Epac, in synergy with cAMP-dependent protein kinase (PKA), is required for cAMP-mediated mitogenesis.

cAMP stimulates proliferation in many cell types. For many years, cAMP-dependent protein kinase represented the only known cAMP effector. however, does not fully mimic the action of cAMP, indicating the existence of a component. Since cAMP-mediated activation of the G-protein Rap1 and its phosphorylation by are strictly required for the effects of cAMP on mitogenesis, we hypothesized that the Rap1 activator Epac might represent the duanyu1529-independent factor. Here we report that Epac acts synergistically with duanyu1529 in cAMP-mediated mitogenesis. We have generated a new dominant negative Epac mutant that revealed that activation of Epac is required for thyroid-stimulating hormone or cAMP stimulation of DNA synthesis. We demonstrate that Epac's action on cAMP-mediated activation of Rap1 and cAMP-mediated mitogenesis depends on the subcellular localization of Epac via its DEP domain. Disruption of the DEP-dependent subcellular targeting of Epac abolished cAMP-Epac-mediated Rap1 activation and thyroid-stimulating hormone-mediated cell proliferation, indicating that an signaling unit is critical for the mitogenic action of cAMP.

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