The role of p21ras in receptor tyrosine kinase signaling.

The notion that ras proteins are required for the stimulation of mitogenesis by different receptor tyrosine kinases (RTKs) has spurred researchers to investigate the precise role of p21ras in signal transduction. A large number of stimuli can drive p21ras in the active conformation, and several proteins that play an important role in regulating the GTP/GDP balance on p21ras have been identified. Indeed, activation of p21ras has been demonstrated to occur by stimulation of guanine nucleotide-releasing proteins (GNRPs) or inhibition of GTPase-activating proteins (GAPs). Moreover, a number of SH2-containing proteins have been implicated in this signaling pathway, such as shc and sem-5/grb2. On the other hand, downstream signaling from p21ras involves an important protein kinase cascade. This pathway seems to be conserved in evolution, and analogous routes have been described in organisms such as yeast, nematodes, and fruit flies. Nevertheless, the direct effector molecule of p21ras that could couple to this kinase cascade is still unknown. Some indications have been obtained that suggest that this function might be partially performed by p120GAP. This review gives an overview of the role of p21ras in signaling from diverse RTKs. Elucidation of this pathway will improve our understanding of mitogenic signaling pathways and the basis of cancer.