THE GTPASE AND RHO-GAP DOMAINS OF P190, A TUMOR-SUPPRESSOR PROTEIN THAT BINDS THE M-R 120,000 RAS GAP, INDEPENDENTLY FUNCTION AS ANTI-RAS TUMOR SUPPRESSORS

p190 is a Tyr-phosphorylatable G protein of M-r 190,000 that binds NH2 -terminal SH2 domains of GAP1, a Pas GAP of M-r 120,000. p190 contains at least two functional domains: a GTPase domain at the NH2 terminus and a GAP domain at the COOH terminus that can attenuate signal-transd ucing activity of three distinct G proteins (Pac, Rho, and CDC42). Her e, we demonstrate that overexpression of either an antisense p190 RNA or a dominant negative mutant (Asn(36)) of p190 GTPase domain (residue s 1-251) but not the wild-type p190 GTPase domain is able to transform normal NIH/3T3 fibroblasts. Furthermore, overexpression of either the wild-type p190 GTPase domain or the COOH-terminal GAP domain can supp ress v-aa-lias-induced malignant transformation. These results indicat e that p190 contains at least two distinct anti-Pas tumor suppressor d omains, the GTPase and GAP domains, and suggest that one of the mechan isms underlying the suppression of Pas-transformation by p190 is the a ttenuation by p190 GAP domain of Rac/Rho/CDC42 signalings, which are e ssential for Pas-transformation, In fact, the p190 GAP domain alone su ppresses the expression of the c-Fos gene, which is mediated by Rac/Rh o/CDC42 and is required for oncogenicity of Ras.