The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1

Abstract

MANY tyrosine kinases, including the receptors for hormones such as epidermal growth factor (EGF), nerve growth factor and insulin, transmit intracellular signals through Ras proteins1-4. Ligand binding to such receptors stimulates Ras guanine-nucleotide-exchange activity5-9 and increases the level of GTP-bound Ras10-12, suggesting that these tyrosine kinases may activate a guanine-nucleotide releasing protein (GNRP). In Caenorhabditis elegans and Drosophila, genetic studies have shown that Ras activation by tyrosine kinases requires the protein Sem-5/drk, which contains a single Src-homology (SH) 2 domain and two flanking SH3 domains13-15. Sem-5 is homologous to the mammalian protein Grb2, ..