Gab1, SHP-2 and Other Novel Regulators of Ras: Targets for Anticancer Drug Discovery?

Ras proteins function as molecular switches that cycle between an inactive GDP-bound state, and an active GTP-bound form that triggers different signaling pathways. Because Ras can integrate both proliferative and anti-apoptotic stimuli, GTP-locked Ras mutants play a critical role in the development of human tumors. Moreover, wild-type Ras relays the transforming potential of a number of molecules involved in tumor development, including protein tyrosine kinases. Consequently, the molecular intermediates that control Ras activation are potential targets of anti-tumoral pharmacology. Besides the canonical Shc / Grb2 / Sos module classically involved in Ras activation, novel effectors have recently been shown to participate in this pathway, including the multivalent Grb2-associated docking protein Gab1, the protein tyrosine phosphatase SHP-2, and the phosphoinositide 3-kinase. Recent genetic advances have shown that these proteins are critically involved in cell proliferation and survival, further suggesting that they could be interesting targets for selective tumor therapy. Here we review recent progress in our understanding of the role of Gab1 and its partners in Ras activation, and other survival / proliferation pathways. Implications for the pharmacological manipulation of this pathway in the treatment of cancer will also be discussed.