Many faces of Ras activation.

Ras proteins were originally identified as the products of oncogenes capable of inducing cell transformation. Over the last twenty-five years they have been studied in great detail because mutant Ras proteins are associated with many types of human cancer. Wild type Ras proteins play a central role in the regulation of proliferation and differentiation of various cell types. They alternate between an active GTP-bound state and an inactive GDP-bound state. Their activation is catalysed by a specialized group of enzymes known as guanine nucleotide exchange factors (GEFs). To date, four subfamilies of GEF molecules have been identified. Although all of them are able to activate Ras, their structure, tissue expression and regulation are significantly diverse. In this review we will summarize the various mechanisms by which these exchange factors activate Ras.