The αvβ3 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 αvβ3 and, as downstream effector, by cdc2 (cdk1). We report that αvβ3 expression in LNCaP (β3-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 αvβ3 integrin, and that it promotes cell migration.
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26 May 2003
Article|
May 27 2003
αvβ3 integrin expression up-regulates cdc2, which modulates cell migration
Thomas Manes,
Thomas Manes
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
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Duo-Qi Zheng,
Duo-Qi Zheng
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
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Simona Tognin,
Simona Tognin
2DIBIT-Department of Biological and Technological Research, University Vita-Salute San Raffaele School of Medicine, 20132 Milan, Italy
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Amy S. Woodard,
Amy S. Woodard
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
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Pier Carlo Marchisio,
Pier Carlo Marchisio
2DIBIT-Department of Biological and Technological Research, University Vita-Salute San Raffaele School of Medicine, 20132 Milan, Italy
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Lucia R. Languino
Lucia R. Languino
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
3Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605
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Thomas Manes
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
Duo-Qi Zheng
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
Simona Tognin
2DIBIT-Department of Biological and Technological Research, University Vita-Salute San Raffaele School of Medicine, 20132 Milan, Italy
Amy S. Woodard
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
Pier Carlo Marchisio
2DIBIT-Department of Biological and Technological Research, University Vita-Salute San Raffaele School of Medicine, 20132 Milan, Italy
Lucia R. Languino
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
3Department 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: [email protected]
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.
Received:
December 30 2002
Revision Received:
April 01 2003
Accepted:
April 11 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 161 (4): 817–826.
Article history
Received:
December 30 2002
Revision Received:
April 01 2003
Accepted:
April 11 2003
Citation
Thomas Manes, Duo-Qi Zheng, Simona Tognin, Amy S. Woodard, Pier Carlo Marchisio, Lucia R. Languino; αvβ3 integrin expression up-regulates cdc2, which modulates cell migration . J Cell Biol 26 May 2003; 161 (4): 817–826. doi: https://doi.org/10.1083/jcb.200212172
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