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Gene Review

GRB14  -  growth factor receptor-bound protein 14

Homo sapiens

Synonyms: GRB14 adapter protein, Growth factor receptor-bound protein 14
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Disease relevance of GRB14


High impact information on GRB14

  • Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family [4].
  • We have determined the crystal structure of the Grb14 BPS region in complex with the tyrosine kinase domain of the insulin receptor [4].
  • Together with the crystal structure of the SH2 domain, we present a model for the interaction of Grb14 with the insulin receptor, which indicates how Grb14 functions as a selective protein inhibitor of insulin signaling [4].
  • Interestingly, the phosphorylation of Grb14 by PKCzeta increased its inhibitory effect on IR tyrosine kinase activity in vitro [5].
  • Importantly, this effect required the recruitment of PKCzeta and the phosphorylation of Grb14, providing in vivo evidences for a regulation of Grb14-inhibitory action by ZIP and PKCzeta [5].

Chemical compound and disease context of GRB14


Biological context of GRB14

  • Screening of a human breast epithelial cell cDNA library with the tyrosine-phosphorylated C terminus of the epidermal growth factor receptor identified a novel member of the GRB7 gene family, designated GRB14 [1].
  • Assignment of the human GRB14 gene to chromosome 2q22-q24 by fluorescence in situ hybridization [8].
  • A GST-Grb14 SH2 domain fusion protein exhibited strong binding to activated platelet-derived growth factor (PDGF) receptors (PDGFRs) in vitro, but association between Grb14 and beta-PDGFRs could not be detected in vivo [1].
  • This study supports a role for the tankyrases in cytoplasmic signal transduction pathways and suggests that vesicle trafficking may be involved in the subcellular localization or signaling function of Grb14 [9].
  • Furthermore, Grb14 phosphorylation was increased under insulin stimulation, suggesting that the PKCzeta-ZIP-Grb14 complex is involved in insulin signaling [5].

Anatomical context of GRB14


Associations of GRB14 with chemical compounds

  • Under serum-free conditions, insulin enhanced Grb14 expression but this effect was repressed by estradiol when both hormones were used in combination [6].
  • Grb10 and its close homologues Grb7 and Grb14, belong to a family of adapter proteins characterized by a proline-rich region, a central PH domain, and a carboxyl-terminal Src homology 2 (SH2) domain [11].
  • The (1)H, (13)C, and (15)N backbone resonance assignments have been made for the Src homology 2 (SH2) domain of the human molecular adapter protein Grb14 [12].
  • Biochemical studies demonstrated that Grb14 binds to activated Ras, which may serve as a timing mechanism for downregulation of insulin signaling [13].

Physical interactions of GRB14

  • Interaction of these two proteins is constitutive and mediated by a PDK-1 binding motif on Grb14 [14].
  • CONCLUSION: Grb14 binds to the Y766 site of MDA-MB-231-FGFR, competing for PLCy activation, thus inducing an arrest of the signaling transduction cascades [7].

Regulatory relationships of GRB14


Other interactions of GRB14

  • Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14 [9].
  • Deletion analyses implicate the N-terminal 110 amino acids of Grb14 and ankyrin repeats 10-19 of tankyrase 2 in mediating this interaction [9].
  • Thus, Grb14 serves as an adaptor protein to recruit PDK-1 to activated insulin receptor, thus promoting Akt phosphorylation and transduction of the insulin signal [14].
  • Using a system in which c-Myc induction drives cell cycle progression independently of estradiol, we demonstrated that Grb14 regulation was specific to estradiol treatment [6].
  • Mapping studies indicated that ZIP interacted through its ZZ zinc finger domain with the phosphorylated insulin receptor interacting region (PIR) of Grb14 [5].


  1. Cloning and characterization of GRB14, a novel member of the GRB7 gene family. Daly, R.J., Sanderson, G.M., Janes, P.W., Sutherland, R.L. J. Biol. Chem. (1996) [Pubmed]
  2. 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. Scharf, P.J., Witney, J., Daly, R., Lyons, B.A. Protein Sci. (2004) [Pubmed]
  3. GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle. Park, J.J., Berggren, J.R., Hulver, M.W., Houmard, J.A., Hoffman, E.P. Physiol. Genomics (2006) [Pubmed]
  4. Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Depetris, R.S., Hu, J., Gimpelevich, I., Holt, L.J., Daly, R.J., Hubbard, S.R. Mol. Cell (2005) [Pubmed]
  5. The adapter protein ZIP binds Grb14 and regulates its inhibitory action on insulin signaling by recruiting protein kinase Czeta. Cariou, B., Perdereau, D., Cailliau, K., Browaeys-Poly, E., Béréziat, V., Vasseur-Cognet, M., Girard, J., Burnol, A.F. Mol. Cell. Biol. (2002) [Pubmed]
  6. Hormonal regulation of the Grb14 signal modulator and its role in cell cycle progression of MCF-7 human breast cancer cells. Kairouz, R., Parmar, J., Lyons, R.J., Swarbrick, A., Musgrove, E.A., Daly, R.J. J. Cell. Physiol. (2005) [Pubmed]
  7. FGF receptor phosphotyrosine 766 is a target for Grb14 to inhibit MDA-MB-231 human breast cancer cell signaling. Cailliau, K., Perdereau, D., Lescuyer, A., Chen, H., Garbay, C., Vilain, J.P., Burnol, A.F., Browaeys-Poly, E. Anticancer Res. (2005) [Pubmed]
  8. Assignment of the human GRB14 gene to chromosome 2q22-q24 by fluorescence in situ hybridization. Baker, E., Sutherland, G.R., Sutherland, R.L., Daly, R.J. Genomics (1996) [Pubmed]
  9. Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14. Lyons, R.J., Deane, R., Lynch, D.K., Ye, Z.S., Sanderson, G.M., Eyre, H.J., Sutherland, G.R., Daly, R.J. J. Biol. Chem. (2001) [Pubmed]
  10. Grb10 and Grb14: enigmatic regulators of insulin action--and more? Holt, L.J., Siddle, K. Biochem. J. (2005) [Pubmed]
  11. Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases. Nantel, A., Mohammad-Ali, K., Sherk, J., Posner, B.I., Thomas, D.Y. J. Biol. Chem. (1998) [Pubmed]
  12. Assignment of backbone 1H, 13C, and 15N resonances of the SH2 domain of human Grb14. Scharf, P.J., Lyons, B.A. J. Biomol. NMR (2002) [Pubmed]
  13. Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Depetris, R.S., Wu, J., Hubbard, S.R. Nat. Struct. Mol. Biol. (2009) [Pubmed]
  14. The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1. King, C.C., Newton, A.C. J. Biol. Chem. (2004) [Pubmed]
  15. Interaction with Grb14 results in site-specific regulation of tyrosine phosphorylation of the insulin receptor. Nouaille, S., Blanquart, C., Zilberfarb, V., Boute, N., Perdereau, D., Roix, J., Burnol, A.F., Issad, T. EMBO Rep. (2006) [Pubmed]
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