Activation of Rho is required for ligand-independent oncogenic signaling by a mutant epidermal growth factor receptor

Mutations in the epidermal growth factor receptor have been identified in s everal human tumor types, including gliomas, These receptor mutants have de letions in their extracellular ligand-binding domains and are, therefore, n o longer regulated by ligand, resulting in constitutive activation of the r eceptor kinase, These mutants have been proposed to transduce oncogenic sig nals via ligand-independent signaling pathways. Avian viral homologues of t hese oncogenic epidermal growth factor receptors exhibit structurally homol ogous deletions and form tumors in chickens. One such mutant, S3v-ErbB, tra nsforms fibroblasts in vitro, and transformation has been correlated with t he formation of a novel tyrosine phosphoprotein complex, V-ErbB-mediated co mplex formation and transformation have been shown to occur independently o f Ras activation. The major aims of this study are to further characterize this ligand-independent v-ErbB oncogenic signaling pathway. Here we show th at both vErbB-mediated phosphoprotein complex formation and transformation are inhibited by a dominant negative mutant of Rho. This inhibition is spec ific for dominant negative Rho; dominant negative mutants of Rac and Cdc42 have no effect on transformation or on tyrosine phosphorylation of the phos phoprotein complex. Based on these observations, we propose that S3v-ErbB s timulates a Rho-dependent tyrosine kinase, resulting in complex formation a nd ultimately oncogenic transformation.