Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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 3-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.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Naturally Derived Small Molecule Disrupts Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Human Prostate Cancer Cells.
K. S. Amin, S. Jagadeesh, G. Baishya, P. G. Rao, N. C. Barua, S. Bhattacharya, and P. P. Banerjee (2014)
Mol. Cancer Ther. 13, 341-352
   Abstract »    Full Text »    PDF »
Quantitative Imaging of Epithelial Cell Scattering Identifies Specific Inhibitors of Cell Motility and Cell-Cell Dissociation.
D. Loerke, Q. le Duc, I. Blonk, A. Kerstens, E. Spanjaard, M. Machacek, G. Danuser, and J. de Rooij (2012)
Science Signaling 5, rs5
   Abstract »    Full Text »    PDF »
p27kip1 Controls Cell Morphology and Motility by Regulating Microtubule-Dependent Lipid Raft Recycling.
B. Belletti, I. Pellizzari, S. Berton, L. Fabris, K. Wolf, F. Lovat, M. Schiappacassi, S. D'Andrea, M. S. Nicoloso, S. Lovisa, et al. (2010)
Mol. Cell. Biol. 30, 2229-2240
   Abstract »    Full Text »    PDF »
A Single Nucleotide Change in the Mouse Genome Accelerates Breast Cancer Progression.
N. Seitzer, T. Mayr, S. Streit, and A. Ullrich (2010)
Cancer Res. 70, 802-812
   Abstract »    Full Text »    PDF »
{beta}1 Integrin Cytoplasmic Variants Differentially Regulate Expression of the Antiangiogenic Extracellular Matrix Protein Thrombospondin 1.
H. L. Goel, L. Moro, J. E. Murphy-Ullrich, C.-C. Hsieh, C.-L. Wu, Z. Jiang, and L. R. Languino (2009)
Cancer Res. 69, 5374-5382
   Abstract »    Full Text »    PDF »
Cyclin-Dependent Kinase Inhibitors Block Leukocyte Adhesion and Migration.
L. Liu, B. Schwartz, Y. Tsubota, E. Raines, H. Kiyokawa, K. Yonekawa, J. M. Harlan, and L. M. Schnapp (2008)
J. Immunol. 180, 1808-1817
   Abstract »    Full Text »    PDF »
Cdc2-mediated Schwann cell migration during peripheral nerve regeneration.
I. S. Han, T. B. Seo, K.-H. Kim, J.-H. Yoon, S.-J. Yoon, and U. Namgung (2007)
J. Cell Sci. 120, 246-255
   Abstract »    Full Text »    PDF »
Aberrant Splicing of Cyclin-Dependent Kinase-Associated Protein Phosphatase KAP Increases Proliferation and Migration in Glioblastoma.
Y. Yu, X. Jiang, B. S. Schoch, R. S. Carroll, P. M. Black, and M. D. Johnson (2007)
Cancer Res. 67, 130-138
   Abstract »    Full Text »    PDF »
Cyclin D1 Induction of Cellular Migration Requires p27KIP1..
Z. Li, X. Jiao, C. Wang, X. Ju, Y. Lu, L. Yuan, M. P. Lisanti, S. Katiyar, and R. G. Pestell (2006)
Cancer Res. 66, 9986-9994
   Abstract »    Full Text »    PDF »
Cyclin D1 Regulates Cellular Migration through the Inhibition of Thrombospondin 1 and ROCK Signaling.
Z. Li, C. Wang, X. Jiao, Y. Lu, M. Fu, A. A. Quong, C. Dye, J. Yang, M. Dai, X. Ju, et al. (2006)
Mol. Cell. Biol. 26, 4240-4256
   Abstract »    Full Text »    PDF »
A Discoidin Domain Receptor 1/SHP-2 Signaling Complex Inhibits {alpha}2beta1-Integrin-mediated Signal Transducers and Activators of Transcription 1/3 Activation and Cell Migration.
C.-Z. Wang, H.-W. Su, Y.-C. Hsu, M.-R. Shen, and M.-J. Tang (2006)
Mol. Biol. Cell 17, 2839-2852
   Abstract »    Full Text »    PDF »
Deregulation of HEF1 Impairs M-Phase Progression by Disrupting the RhoA Activation Cycle.
