Activation of Rho Is Required for Ligand-independent Oncogenic Signaling by a Mutant Epidermal Growth Factor Receptor

• Published in: The Journal of biological chemistry 2001-02, Vol.276 (5), p.3691-3695
• Main Authors: Boerner, Julie L., Danielsen, Andrew, McManus, Michael J., Maihle, Nita J.
• Format: Article
• Language: English
• Subjects: Animals; cdc42 GTP-Binding Protein - metabolism; Cell Transformation, Neoplastic - metabolism; Chickens; Colony-Forming Units Assay; ErbB Receptors - metabolism; Fibroblasts - metabolism; Mutation; Oncogene Proteins v-erbB - metabolism; Oncogene Proteins v-erbB - physiology; Phosphoproteins - metabolism; rac GTP-Binding Proteins - metabolism; rho GTP-Binding Proteins - metabolism; Rho protein; S3v-ErbB protein; Signal Transduction - physiology; v-ErbB protein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M003801200

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.