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J. Biol. Chem., Vol. 283, Issue 23, 15861-15868, June 6, 2008

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Disrupted RabGAP Function of the p85 Subunit of Phosphatidylinositol 3-Kinase Results in Cell Transformation^*

M. Dean Chamberlain¹, Tim Chan^¶, Jennifer C. Oberg, Andrea D. Hawrysh, Kristy M. James, Anurag Saxena^¶, Jim Xiang^||, and Deborah H. Anderson^||2

From the Cancer Research Unit, Health Research Division, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan S7N 4H4, Canada and the Departments of Biochemistry, ^||Oncology, and ^¶Pathology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada

Rab proteins regulate vesicle fusion events during the endocytosis, recycling, and degradation of activated receptor tyrosine kinases. The p85 subunit of phosphatidylinositol 3-kinase has GTPase-activating protein activity toward Rab5 and Rab4, an activity severely reduced by a single point mutation (p85-R274A). Expression of p85-R274A resulted in increased platelet-derived growth factor receptor (PDGFR) activation and downstream signaling (Akt and MAPK) and in decreased PDGFR degradation. We now report that the biological consequences of p85-R274A expression cause cellular transformation as determined by the following: aberrant morphological phenotype, loss of contact inhibition, growth in soft agar, and tumor formation in nude mice. Immunohistochemistry shows that the tumors contain activated PDGFR and high levels of activated Akt. Coexpression of a dominant negative Rab5-S34N mutant attenuated these transformed properties. Our results demonstrate that disruption of the RabGAP function of p85 due to a single point mutation (R274A) is sufficient to cause cellular transformation via a phosphatidylinositol 3-kinase-independent mechanism partially reversed by Rab5-S34N expression. This critical new role for p85 in the regulation of Rab function suggests a novel role for p85 in controlling receptor signaling and trafficking through its effects on Rab GTPases.

Received for publication, February 5, 2008 , and in revised form, March 17, 2008.

^* This work was supported in part by the Canadian Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a doctoral scholarship from the Canadian Institutes of Health Research Regional Partnership Program.

² To whom correspondence should be addressed. Tel.: 306-655-2538; Fax: 306-655-2635; E-mail: deborah.anderson{at}saskcancer.ca.

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