Growth factor triggering of protein tyrosine kinase receptors induces signals that cascade to the nucleus, activating mitogenic as well as other responses. Critical components of this process include adapter proteins such as Shc, IRS-1 and Gab 1 (GRB-associated binder-1) that lack detectable catalytic activity (1-3,8). Gab1 can be phosphorylated by multiple receptor tyrosine kinase (RTKs), including: insulin receptor (IR), platelet derived growth factor receptor beta] (PDGFRbeta]), hepatocyte growth factor/scatter factor receptor (HGFR/SFR or c Met), and epidermal growth factor receptor (EGF), as well as in response to cell cell adhesion. Gab1 is tyrosine phosphorylated on at least 16 sites, some of which serve as binding sites for phosphoatidylinositol 3 kinase (PI3K), Grb2, PLC gamma 1, Nck, and SHP2. Phosphorylation of Gab1 on tyrosines 627 and 659 is critical for its binding to SHP2, and for activation of the ERK/MAPK pathway in response to EGF.