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Published online 10 February 2003. doi:10.1083/jcb.200209105
 The Rockefeller University Press, 0021-9525 $8.00
The Journal of Cell Biology
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© The Rockefeller University Press, 0021-9525
The Journal of Cell Biology

Report

Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the ß2-adrenergic receptor



Savithri Rangarajan1, Jorrit M. Enserink1, H. Bea Kuiperij1, Johan de Rooij1, Leo S. Price1, Frank Schwede2 and Johannes L. Bos1

1 Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, Netherlands
2 BIOLOG Life Science Institute, D-2807 Bremen, Germany

Address correspondence to Johannes L. Bos, Dept. of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, Netherlands. Tel.: 31-30-2538977. Fax: 31-30-2539035. E-mail: J.L.Bos{at}med.uu.nl

cAMP controls many cellular processes mainly through the activation of protein kinase A (PKA). However, more recently PKA-independent pathways have been established through the exchange protein directly activated by cAMP (Epac), a guanine nucleotide exchange factor for the small GTPases Rap1 and Rap2. In this report, we show that cAMP can induce integrin-mediated cell adhesion through Epac and Rap1. Indeed, when Ovcar3 cells were treated with cAMP, cells adhered more rapidly to fibronectin. This cAMP effect was insensitive to the PKA inhibitor H-89. A similar increase was observed when the cells were transfected with Epac. Both the cAMP effect and the Epac effect on cell adhesion were abolished by the expression of Rap1–GTPase-activating protein, indicating the involvement of Rap1 in the signaling pathway. Importantly, a recently characterized cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate, which specifically activates Epac but not PKA, induced Rap-dependent cell adhesion. Finally, we demonstrate that external stimuli of cAMP signaling, i.e., isoproterenol, which activates the G{alpha}s-coupled ß2-adrenergic receptor can induce integrin-mediated cell adhesion through the Epac-Rap1 pathway. From these results we conclude that cAMP mediates receptor-induced integrin-mediated cell adhesion to fibronectin through the Epac-Rap1 signaling pathway.

Key Words: integrins; cyclic nucleotides; GTPases; guanine nucleotide exchange factor; cell adhesion


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