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J. Biol. Chem., Vol. 282, Issue 38, 28226-28236, September 21, 2007

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The Role of Phosphoinositide 3-Kinase C2 in Insulin Signaling^*

Marco Falasca²¹, William E. Hughes³, Veronica Dominguez⁴, Gianluca Sala², Florentia Fostira⁴, Michelle Q. Fang³, Rosanna Cazzolli³, Peter R. Shepherd^¶, David E. James^||3, and Tania Maffucci⁴

From the Inositide Signalling Group, Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, 4 Newark Street, London E1 2AT, United Kingdom, the Phospholipid Biology Group and the ^||Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia, and the ^¶Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand

The members of the class II phosphoinositide 3-kinase (PI3K) family can be activated by several stimuli, indicating that these enzymes can regulate many intracellular processes. Nevertheless, to date, there has been no definitive identification of their in vivo product, their mechanism(s) of activation, or their precise intracellular roles. By metabolic labeling, we here identify phosphatidylinositol 3-phosphate as the sole in vivo product of the insulin-dependent activation of PI3K-C2, confirming the emerging role of such a phosphoinositide in signaling. We demonstrate that activation of PI3K-C2 involves its recruitment to the plasma membrane and that activation is mediated by the GTPase TC10. This is the first report showing a membrane targeting-mediated mechanism of activation for PI3K-C2 and that a small GTP-binding protein can activate a class II PI3K isoform. We also demonstrate that PI3K-C2 contributes to maximal insulin-induced translocation of the glucose transporter GLUT4 to the plasma membrane and subsequent glucose uptake, definitely assessing the role of this enzyme in insulin signaling.

Received for publication, May 29, 2007 , and in revised form, July 13, 2007.

^* This work was supported in part by Diabetes UK (RD Lawrence Fellowship BDA:RD04/0002884), British Heart Foundation Grant PG/06/022/20348 (to M. F.) and the Fondazione Carichieti. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

² Supported by Association for International Cancer Research Grant 05-127.

³ Supported by the National Health and Medical Research Council, Australia.

⁴ Supported by RD Lawrence Fellowship Grant BDA:RD04/0002884 from Diabetes UK.

¹ To whom correspondence should be addressed. Tel.: 44-20-7882-8243; Fax: 44-20-7882-2186; E-mail: m.falasca{at}qmul.ac.uk.

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