D. Dadke, M. Jarnik, E. N. Pugacheva, M. K. Singh, and E. A. Golemis (2006)
Mol. Biol. Cell 17, 1204-1217
   Abstract »    Full Text »    PDF »
{beta}1 Integrins Modulate Cell Adhesion by Regulating Insulin-Like Growth Factor-II Levels in the Microenvironment.
H. L. Goel, L. Moro, M. King, N. Teider, M. Centrella, T. L. McCarthy, M. Holgado-Madruga, A. J. Wong, E. Marra, and L. R. Languino (2006)
Cancer Res. 66, 331-342
   Abstract »    Full Text »    PDF »
HCaRG increases renal cell migration by a TGF-{alpha} autocrine loop mechanism.
C. E. Hader, S. Tremblay, N. Solban, D. Gingras, R. Beliveau, S. N. Orlov, P. Hamet, and J. Tremblay (2005)
Am J Physiol Renal Physiol 289, F1273-F1280
   Abstract »    Full Text »    PDF »
Cyclin E Overexpression Obstructs Infiltrative Behavior in Breast Cancer: A Novel Role Reflected in the Growth Pattern of Medullary Breast Cancers.
P. Berglund, M. Stighall, K. Jirstrom, S. Borgquist, A. Sjolander, I. Hedenfalk, and G. Landberg (2005)
Cancer Res. 65, 9727-9734
   Abstract »    Full Text »    PDF »
Regulation of Microfilament Organization by Kaposi Sarcoma-associated Herpes Virus-cyclin{middle dot}CDK6 Phosphorylation of Caldesmon.
M. E. Cuomo, A. Knebel, G. Platt, N. Morrice, P. Cohen, and S. Mittnacht (2005)
J. Biol. Chem. 280, 35844-35858
   Abstract »    Full Text »    PDF »
{beta}1A Integrin Expression Is Required for Type 1 Insulin-Like Growth Factor Receptor Mitogenic and Transforming Activities and Localization to Focal Contacts.
H. L. Goel, M. Breen, J. Zhang, I. Das, S. Aznavoorian-Cheshire, N. M. Greenberg, A. Elgavish, and L. R. Languino (2005)
Cancer Res. 65, 6692-6700
   Abstract »    Full Text »    PDF »
Down-regulation of BRCA2 Expression by Collagen Type I Promotes Prostate Cancer Cell Proliferation.
L. Moro, A. A. Arbini, E. Marra, and M. Greco (2005)
J. Biol. Chem. 280, 22482-22491
   Abstract »    Full Text »    PDF »
Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression.
S. Achilefu, S. Bloch, M. A. Markiewicz, T. Zhong, Y. Ye, R. B. Dorshow, B. Chance, and K. Liang (2005)
PNAS 102, 7976-7981
   Abstract »    Full Text »    PDF »
Phosphorylation of actopaxin regulates cell spreading and migration.
D. M. Clarke, M. C. Brown, D. P. LaLonde, and C. E. Turner (2004)
J. Cell Biol. 166, 901-912
   Abstract »    Full Text »    PDF »
Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by {beta}1 integrins.
H. L. Goel, M. Fornaro, L. Moro, N. Teider, J. S. Rhim, M. King, and L. R. Languino (2004)
J. Cell Biol. 166, 407-418
   Abstract »    Full Text »    PDF »
Hgc1, a novel hypha-specific G1 cyclin-related protein regulates Candida albicans hyphal morphogenesis.
X. Zheng, Y. Wang, and Y. Wang (2004)
EMBO J. 23, 1845-1856
   Abstract »    Full Text »    PDF »
Cytoplasmic p21Cip1 Is Involved in Ras-induced Inhibition of the ROCK/LIMK/Cofilin Pathway.
S. Lee and D. M. Helfman (2004)
J. Biol. Chem. 279, 1885-1891
   Abstract »    Full Text »    PDF »
Other Noteworthy Papers This Week.
(2003)
Sci. Aging Knowl. Environ. 2003, nw74-74
   Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882