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MBC in Press, published online ahead of print June 14, 2006
Mol. Biol. Cell 10.1091/mbc.E05-11-1083

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Submitted on November 28, 2005
Revised on May 22, 2006
Accepted on June 7, 2006

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

Roy M. Katso,*{dagger} Olivier E. Pardo,{ddagger} Andrea Palamidessi,{sect} Clemens Franz,* Marin Marinov,|| Angela De Laurentiis,|| Julian Downward,{ddagger} Giorgio Scita,{sect} 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; {ddagger}CRUK London Research Institute, London WC2A 3PX, United Kingdom; {sect}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; Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom

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{beta} (PI3KC2{beta}) associates with the Eps8/Abi1/Sos1 complex, and is recruited to the EGF receptor as part of a multi-protein signaling complex also involving Shc and Grb2. Increased expression of PI3KC2{beta} 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{beta} reduced Rac activity, membrane ruffling and cell migration. Moreover, PI3KC2{beta}-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2{beta} regulates the migration and survival of human tumor cells by distinct molecular mechanisms.

{dagger}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)




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