Visit our Expo - Redox and Inflammation signaling 2012

Epac and Rap1 in the control of cell adhesion
Johannes L. Bos
Department of Physiological Chemistry and Centre for Biomedical Genetics, University
Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Rap1 is a Ras-like small GTPase originally identified as a revertant of Ras-induced cell
transformation, but current studies in both lower eakaryotes and mammalian cells have
revealed that the main function of Rap in the control of cell adhesion. Rap1 is activated by a
variety of different stimuli, some of which are mediated by cAMP. We have identified
previously two guanine nucleotide exchange factors (GEFs) for Rap1, Epac1 and Epac2.
These two GEFs have a cAMP-binding domain and respond to cAMP. Structural analyses
revealed that the cAMP binding domain functions as an auto-inhibitory domain, preventing
binding of Rap by steric hindrance. By structure-based drug design we developed a cAMP
analog 8-pCPT-2'OMe-cAMP (007) that efficiently activates Epac but not protein kinase A
(PKA). Indeed in various cell lines 007 was able to induce Rap1 activation, but not PKA. 007
did not induce the activation of ERK, challenging the model that cAMP-induced activation of
ERK is mediated by Rap1. Using this analog we could show that both Epac and Rap1
regulates integrin-mediated cell adhesion and E-cadherin and VE-cadherin-mediated cell
junction formation. Our results suggest that Rap1 may have a more general function in cell
adhesion, perhaps in the recruitment of cell adhesion molecules.
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