation, deletion mutant in vitro binding, CHO cell overexpression with metabolic readouts The Journal of biological chemistry High 9748281
2001 Grb14 directly inhibits insulin receptor (IR) substrate phosphorylation in vitro, acting as an uncompetitive inhibitor with respect to peptide substrate but not altering Km for ATP. The PIR/BPS domain alone is sufficient for this inhibitory effect; the SH2 domain has no effect on IR catalytic activity. In CHO-IR cells, Grb14 binding protects the IR from tyrosine phosphatases, maintaining it in a phosphorylated state, but delays Akt and ERK1/2 activation. In vitro kinase assay with deletion mutants, CHO cell co-immunoprecipitation, western blot for downstream signaling The Journal of biological chemistry High 11726652
2001 Tankyrase 2 was identified as a novel binding partner for Grb14 via yeast two-hybrid screen. The interaction is mediated by the N-terminal 110 amino acids of Grb14 and ankyrin repeats 10–19 of tankyrase 2. Both proteins co-fractionate in the low-density microsome fraction in vivo, and their association can be detected by co-immunoprecipitation. Yeast two-hybrid, co-immunoprecipitation, subcellular fractionation, deletion analysis The Journal of biological chemistry Medium 11278563
2002 ZIP (PKCζ-interacting protein) binds Grb14 through its ZZ zinc finger domain interacting with the PIR domain of Grb14, forming a PKCζ–ZIP–Grb14 heterotrimeric complex. PKCζ phosphorylates Grb14 in vitro and in vivo, and this phosphorylation is increased by insulin stimulation. Phosphorylation of Grb14 by PKCζ further enhances Grb14's inhibitory effect on IR tyrosine kinase activity. In Xenopus oocytes, ZIP potentiates Grb14's inhibitory action on insulin-induced maturation in a PKCζ- and phosphorylation-dependent manner. Co-immunoprecipitation, in vitro kinase assay, in vivo [32P] labeling, Xenopus oocyte functional assay, deletion mapping Molecular and cellular biology High 12242277
2003 The isolated PIR domain of Grb14 is intrinsically unstructured (lacks secondary structure) as demonstrated by NMR, yet retains full biological activity, inhibiting insulin-induced oocyte maturation in Xenopus. NMR (15N-labeled recombinant PIR), Xenopus oocyte functional assay FEBS letters Medium 14623073
2004 Grb14 knockout in mice leads to improved glucose tolerance, lower circulating insulin, increased glycogen synthesis in liver and skeletal muscle, and enhanced insulin-induced glucose uptake in soleus muscle. In liver, despite lower IR autophosphorylation, IRS-1 phosphorylation and PKB activation are enhanced. This demonstrates Grb14 as a tissue-specific in vivo repressor of IR-mediated IRS-1 tyrosine phosphorylation. Gene targeting (knockout mouse), glucose/insulin tolerance tests, ex vivo tissue metabolic assays, western blot for signaling The EMBO journal High 14749734
2004 The PIR domain of Grb14 is natively unstructured but contains a potentially structured short stretch (residues 399–407) that may undergo a structural transition upon binding to a partner, as evidenced by SAXS and circular dichroism with TFE. Small-angle X-ray scattering (SAXS), circular dichroism, sequence analysis Biophysical journal Medium 15465854
2004 Grb14 binds PDK-1 constitutively through a PDK-1 binding motif on Grb14. This interaction is required for insulin-triggered membrane translocation of PDK-1 and facilitates Akt activation. Disruption of this interaction by point mutation or SH2 domain deletion significantly decreases insulin-dependent Akt activation. Directed proteomics pulldown, co-immunoprecipitation, point mutagenesis, subcellular fractionation, Akt activity assay The Journal of biological chemistry High 15210700
2004 In adipose tissue of ob/ob mice, Goto-Kakizaki rats, and type 2 diabetic humans, Grb14 expression is increased. Insulin stimulates Grb14 expression in 3T3-F442A adipocytes, while thiazolidinediones decrease it, indicating hormonal regulation of Grb14 abundance as part of insulin resistance. Western blot, RT-PCR, 3T3-F442A cell culture treatment assays FASEB journal Medium 15059968
