A GRB2-ASSOCIATED DOCKING PROTEIN IN EGF-RECEPTOR AND INSULIN-RECEPTOR SIGNALING

THE protein Grb2 plays a central role in signalling by receptor protei n-tyrosine kinases(1,2), where its SH2 domain binds to the receptor an d its two SH3 domains link to effecters. One target effector is Sos, s o Grb2 links receptor protein-tyrosine kinases with the Ras signalling pathway. The SH3 domains can also couple to other signalling proteins , including Vav(3), c-AbI(4) and dynamin(5), We have identified severa l bands in glial and medulloblastoma tumours that are recognized by Gr b2 but these did not correspond to any known protein. Here we use reco mbinant Grb2 to isolate a complementary DNA called Gab1 (for Grb2-asso ciated binder-1). Gab1 shares amino-acid homology and several structur al features with IRS-1 (insulin-receptor substrate-1; refs 6,7), is a substate of the EGF and insulin receptors, and can act as a docking pr otein for several SH2-containing proteins, Overexpression of Gab1 enha nces cell growth and results in transformation. We conclude that Gab1 is a new protein in EGF and insulin receptor signalling which could in tegrate signals from different systems.