Growth factor receptor
bound-7 (GRB-7)

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Gene: maps to 17q11.2-17q12.
mRNA: size: 2.2 kb.
Protein: the 539-amino acid (aa), 59-kDa Grb-7 contains a proline-rich sequence in its NH2-terminus, a distinct central region with a pleckstrin homology (PH) domain, and an Src-homology-2 (SH2) domain in its COOH-terminus. The PH domain could interact with phospholipids (Harlen J.E. et al., 1994) and be involved in signal transduction pathways related to cell growth. SH2-domain-expressing molecules may interact with proteins containing phosphotyrosine motifs and appear to function as essential components in signal transduction pathways after receptor tyrosine kinase activation by ligands such as EGF, insulin, or PDGF.
A 447-aa, 50-kDa Grb-7 variant (Grb-7V) lacking the SH2 domain has been found in invasive esophageal carcinoma cells. In these cells, Grb-7 was shown to be tyrosyl phosphorylated by EGF stimulation. Also, EGF stimulated the in vitro (Matrigel assay) invasive potential of these cells, a phenomenon that was suppressed when Grb-7 and Grb-7V protein levels were reduced by expression of an antisense RNA (Tanaka S. et al., 1998).

Cell lines:
- GRB-7 gene co-amplified with HER-2 in BT-474 and SK-BR-3 breast cancer cell (BCC) lines. No GRB-7 gene amplification nor overexpression in BT-20, BT-483, MDA-MB-231, MDA-MB-361, MDA-MB-453, T-47D, MCF-7, ZR-75-1 BCC.

- GRB-7 binds tightly to HER-2 through its SH2 domain, such that a large fraction of tyrosine phosphorylated HER-2 is bound to GRB-7 in SK-BR-3 BCC (Stein D. et al., 1994).

- In human BCC lines, co-immunoprecipitation of Grb7 with both erbB3 and erbB4 was detected upon heregulin stimulation. This association was direct and mediated by the Grb7 Src homology (SH)2 domain. Co-expression of erbB2 with erbB3 point mutants was used to map Grb7 binding sites. This demonstrated that tyrosine 1180 and 1243 represent the major and minor sites of Grb7 interaction, respectively. 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. Substitution analysis indicated that an Arg residue at +3 could act as a selectivity determinant, but the effect was context-dependent. Consequently, the Grb2 and Grb7 SH2 domains possess overlapping, but distinct, specificities (Fiddes R.J. et al., 1998).

Tumors:
- Co-amplification and overexpression of GRB-7 and HER-2 often observed.

Fiddes R.J. et al. (1998) Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3. J. Biol. Chem. 273, 7717-7724.
Harlen J.E. et al. (1994) Pleckstrin homology domains bind to phosphatidylinositol-4, 5-bisphosphate. Nature 371, 168-170.
Kishi T. et al. (1997) Molecular cloning of human GRB-7 co-amplified with CAB1 and c-ERBB-2 in primary gastric cancer. Biochem. Biophys. Res. Commun. 232, 5-9.
Margolis B. et al. (1992) High-efficiency expression/cloning of epidermal growth factor-receptor-binding proteins with Src homology 2 domains. Proc. Natl. Acad. Sci. USA 89, 8894-8898.
Stein D. et al. (1994) The SH2 domain protein GRB-7 is co-amplified, overexpressed and in tight complex with HER2 in breast cancer. EMBO J. 13, 1331-1340.
Tanaka S. et al. (1998) A novel variant of human Grb7 is associated with invasive esophageal carcinoma. J. Clin. Invest. 102, 821-827.