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Rangarajan, S. et al. Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the 2-adrenergic receptor. J. Cell Biol. 160, 487-493.Demonstrated for the first time the requirement of endogenous Rap for integrin activation by the use of 8-pCPT-2'-O-Me-cAMP, a specific activator of the RapGEF Epac

Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Netherlands.
The Journal of Cell Biology (Impact Factor: 9.83). 03/2003; 160(4):487-93. DOI: 10.1083/jcb.200209105
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ABSTRACT

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 beta 2-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.

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    • "In U937 cells, treatment with 8-pCPT-2 0 -O-Me-cAMP increased the number of polarised cells on fibronectin, spatially distributing EPAC to the rear of the cell and stimulating chemotaxis (Lorenowicz et al., 2006). Indeed, b-AR activation in Ovar3 cells induced integrin-mediated adhesion to fibronectin via a cAMP, EPAC and Rap1-dependent pathway (Rangarajan et al., 2003). However, both PKA and EPAC were required for integrin-mediated adhesion to modulate human umbilical vein endothelial cell migration (Lorenowicz et al., 2008). "
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    • "In U937 cells, treatment with 8-pCPT-2 0 -O-Me-cAMP increased the number of polarised cells on fibronectin, spatially distributing EPAC to the rear of the cell and stimulating chemotaxis (Lorenowicz et al., 2006). Indeed, b-AR activation in Ovar3 cells induced integrin-mediated adhesion to fibronectin via a cAMP, EPAC and Rap1-dependent pathway (Rangarajan et al., 2003). However, both PKA and EPAC were required for integrin-mediated adhesion to modulate human umbilical vein endothelial cell migration (Lorenowicz et al., 2008). "

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    • "Although it has been argued that it is actually 007's indirect activation of PKA, rather than activation of EPAC1, that resulted in inhibition of migration and proliferation of prostate cancer (Menon et al., 2012). In ovarian cancer, EPAC1 seems to have pro-migratory effects in some cell lines (Ovcar3) (Rangarajan et al., 2003), and anti-migratory effects in others (ES-2) (Bastian et al., 2009). In order to improve the development of anti-metastasis therapeutic strategies, it is of paramount importance that we determine the role of EPAC1 in the context of each cancer and elucidate the mechanism by which it boosts or attenuates migration in each case. "
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