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Originally published In Press as doi:10.1074/jbc.M003801200 on November 10, 2000

J. Biol. Chem., Vol. 276, Issue 5, 3691-3695, February 2, 2001
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Activation of Rho Is Required for Ligand-independent Oncogenic Signaling by a Mutant Epidermal Growth Factor Receptor*

Julie L. BoernerDagger §, Andrew Danielsen, Michael J. McManus||, and Nita J. MaihleDagger **

From the Dagger  Tumor Biology Program, Department of Biochemistry, and  Department of Pediatrics, Mayo Clinic, Rochester, Minnesota 55905

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.

* This work was supported by National Institutes of Health Grants CA75238 (to M. J. M.) and CA 79808 (to N. J. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Submitted in partial fulfillment of doctoral thesis requirements in the Mayo Graduate School. Supported by National Institutes of Health Training Grant CA 75926 (to the Tumor Biology Program of the Mayo Graduate School). Current address: Dept. of Microbiology, University of Virginia Health Science Center, Charlottesville, VA 22908.

|| Current address: Dept. of Molecular and Experimental Medicine, Scripps Research Inst., La Jolla, CA 92037.

** To whom correspondence should be addressed: Mayo Clinic, 200 1st St. SW, Rochester, MN 55905. Tel.: 507-284-8121; E-mail: Maihle@mayo.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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