Role of EPAC1 Signalosomes in Cell Fate: Friends or Foes?

Abstract

The compartmentation of signaling processes is accomplished by the assembly of protein complexes called signalosomes. These signaling platforms colocalize enzymes, substrates, and anchoring proteins into specific subcellular compartments. Exchange protein directly activated by cAMP 1 (EPAC1) is an effector of the second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) that is associated with multiple roles in several pathologies including cardiac diseases. Both EPAC1 intracellular localization and molecular partners are key players in the regulation of cell fate, which may have important therapeutic potential. In this review, we summarize the recent findings on EPAC1 structure, regulation, and pharmacology. We describe the importance of EPAC1 subcellular distribution in its biological action, paying special attention to its nuclear localization and mechanism of action leading to cardiomyocyte hypertrophy. In addition, we discuss the role of mitochondrial EPAC1 in the regulation of cell death. Depending on the cell type and stress condition, we present evidence that supports either a protective or detrimental role of EPAC1 activation.

GRKs and Epac1 Interaction in Cardiac Remodeling and Heart Failure

“…The intracellular levels and diffusion of cAMP are further regulated by a large family of cyclic nucleotide-degrading enzymes named phosphodiesterases (PDEs) [ 16 ]. Cyclic AMP binds to protein kinase A (PKA) for the phosphorylation of target proteins or exchange proteins directly activated by cAMP (Epac), which function as guanine nucleotide exchange factors for the small GTPase Rap [ 17 ]. The coupling of GPCRs to Gα q promotes phospholipase C (PLC) activation, which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).…”

“…CNB-B regulates Epac1 GEF activity. Epac1 lacks a second CNB domain (CNB-A) present in Epac2, which is involved in Epac2 localization [ 17 , 86 ]. This could explain the different subcellular localization of the two isoforms, Epac1 and Epac2.…”

“…The catalytic domain located in the C-terminus presents a Ras association domain (RA), a Ras exchange motif (REM), and a cell division and cycle 25 homology domain (CDC25-HD). The latter is responsible for Epac1 catalytic activity and also contains s a nuclear targeting signal [ 7 , 17 , 88 ].…”

“…At the molecular level, Epac1 has been shown to form signalosomes in different subcellular compartments, including the nucleus and mitochondria, where it exerts differential functions (see below [ 17 ]). For instance, work from our laboratory found that Epac1 −/− mice were protected against cardiac ischemia–reperfusion injury [ 99 ].…”

“…Consequently, the β2-AR signaling switches to a β1-AR-like pro-hypertrophic signaling, and increases cardiomyocyte remodeling [ 108 ]. These data indicate that the differential interaction of Epac1 with β-arr2 contributes to the specificity of β1-AR and β2-AR signaling, and Epac1 compartmentalization participates in the distinct functions of the β-AR subtypes [ 17 , 108 ]. Interestingly, the interaction of β-arr seems not to be limited to Epac1, since a more recent study reported that the Epac2 isoform can directly interact with β-arr1 to regulate insulin secretion in pancreatic β cells [ 117 ].…”