title: Activation of Rho is required for ligand-independent oncogenic signaling by a mutant epidermal growth factor receptor.
abstract: Mutations in the epidermal growth factor receptor have been identified in several human tumor types, including gliomas. These receptor mutants have deletions in their extracellular ligand-binding domains and are, therefore, no longer regulated by ligand, resulting in constitutive activation of the receptor kinase. These mutants have been proposed to transduce oncogenic signals via ligand-independent signaling pathways. Avian viral homologues of these oncogenic epidermal growth factor receptors exhibit structurally homologous deletions and form tumors in chickens. One such mutant, S3v-ErbB, transforms fibroblasts in vitro, and transformation has been correlated with the formation of a novel tyrosine phosphoprotein complex. V-ErbB-mediated complex formation and transformation have been shown to occur independently of Ras activation. The major aims of this study are to further characterize this ligand-independent v-ErbB oncogenic signaling pathway. Here we show that both v-ErbB-mediated phosphoprotein complex formation and transformation are inhibited by a dominant negative mutant of Rho. This inhibition is specific for dominant negative Rho; dominant negative mutants of Rac and Cdc42 have no effect on transformation or on tyrosine phosphorylation of the phosphoprotein complex. Based on these observations, we propose that S3v-ErbB stimulates a Rho-dependent tyrosine kinase, resulting in complex formation and ultimately oncogenic transformation.
authors: Tumor Biology Program, Department of Biochemistry, and Department of Pediatrics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: J L
authors: JL
authors: Boerner
authors: A
authors: A
authors: Danielsen
authors: M J
authors: MJ
authors: McManus
authors: N J
authors: NJ
authors: Maihle
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002645:Chickens; D003114:Colony-Forming Units Assay; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D009154:Mutation; D018739:Oncogene Proteins v-erbB / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D018739:Oncogene Proteins v-erbB; D010750:Phosphoproteins; D066246:ErbB Receptors; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins