HGNC Approved Gene Symbol: GRB7
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:39,737,938-39,747,285 (from NCBI)
Using the CORT (cloning of receptor targets) method devised by Skolnik et al. (1991) to screen a high expression mouse library, Margolis et al. (1992) isolated the gene for murine Grb7, which encodes a protein of 535 amino acids. GRB7 is homologous to ras-GAP (ras-GTPase-activating protein). It contains an SH2 domain and is highly expressed in liver and kidney. This gene defines the GRB7 family, whose members include the mouse gene Grb10 (601523) and the human gene GRB14 (601524).
Tanaka et al. (1998) isolated cDNAs of a putative GRB7 signal transduction molecule and a novel splice variant, GRB7V, from an invasive human esophageal carcinoma. Although both GRB7 isoforms share homology with the Mig10 cell migration gene of Caenorhabditis elegans, the GRB7V isoform lacks 88 basepairs in the C terminus; the resultant frameshift leads to substitution of an SH2 domain with a short hydrophobic sequence.
Tanaka et al. (1998) found that the wildtype GRB7 protein, but not the GRB7V isoform, was rapidly tyrosyl phosphorylated in response to EGF stimulation in esophageal carcinoma cells. Analysis of human esophageal tumor tissues and regional lymph nodes with metastases revealed that GRB7V was expressed in 40% of GRB7-positive esophageal carcinomas. GRB7V expression was enhanced after metastatic spread to lymph nodes as compared to the original tumor tissues. Transfection of an antisense GRB7 RNA expression construct lowered endogenous GRB7 protein levels and suppressed the invasive phenotype exhibited by esophageal carcinoma cells. These findings suggested that GRB7 isoforms are involved in cell invasion and metastatic progression of human esophageal carcinomas.
By yeast 2-hybrid analysis, in vitro protein binding assays, and pull-down experiments with a breast cancer cell line, Vayssiere et al. (2000) showed that RND1 (609038) interacts with GRB7. They determined that the interaction involves the switch II loop of RND1, a region crucial for guanine nucleotide exchange in all GTPases, and an SH2 domain of GRB7, a region crucial for GRB7 interaction with several activated receptors.
By sequence analysis, Dong et al. (1997) mapped the GRB7 gene to chromosome 17q21-q22, near the topoisomerase-2 (126430) gene.
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]
Margolis, B., Silvennoinen, O., Comoglio, F., Roonprapunt, C., Skolnik, E., Ullrich, A., Schlessinger, J. High-efficiency expression/cloning of epidermal growth factor-receptor-binding proteins with Src homology 2 domains. Proc. Nat. Acad. Sci. 89: 8894-8898, 1992. [PubMed: 1409582] [Full Text: https://doi.org/10.1073/pnas.89.19.8894]
Skolnik, E. Y., Margolis, B., Mohammadi, M., Lowenstein, E., Fischer, R., Drepps, A., Ullrich, A., Schlessinger, J. Cloning of PI3 kinase- associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 65: 83-90, 1991. [PubMed: 1849461] [Full Text: https://doi.org/10.1016/0092-8674(91)90410-z]
Tanaka, S., Mori, M., Akiyoshi, T., Tanaka, Y., Mafune, K., Wands, J. R., Sugimachi, K. A novel variant of human Grb7 is associated with invasive esophageal carcinoma. J. Clin. Invest. 102: 821-827, 1998. [PubMed: 9710451] [Full Text: https://doi.org/10.1172/JCI2921]
Vayssiere, B., Zalcman, G., Mahe, Y., Mirey, G., Ligensa, T., Weidner, K. M., Chardin, P., Camonis, J. Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family. FEBS Lett. 467: 91-96, 2000. [PubMed: 10664463] [Full Text: https://doi.org/10.1016/s0014-5793(99)01530-6]