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Gene Review

GRB7  -  growth factor receptor-bound protein 7

Homo sapiens

Synonyms: B47, Epidermal growth factor receptor GRB-7, GRB7 adapter protein, Growth factor receptor-bound protein 7
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Disease relevance of GRB7


High impact information on GRB7

  • 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 [5].
  • Although both Grb7 isoforms share homology with the Mig-10 cell migration gene, the Grb7V isoform lacks 88 base pairs in the C terminus; the resultant frame shift leads to substitution of an SH2 domain with a short hydrophobic sequence [6].
  • Analysis of human esophageal tumor tissues and regional lymph nodes with metastases revealed that Grb7V was expressed in 40% of Grb7-positive esophageal carcinomas [6].
  • These findings suggest that Grb7 isoforms are involved in cell invasion and metastatic progression of human esophageal carcinomas [6].
  • Finally, transfection of an antisense Grb7 RNA expression construct lowered endogenous Grb7 protein levels and suppressed the invasive phenotype exhibited by esophageal carcinoma cells [6].

Chemical compound and disease context of GRB7

  • These findings suggest a possible relationship of Grb7 signaling in association with expression of tyrosine kinase receptors in aggressive human esophageal cancer [7].

Biological context of GRB7

  • 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 [8].
  • These findings may be of particular interest because the transition from high grade intraepithelial neoplasia to invasive carcinoma is a crucial step in malignant transformation in Barrett's carcinogenesis and might underline the putative role of GRB7 and ERBB2 in cell migration and tumor invasion [2].
  • We evaluated gene amplification and mRNA expression of GRB7 and ERBB2 in Barrett's carcinoma and its associated precursor lesions to assess their possible role in Barrett's malignant transformation [2].
  • Notably, targeted knockdown of either GRB7 or STARD3 also leads to decreased cell proliferation and cell-cycle progression, albeit to a lesser extent compared with ERBB2 knockdown [9].
  • Analysis of array-based comparative genomic hybridization and expression profiling data indicate that the minimum region of recurrent amplification (i.e., the amplicon "core") at 17q12 includes two other genes, GRB7 and STARD3, which exhibit elevated expression when amplified [9].

Anatomical context of GRB7


Associations of GRB7 with chemical compounds

  • There was a correlation between GRB7 and ERBB2 in BCA at the DNA level (r(s) = 0.76, p < 0.001) and the mRNA level (r(s) = 0.89, p < 0.001) [2].
  • In addition, both FAK binding to PI 3-kinase via its autophosphorylated Tyr(397) and integrin-mediated cell adhesion increased Grb7 association with phosphoinositides [14].
  • Although these recognition sequences possess an Asn residue at +2 relative to the phosphotyrosine and therefore represent potential Grb2 binding sites, phosphopeptide competition and "pull-down" experiments demonstrated that they interact preferentially with the Grb7 versus the Grb2 SH2 domain [15].
  • Grb7 associated with activated PDGF beta-receptors in vivo, and the association was dramatically reduced by substitution of Tyr-716 or Tyr-775 with a phenylalanine residue [16].
  • Using tetracycline-regulated expression system, we showed that overexpression of Grb7 enhanced cell migration toward fibronectin, whereas overexpression of its SH2 domain alone inhibited cell migration [17].

Physical interactions of GRB7

  • Moreover, the structure suggests the mechanism by which the Grb7 SH2 domain binds selectively to pTyr-1139 (pYVNQ) in Her2, which along with Grb7 is co-amplified in human breast cancers [18].

Enzymatic interactions of GRB7

  • We also found that Grb7 could be phosphorylated by FAK, which was dependent on the FAK kinase activity but not the presence of the Src family kinases [19].

Regulatory relationships of GRB7


Other interactions of GRB7

  • GRB7 is tightly linked to ERBB2 and is coamplified and coexpressed with this gene in several cancer types [21].
  • This effort identified ErbB4, one of the EGF/heregulin receptors, and Grb7, an adapter protein associated with ErbB4 (ErbB, epidermal growth factor receptor family protein; EGF, epidermal growth factor; Grb, growth factor receptor bound) [22].
  • We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936 [11].
  • Our results point to the involvement of several ErbB-specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer [23].
  • Mutation, elevated expression, and correlations between expression levels of KRAS2, GRB7, and KIT are consistent with their involvement in the development of TGCTs [10].

