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J. Biol. Chem., Vol. 279, Issue 47, 48607-48614, November 19, 2004

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The p85 Subunit of Phosphatidylinositol 3'-Kinase Binds to and Stimulates the GTPase Activity of Rab Proteins^*

M. Dean Chamberlain¶, Tangyne R. Berry, M. Chris Pastor, and Deborah H. Anderson||**

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

Rab5 and Rab4 are small monomeric GTPases localized on early endosomes and function in vesicle fusion events. These Rab proteins regulate the endocytosis and recycling or degradation of activated receptor tyrosine kinases such as the platelet-derived growth factor receptor (PDGFR). The p85 subunit of phosphatidylinositol 3'-kinase contains a BH domain with sequence homology to GTPase activating proteins (GAPs), but has not previously been shown to possess GAP activity. In this report, we demonstrate that p85 has GAP activity toward Rab5, Rab4, Cdc42, Rac1 and to a lesser extent Rab6, with little GAP activity toward Rab11. Purified recombinant Rab5 and p85 can bind directly to each other and not surprisingly, the p85-encoded GAP activity is present in the BH domain. Because p85 stays bound to the PDGFR during receptor endocytosis, p85 will also be localized to the same early endosomal compartment as Rab5 and Rab4. Taken together, the physical co-localization and the ability of p85 to preferentially stimulate the down-regulation of Rab5 and Rab4 GTPases suggests that p85 regulates how long Rab5 and Rab4 remain in their GTP-bound active state. Cells expressing BH domain mutants of p85 show a reduced rate of PDGFR degradation as compared with wild type p85 expressing cells. These cells also show sustained activation of the mitogen-activated protein kinase and Akt pathways. Thus, the p85 protein may play a role in the down-regulation of activated receptors through its temporal control of the GTPase cycles of Rab5 and Rab4.

Received for publication, August 25, 2004

^* This work was supported in part by the Natural Sciences and Engineering Research Council and the Saskatchewan Cancer Agency Research Fund. 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.

^¶ Recipient of a Canadian Institutes of Health Research Regional Partnership Program doctoral award.

^** To whom correspondence should be addressed: Cancer Research Unit, Health Research Division, Saskatchewan Cancer Agency, 20 Campus Dr., Saskatoon, Saskatchewan S7N 4H4, Canada. Tel.: 306-655-2538; Fax: 306-655-2898; E-mail: danderson{at}scf.sk.ca.

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