Potential Roles of p21ras in Growth Factor Signalling — An Overview

Abstract

The ras proteins are small guanine nucleotide binding, plasma membrane localised proteins which oscillate between an inactive GDP bound state and an active GTP bound state. These two states of normal p21ras are controlled by GTPase activity accelerated by the two GTPase activating proteins p120 GAP and Neurofibromin and by guanine nucleotide exchange factors. Accumulating evidence suggests that one function of growth factor stimulation is to promote an increase in the level of GTP bound p21ras, perhaps by stimulating guanine nucleotide exchange. From experiments in which cellular p21ras action is blocked through microinjection of antibodies or the expression of interfering mutants it is apparent that p21ras is required for tyrosine kinase growth factor receptors to transmit signals leading to mitogenesis or differentiation (Mulcahy et al, 1985; Feig and Cooper, 1988). However it has not been clear what intracellular signalling pathways require p21ras function for their activation by tyrosine kinases. We and others have recently shown that the activation of the MAP kinase pathway by growth factor signalling requires p21ras action. Phosphorylation in response to NGF require cellular p21ras action (de Vries-Smits et al, 1992; Wood et al, 1992; Thomas et al, 1992). We initially discovered a role for p21ras in activation of the MAP kinase pathway by reasoning that if the activation of tyrosine kinase growth factor receptors is to promote an increase in ras-GTP then oncogenic p21ras, since it is locked in the GTP bound form, will activate signalling in the absence of tyrosine kinase activation. By searching for kinases activated following the introduction of recombinant p21ras by scrape loading we showed that oncogenic p21ras activates MAP kinase within 5 minutes (Leevers and Marshall, 1992).