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J. Cell Biol. 161 (4): 817-826

Copyright © 2003 by the Rockefeller University Press.

Article

{alpha}vß3 integrin expression up-regulates cdc2, which modulates cell migration

Thomas Manes1, Duo-Qi Zheng1, Simona Tognin2, Amy S. Woodard1, Pier Carlo Marchisio2, and Lucia R. Languino1,3

1 Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
2 DIBIT-Department of Biological and Technological Research, University Vita-Salute San Raffaele School of Medicine, 20132 Milan, Italy
3 Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605

Address correspondence to L.R. Languino, Dept. of Cancer Biology, University of Massachusetts Medical School, LRB, 364 Plantation St., Room 417, Worcester, MA 01605. Tel.: (508) 856-1606. Fax: (508) 856-3845. E-mail: Lucia.Languino{at}umassmed.edu

Abstract: The {alpha}vß3 integrin has been shown to promote cell migration through activation of intracellular signaling pathways. We describe here a novel pathway that modulates cell migration and that is activated by {alpha}vß3 and, as downstream effector, by cdc2 (cdk1). We report that {alpha}vß3 expression in LNCaP (ß3-LNCaP) prostate cancer cells causes increased cdc2 mRNA levels as evaluated by gene expression analysis, and increased cdc2 protein and kinase activity levels. We provide three lines of evidence that increased levels of cdc2 contribute to a motile phenotype on integrin ligands in different cell types. First, increased levels of cdc2 correlate with more motile phenotypes of cancer cells. Second, ectopic expression of cdc2 increases cell migration, whereas expression of dominant-negative cdc2 inhibits migration. Third, cdc2 inhibitors reduce cell migration without affecting cell adhesion. We also show that cdc2 increases cell migration via specific association with cyclin B2, and we unravel a novel pathway of cell motility that involves, downstream of cdc2, caldesmon. cdc2 and caldesmon are shown here to localize in membrane ruffles in motile cells. These results show that cdc2 is a downstream effector of the {alpha}vß3 integrin, and that it promotes cell migration.

Key Words: cell adhesion; cyclin B2; caldesmon; prostate cancer; purvalanola

Amy S. Woodard's present name and address is Amy S. Woodard Freyman, Genetics Institute/Wyeth-Ayerst Research, 87 Cambridge Park Dr., Cambridge, MA 02140.

* Abbreviations used in this paper: 2D, two dimensional; 3D, three dimensional; FN, fibronectin; IB, immunoblotting; MEF, mouse embryonic fibroblast; VN, vitronectin; wt, wild type.

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