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J. Biol. Chem., Vol. 279, Issue 43, 44889-44896, October 22, 2004

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The cAMP-Epac-Rap1 Pathway Regulates Cell Spreading and Cell Adhesion to Laminin-5 through the ₃₁ Integrin but Not the ₆₄ Integrin^*

Jorrit M. Enserink¶, Leo S. Price¶||, Trond Methi, Milada Mahic, Arnoud Sonnenberg**, Johannes L. Bos||, and Kjetil Taskén

From the Biotechnology Centre of Oslo, University of Oslo, Blindern, N-0317 Oslo, Norway, the ^||Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands, and the ^**Division of Cell Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Laminin-5 is an important constituent of the basal lamina. The receptors for laminin-5, the integrins ₃₁ and ₆₄, have been associated with epithelial wound migration and carcinoma invasion. The signal transduction mechanisms that regulate these integrins are not well understood. We report here that the small GTPase Rap1 regulates the adhesion of a number of cell lines to various extracellular matrix proteins including laminin-5. cAMP also mediates cell adhesion and spreading on laminin-5, a process that is independent of protein kinase A but rather dependent on Epac1, a cAMP-dependent exchange factor for Rap. Interestingly, although both ₃₁ and ₆₄ mediate adhesion to laminin-5, only ₃₁-dependent adhesion is dependent on Rap1. These results provide evidence for a function of the cAMP-Epac-Rap1 pathway in cell adhesion and spreading on different extracellular matrix proteins. They also define different roles for the laminin-binding integrins in regulated cell adhesion and subsequent cell spreading.

Received for publication, April 26, 2004 , and in revised form, August 2, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Ludwig Inst. for Cancer Research, University of California, San Diego 9500 Gilman Dr., La Jolla, CA 92093-0670.

^¶ These authors contributed equally to this work.

To whom correspondence should be addressed: The Biotechnology Centre of Oslo, University of Oslo, P.O. Box 1125, Blindern, N-0317 Oslo, Norway. Tel.: 47-22840505; Fax: 47-22840506; E-mail: kjetil.tasken{at}biotek.uio.no.

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