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J. Cell Biol. 151 (2): 249-262

Copyright © 2000 by the Rockefeller University Press.

Original Article

Role of the Pi3k Regulatory Subunit in the Control of Actin Organization and Cell Migration

Concepción Jiméneza, Rosario Armas Portelab, Mario Melladoa, Jose Miguel Rodríguez-Fradea, John Collardc, Antonio Serranoa, Carlos Martínez-Aa, Jesus Avilab, , and Ana C. Carreraa

a Department of Immunology and Oncology, Centro Nacional de Biotecnología,
b Centro de Biología Molecular, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049, Spain
c The Netherlands Cancer Institute, Division of Cell Biology, 1066 CX, Amsterdam, The Netherlands
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Carretera de Colmenar Km 16, Cantoblanco, Madrid E-28049, Spain.34-91-372-049334-91-585-4849

Abstract: Cell migration represents an important cellular response that utilizes cytoskeletal reorganization as its driving force. Here, we describe a new signaling cascade linking PDGF receptor stimulation to actin rearrangements and cell migration. We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes. Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85{alpha} regulatory subunit of PI3K. Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen. These observations show the essential role of the PI3K regulatory subunit p85{alpha} in controlling PDGF receptor–induced cytoskeletal changes and cell migration, illustrating a novel signaling pathway that links receptor stimulation at the cell membrane with actin dynamics.

Key Words: N-WASP • Cdc42 • PDGF • phosphatidylinositol 3-kinase • actin cytoskeleton

Abbreviations used in this paper: Ab, antibody; DN, dominant negative; ECM, extracellular matrix; F-actin, filamentous actin; GEF, guanine nucleotide exchange factors; N-WASP, N-Wiskott-Aldrich Syndrome family protein; LPA, lysophosphatidic acid; PDGF, platelet-derived growth factor; PDGF-R, PDGF receptor; PI3K, phosphoinositide 3-kinase.

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