HGNC Approved Gene Symbol: GRB14
Cytogenetic location: 2q24.3 Genomic coordinates (GRCh38): 2:164,492,417-164,621,482 (from NCBI)
Many intracellular targets for receptor tyrosine kinases (RTKs) contain one or more SH2 (Src homology region 2) domains. These are conserved, noncatalytic domains that bind to short peptide sequences containing phosphotyrosine. After RTK activation, autophosphorylation occurs, and SH2 proteins bind to specific RTKs. Proteins containing SH2 domains are also thought to mediate other protein-protein interactions during signal transduction.
Daly et al. (1996) screened a human breast epithelial cell cDNA library with the tyrosine-phosphorylated C terminus of the epidermal growth factor receptor (EGFR) and identified GRB14. GRB14 is a member of the GRB7 family, whose members include the mouse genes Grb7 (601522) and Grb10 (601523). GRB14, Grb7 and Grb10 all contain a C-terminal SH2 domain and a central domain with similarity to the C. elegans protein F10E9.6/mig10. Daly et al. (1996) identified a third region of similarity, an N-terminal motif, P(S/A)IPNPFPEL, which contains the consensus PXXP SH3 binding domain, suggesting that an SH3 protein may bind to these proteins.
Daly et al. (1996) found that GRB14 gene expression was highest in the testis, ovary, heart, liver, skeletal muscle, kidney, and pancreas. Moderate expression was detected in the small intestine, colon, peripheral blood leukocytes, brain, and placenta, while expression in the spleen, thymus, prostate, and lung was low or undetectable. GRB14 expression was detected in some breast cancer cell lines and correlated with estrogen receptor positivity. GRB14 expression was also observed in human prostate cancer cell lines. Daly et al. (1996) speculated that GRB14 is a target for a platelet-derived growth factor (PDGF)-regulated serine kinase.
GBR14 is a tissue-specific negative regulator of insulin receptor (INSR; 147670) signaling, and INSR inhibition is mediated by the GRB14 BPS region (between PH and SH2). In order to elucidate the molecular mechanism by which human GRB14 negatively regulates insulin receptor signaling, Depetris et al. (2005) determined the crystal structure of the GRB14 BPS region in complex with the phosphorylated kinase domain of INSR. The structure revealed that the N-terminal portion of the BPS region binds as a selective pseudosubstrate inhibitor in the substrate peptide binding groove of the kinase.
By sequence analysis, Dong et al. (1997) mapped the GRB14 gene to chromosome 2.
Daly, R. J., Sanderson, G. M., Janes, P. W., Sutherland, R. L. Cloning and characterization of GRB14, a novel member of the GRB7 gene family. J. Biol. Chem. 271: 12502-12510, 1996. [PubMed: 8647858] [Full Text: https://doi.org/10.1074/jbc.271.21.12502]
Depetris, R. S., Hu, J., Gimpelevich, I., Holt, L. J., Daly, R. J., Hubbard, S. R. Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Molec. Cell 20: 325-333, 2005. [PubMed: 16246733] [Full Text: https://doi.org/10.1016/j.molcel.2005.09.001]
Dong, L. Q., Du, H., Porter, S. G., Kolakowski, L. F., Jr., Lee, A. V., Mandarino, L. J., Fan, J., Yee, D., Liu, F. Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10-gamma. J. Biol. Chem. 272: 29104-29112, 1997. Note: Erratum: J. Biol. Chem. 273: 4288 only, 1998. [PubMed: 9360986] [Full Text: https://doi.org/10.1074/jbc.272.46.29104]