Chapter 186 - Epac, cAMP-Regulated Guanine Nucleotide Exchange Factors for Rap1 and Rap2

Abstract

Epac or cAMP-GEF are highly conserved and rather ubiquitously expressed proteins which serve as guanine nucleotide exchange factors (GEFs) for the small G proteins Rap1 and Rap2, and induce signal transduction pathways independent from protein kinase A (PKA). In humans the Epac family consists of two members, Epac1 and Epac2. The N-terminal regulatory region of Epac1 consists of a DEP (Dishevelled, egl-10, pleckstrin) domain, responsible for membrane localization, and a cyclic nucleotide binding (CNB) domain specific for cAMP. The C-terminal catalytic region consists of a REM domain, a RA domain, and a CDC25 homology domain. The CDC25 homology domain mediates the exchange of guanine nucleotides bound to the target G protein—in the case of Epac, Rap1 and Rap2. The REM domain is responsible for the stabilization of the CDC25 homology domain, but not directly involved in the catalysis of nucleotide exchange. RA domains are commonly found in the effector proteins of G proteins of the Ras subfamily, and mediate the specific interaction with the GTP bound form of the G protein. Biochemical studies suggest that Epac exists in equilibrium between an inactive and an active conformation, whereby binding of cAMP shifts this equilibrium to the active side and thereby increases the exchange activity by at least two orders of magnitude. Epac mediates the activation of Rap1 and Rap2 in response to stimuli that elevate intracellular cAMP levels. One important function of Rap is the induction of integrin-mediated cell adhesion and E-cadherin-mediated cell junction formation.