Analytical, diagnostic and therapeutic context of GRB7


  1. Expression of HER2 and the coamplified genes GRB7 and MLN64 in human breast cancer: quantitative real-time reverse transcription-PCR as a diagnostic alternative to immunohistochemistry and fluorescence in situ hybridization. Vinatzer, U., Dampier, B., Streubel, B., Pacher, M., Seewald, M.J., Stratowa, C., Kaserer, K., Schreiber, M. Clin. Cancer Res. (2005) [Pubmed]
  2. Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma. Walch, A., Specht, K., Braselmann, H., Stein, H., Siewert, J.R., Hopt, U., Höfler, H., Werner, M. Int. J. Cancer (2004) [Pubmed]
  3. ERBB2 amplifications in esophageal adenocarcinoma. Dahlberg, P.S., Jacobson, B.A., Dahal, G., Fink, J.M., Kratzke, R.A., Maddaus, M.A., Ferrin, L.J. Ann. Thorac. Surg. (2004) [Pubmed]
  4. Differential functions of growth factor receptor-bound protein 7 (GRB7) and its variant GRB7v in ovarian carcinogenesis. Wang, Y., Chan, D.W., Liu, V.W., Chiu, P., Ngan, H.Y. Clin. Cancer Res. (2010) [Pubmed]
  5. 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]
  6. A novel variant of human Grb7 is associated with invasive esophageal carcinoma. Tanaka, S., Mori, M., Akiyoshi, T., Tanaka, Y., Mafune, K., Wands, J.R., Sugimachi, K. J. Clin. Invest. (1998) [Pubmed]
  7. Coexpression of Grb7 with epidermal growth factor receptor or Her2/erbB2 in human advanced esophageal carcinoma. Tanaka, S., Mori, M., Akiyoshi, T., Tanaka, Y., Mafune, K., Wands, J.R., Sugimachi, K. Cancer Res. (1997) [Pubmed]
  8. 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]
  9. RNA interference-based functional dissection of the 17q12 amplicon in breast cancer reveals contribution of coamplified genes. Kao, J., Pollack, J.R. Genes Chromosomes Cancer (2006) [Pubmed]
  10. Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors. McIntyre, A., Summersgill, B., Spendlove, H.E., Huddart, R., Houlston, R., Shipley, J. Neoplasia (2005) [Pubmed]
  11. Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor. Thömmes, K., Lennartsson, J., Carlberg, M., Rönnstrand, L. Biochem. J. (1999) [Pubmed]
  12. The adaptor Grb7 links netrin-1 signaling to regulation of mRNA translation. Tsai, N.P., Bi, J., Wei, L.N. EMBO J. (2007) [Pubmed]
  13. The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. Stein, D., Wu, J., Fuqua, S.A., Roonprapunt, C., Yajnik, V., D'Eustachio, P., Moskow, J.J., Buchberg, A.M., Osborne, C.K., Margolis, B. EMBO J. (1994) [Pubmed]
  14. Association of Grb7 with phosphoinositides and its role in the regulation of cell migration. Shen, T.L., Han, D.C., Guan, J.L. J. Biol. Chem. (2002) [Pubmed]
  15. Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3. Fiddes, R.J., Campbell, D.H., Janes, P.W., Sivertsen, S.P., Sasaki, H., Wallasch, C., Daly, R.J. J. Biol. Chem. (1998) [Pubmed]
  16. Grb7 is a downstream signaling component of platelet-derived growth factor alpha- and beta-receptors. Yokote, K., Margolis, B., Heldin, C.H., Claesson-Welsh, L. J. Biol. Chem. (1996) [Pubmed]
  17. Association of focal adhesion kinase with Grb7 and its role in cell migration. Han, D.C., Guan, J.L. J. Biol. Chem. (1999) [Pubmed]
  18. Structural basis for dimerization of the Grb10 Src homology 2 domain. Implications for ligand specificity. Stein, E.G., Ghirlando, R., Hubbard, S.R. J. Biol. Chem. (2003) [Pubmed]
  19. Role of Grb7 targeting to focal contacts and its phosphorylation by focal adhesion kinase in regulation of cell migration. Han, D.C., Shen, T.L., Guan, J.L. J. Biol. Chem. (2000) [Pubmed]
  20. Gene expression profiling detects gene amplification and differentiates tumor types in breast cancer. Dressman, M.A., Baras, A., Malinowski, R., Alvis, L.B., Kwon, I., Walz, T.M., Polymeropoulos, M.H. Cancer Res. (2003) [Pubmed]
  21. New insights into testicular germ cell tumorigenesis from gene expression profiling. Skotheim, R.I., Monni, O., Mousses, S., Fosså, S.D., Kallioniemi, O.P., Lothe, R.A., Kallioniemi, A. Cancer Res. (2002) [Pubmed]
  22. NIK is a component of the EGF/heregulin receptor signaling complexes. Chen, D., Xu, L.G., Chen, L., Li, L., Zhai, Z., Shu, H.B. Oncogene (2003) [Pubmed]
  23. Prognostic value of ERBB family mRNA expression in breast carcinomas. Bièche, I., Onody, P., Tozlu, S., Driouch, K., Vidaud, M., Lidereau, R. Int. J. Cancer (2003) [Pubmed]
  24. Structural determinants of the interaction between the erbB2 receptor and the Src homology 2 domain of Grb7. Janes, P.W., Lackmann, M., Church, W.B., Sanderson, G.M., Sutherland, R.L., Daly, R.J. J. Biol. Chem. (1997) [Pubmed]
  25. Grb7 expression and cellular migration in chronic lymphocytic leukemia: a comparative study of early and advanced stage disease. Haran, M., Chebatco, S., Flaishon, L., Lantner, F., Harpaz, N., Valinsky, L., Berrebi, A., Shachar, I. Leukemia (2004) [Pubmed]
  26. Sequence analysis identifies a ras-associating (RA)-like domain in the N-termini of band 4.1/JEF domains and in the Grb7/10/14 adapter family. Wojcik, J., Girault, J.A., Labesse, G., Chomilier, J., Mornon, J.P., Callebaut, I. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  27. Molecular cloning of human GRB-7 co-amplified with CAB1 and c-ERBB-2 in primary gastric cancer. Kishi, T., Sasaki, H., Akiyama, N., Ishizuka, T., Sakamoto, H., Aizawa, S., Sugimura, T., Terada, M. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
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