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Vol. 17, Issue 9, 3729-3744, September 2006

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Phosphoinositide 3-Kinase C2 Regulates Cytoskeletal Organization and Cell Migration via Rac-dependent Mechanisms

Roy M. Katso^*,, Olivier E. Pardo, Andrea Palamidessi, Clemens M. Franz^*, Marin Marinov^||, Angela De Laurentiis^||, Julian Downward, Giorgio Scita, Anne J. Ridley^*,¶, Michael D. Waterfield^*,¶, and Alexandre Arcaro^||

*Ludwig Institute for Cancer Research, Royal Free and University College Hospital Medical School, London W1W 7BS, United Kingdom; CRUK London Research Institute, London WC2A 3PX, United Kingdom; European Institute of Oncology, The FIRC Institute for Molecular Oncology, 20139 Milano, Italy; ^||Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland; and ^¶Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom

Submitted November 28, 2005; Revised May 22, 2006; Accepted June 7, 2006
Monitoring Editor: Richard Assoian

Receptor-linked class I phosphoinositide 3-kinases (PI3Ks) induce assembly of signal transduction complexes through protein–protein and protein–lipid interactions that mediate cell proliferation, survival, and migration. Although class II PI3Ks have the potential to make the same phosphoinositides as class I PI3Ks, their precise cellular role is currently unclear. In this report, we demonstrate that class II phosphoinositide 3-kinase C2 (PI3KC2) associates with the Eps8/Abi1/Sos1 complex and is recruited to the EGF receptor as part of a multiprotein signaling complex also involving Shc and Grb2. Increased expression of PI3KC2 stimulated Rac activity in A-431 epidermoid carcinoma cells, resulting in enhanced membrane ruffling and migration speed of the cells. Conversely, expression of dominant negative PI3KC2 reduced Rac activity, membrane ruffling, and cell migration. Moreover, PI3KC2-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2 regulates the migration and survival of human tumor cells by distinct molecular mechanisms.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-11-1083) on June 14, 2006.

Present address: Systems Research, GlaxoSmithKline Pharmaceuticals, Gunnels Wood Road, Stevenage, SG 2N1 Hertfordshire, United Kingdom.

Address correspondence to: Alexandre Arcaro (Alexandre.Arcaro{at}kispi.unizh.ch)

Abbreviations used: EGFR, epidermal growth factor receptor; Erk, extracellular signal-regulated kinase; F-actin, filamentous actin; MEK, mitogen-activated Erk kinase; JNK, c-Jun N-terminal kinase; mTOR, mammalian target of rapamycin; PH, pleckstrin homology; PI, phosphatidylinositol; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; pY, phosphotyrosine; SCF, stem cell factor; SCLC, small cell lung cancer; SH, Src homology.

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