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, occupying the substrate peptide-binding groove of the kinase. Together with the SH2 domain crystal structure, a model is presented in which Grb14 simultaneously anchors via its SH2 domain to IR phosphotyrosines and occludes the substrate groove via BPS. X-ray crystallography (BPS–IR kinase domain complex and SH2 domain), structural modeling Molecular cell High 16246733
2000 Grb14 binds activated FGFR1 in a kinase-activity-dependent manner in mammalian cells; the SH2 domain partially mediates binding, but full-length Grb14 restricts specificity to FGFR1 (not PDGFR). Deletion of SH2 eliminates dependence on receptor activation. Overexpression of Grb14 inhibits FGF-2-induced cell proliferation, while an SH2 point mutant that cannot bind FGFR1 enhances mitogenesis. FGF-2 treatment enhances Grb14 serine/threonine phosphorylation. Yeast two-hybrid, co-immunoprecipitation, in vitro binding, cell proliferation assay, point mutagenesis The Journal of biological chemistry High 10713090
2005 Grb14 overexpression inhibits insulin- and estrogen-induced cell cycle progression in MCF-7 breast cancer cells, associated with decreased ERK1/2 activation in insulin-stimulated Grb14-overexpressing cells. Estradiol blocks the insulin-induced upregulation of Grb14 expression. Overexpression in MCF-7 cells, cell cycle analysis, western blot for ERK1/2 phosphorylation Journal of cellular physiology Medium 15372466
2006 Using real-time BRET in living cells, Grb14 is rapidly recruited to the activated IR upon insulin stimulation in a dose-dependent manner. Grb14 reduces insulin-induced IR–PTP1B interaction (BRET). Grb14 protects IR kinase-loop tyrosines (Y1158/Y1162/Y1163) from dephosphorylation by PTP1B while favoring dephosphorylation of Y972, thereby decreasing IRS-1 recruitment to the IR and reducing ERK pathway activation. BRET in living HEK cells, site-specific phosphotyrosine antibodies, co-immunoprecipitation EMBO reports High 16582879
2006 Grb14 undergoes insulin-induced dimerization as demonstrated by BRET saturation experiments, likely as a result of two Grb14 molecules binding simultaneously on the activated IR dimer. Grb14 reduces IR–PTP1B interaction in living cells, protecting kinase-loop phosphotyrosines while favoring dephosphorylation of Y972. BRET saturation experiments, co-immunoprecipitation, site-specific phospho-antibodies Biochemical pharmacology Medium 16934761
2005 The PTB domain of IRS-1 binds to the NPXY motif of Grb14 in a phosphorylation-independent manner. Grb14–IRS-1 complexes are detected in retinal tissue lysates. This suggests that Grb14 may sequester IRS-1 via its NPXY motif, acting as a dominant negative for IRS-1 function in the retina. Yeast two-hybrid (bovine retinal library screen), in vitro pulldown, co-immunoprecipitation from retinal lysates Biochemistry Medium 15924411
2009 Crystal structure of Grb14 RA and PH domains reveals they form an integrated dimeric structural unit. Biochemical studies demonstrate that Grb14 binds activated Ras (GTP-loaded), suggesting a timing mechanism for downregulation of insulin signaling. The RA-PH tandem unit is structurally related to RIAM, lamellipodin, and MIG-10. X-ray crystallography (RA-PH domains of Grb10, 2.6 Å), biochemical Ras-binding assay for Grb14 Nature structural & molecular biology High 19648926
2009 In compound Grb10/Grb14 double-knockout mice, ablation of both adaptors does not further enhance insulin-induced IRS-1 phosphorylation or Akt activation beyond single knockouts, suggesting context-dependent limiting mechanisms including IR hypophosphorylation and decreased IRS-1 expression. However, double KO mice are protected from high-fat diet-induced glucose intolerance whereas single KOs are not. Compound gene knockout mice, insulin tolerance and glucose tolerance tests, western blot for IR/IRS-1/Akt signaling Molecular endocrinology High 19541746
2009 Molecular determinants of Grb14–IR interaction: Grb14 L404 contacts IR L1038 (αC-helix) and Grb14 R385 contacts IR K1168 (activation loop). The L404 contact is likely important for IR-binding specificity among Grb7 family members. Phosphorylation status of Grb14-S370 controls biological activity. Insulin-induced Grb14–PDK1 interaction is required in addition to Grb14–IR binding for maximal inhibition of insulin signaling. Mutagenesis, co-immunoprecipitation, BRET, Xenopus oocyte assay, Grb14 KO MEF complementation assay Molecular endocrinology High 19359342
2010 Grb14 is recruited to activated FGFR1 in a trimeric complex also containing PLCγ. Grb14 binding to pY766 of FGFR1 (the PLCγ binding site) alters FGF-induced PLCγ phosphorylation and activation. A molecular model proposes that Grb14 binding induces a conformational change that traps and inactivates PLCγ. BRET, Xenopus oocyte functional assay (FGF-induced maturation), site-directed mutagenesis of FGFR pY766 FEBS letters Medium 20932831
2011 Phosphorylation of Tyr-347 in the BPS domain of Grb14 is critical for competitive inhibition of PTP1B activity. Rhodopsin-regulated Src kinase activation in retina phosphorylates Grb14. Ablation of Grb14 results in significantly elevated retinal PTP1B activity in vivo, identifying Grb14 as an endogenous, phosphorylation-regulated inhibitor of PTP1B. In vitro PTP1B activity assay, site-directed mutagenesis (Y347), retinal Grb14 KO mice, in vivo phosphorylation assays Molecular and cellular biology High 21791607
2011 Grb14 promotes closure of photoreceptor-specific CNG channel alpha subunit (CNGA1) through its RA domain via electrostatic interaction. Grb14 competes with cGMP for the CNGA1 binding pocket; Glu180-182 in Grb14 are critical for electrostatic interaction with Arg559 in the cGMP-binding pocket of CNGA1. Lys140 also participates. Grb7 and Grb10 do not modulate channel activity, indicating specificity. In vitro binding assay, electrophysiology (CNG channel recordings), site-directed mutagenesis of Grb14 RA domain Protein & cell Medium 22180090
2011 In thyroid cancer cells, Grb14 knockdown diminishes RET phosphorylation and reduces Akt and STAT3 activation, decreasing cell proliferation and invasion. Forced Grb14 expression interrupts IR signaling but facilitates RET activation and STAT3/Akt phosphorylation, enhancing cell invasion and metastasis in xenograft models. Stable shRNA knockdown, forced overexpression, western blot, in vitro invasion assay, orthotopic mouse xenograft Oncogene Medium 22158039
2012 Grb14 SH2 domain binds to the ITAM-like sequence of the phagocytic receptor CEACAM3 (identified by SH2 domain microarray). Grb14 is rapidly recruited to sites of bacteria–host cell contact. Both knockdown and overexpression of Grb14 reduce CEACAM3-mediated phagocytosis of Neisseria gonorrhoeae, establishing Grb14 as a negative regulator of CEACAM3-initiated bacterial phagocytosis. SH2 domain microarray, co-immunoprecipitation, FRET-FLIM, 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. The RA and PH domains form an integrated unit capable of simultaneously binding activated Ras and phosphoinositide lipids. Binding mode of Grb14 RA to Ras resembles RalGDS and Raf1 RA domains but with distinct features. X-ray crystallography (2.4 Å, Grb14 RA-PH + H-Ras G12V complex) PloS one High 23967305
2008 In rat liver in vivo, insulin injection causes rapid, dose-dependent redistribution of endogenous Grb14 from cytosol to plasma membrane and then to Golgi/endosome fractions, paralleling IR phosphorylation. Co-immunoprecipitation shows Grb14 associates with phosphorylated IR beta-subunit in these fractions. Removal of endogenous Grb14 from membrane fractions by KCl treatment increases IR tyrosine kinase activity, demonstrating that endogenous Grb14 exerts negative feedback on IR activity in vivo. Rat liver subcellular fractionation, co-immunoprecipitation, in vitro IR kinase assay after KCl extraction The FEBS journal High 18657188
2008 Grb14 knockdown in primary hepatocytes via RNAi enhances insulin-induced Akt, GSK3, and FOXO1 phosphorylation, consistent with IR inhibition by Grb14. However, Grb14 depletion completely abrogates insulin-induced SREBP-1c maturation, blunting lipogenic gene expression despite improved Akt signaling, revealing a dual role for Grb14 in liver: inhibitor of IR and positive regulator of SREBP-1c-mediated lipogenesis. RNAi in primary mouse hepatocytes, western blot, gene expression analysis Endocrinology Medium 18339716
2013 In rod photoreceptors, Grb14 deletion accelerates response decay (decreased integration time and τREC) and decreases the limiting time constant τD, indicating that Grb14 modulates both cGMP-gated channel sensitivity and the rate of PDE6 inactivation. Grb14 effects are present in dark-adapted rods and enhanced after bleaching adaptation. Suction-electrode recordings from single mouse rods (Grb14 KO vs. WT), dark- and light-adapted conditions The Journal of biological chemistry Medium 24273167
2013 In retinal neurons, phosphorylation of the BPS region of Grb14 promotes IR activation by inhibiting PTP1B, whereas unphosphorylated Grb14 acts with PTP1B to negatively regulate IR. Decreased Grb14 phosphorylation was observed in diabetic Ins2Akita mouse retinas, correlating with decreased IR activation. Co-immunoprecipitation, proximity ligation assay (PLA), phospho-specific analysis, Ins2Akita diabetic mouse retina Cell communication and signaling Medium 24350791
2014 GSK-3 phosphorylates serine residues (Ser358, Ser362, Ser366) in the N-terminal BPS domain of Grb14. Pharmacological inhibition or knockdown of GSK-3 facilitates Grb14-IR complex formation. Serine-to-alanine substitution at these sites also facilitates Grb14-IR binding. Phospho-Ser366 of endogenous Grb14 is regulated by insulin in HepG2 cells, establishing GSK-3-mediated phosphorylation as a negative regulator of Grb14-IR complex formation. In vitro kinase assay, proximity ligation assay, pharmacological GSK-3 inhibition, siRNA knockdown, site-directed mutagenesis Journal of biochemistry High 24535599
2015 Chfr ubiquitin ligase is a binding partner of Grb14 (binding at T220 of Grb14 upon insulin stimulation) and potentiates Grb14's inhibitory effect on insulin-induced cell division. Chfr ligase activity and phosphorylation of its T39 residue (an Akt target) are required. In the presence of insulin, Chfr binding to Grb14 activates Chfr E3 ligase, leading to Aurora A and Polo-like kinase degradation and blocking cell division. Co-immunoprecipitation, Xenopus oocyte G2/M assay, mutagenesis (T220, Chfr T39, Chfr RING domain), mammalian cell proliferation assays Cellular signalling High 25578860
2016 Grb14 knockdown in mouse liver silences de novo fatty acid synthesis despite enhancing Akt signaling. Mechanistically, Grb14 binds p62/sqstm1; upon Grb14 knockdown, released p62 activates the transcription factor Nrf2, which represses the lipogenic nuclear receptor LXR, thereby suppressing lipogenesis. This identifies Grb14 as a signaling node linking the IR to the p62-Nrf2-LXR pathway. Liver-specific AAV shRNA knockdown in lean and obese mice, western blot, gene expression, de novo lipogenesis assay, co-immunoprecipitation of Grb14-p62 Molecular and cellular biology High 27215388
2017 Phosphorylation of N-terminal BPS domain serines (Ser358, Ser362, Ser366) by GSK-3 negatively regulates Grb14–IR complex formation; glutamic acid substitutions at these sites reduce Kd from ~8 nM to undetectable by SPR. Protein phosphatase 1 (PP1) dephosphorylates Ser358 and Ser362, and this dephosphorylation facilitates Grb14–IR complex formation. In vitro kinase assay, surface plasmon resonance (SPR), yeast two-hybrid, co-immunoprecipitation, phosphopeptide phosphatase assay Journal of biochemistry / Journal of peptide science High 28130417 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 52 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
2008 Dual effect of the adapter growth factor receptor-bound protein 14 (grb14) on insulin action in primary hepatocytes. Endocrinology 20 18339716
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
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

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