Epac1 interacts with importin ?1 and controls neurite outgrowth independently of cAMP and Rap1.

ABSTRACT: Exchange protein directly activated by cAMP-1 (Epac1) is a cAMP sensor that regulates multiple cellular functions including cellular migration, proliferation and differentiation. Classically, Epac1 is thought to exert its effects through binding of cAMP leading to a conformational change in Epac1 and its accumulation at the plasma membrane (PM) where it activates Rap1. In search for regulators of Epac1 activity, we show here that importin ?1 (imp?1) is an Epac1 binding partner that prevents PM accumulation of Epac1. We demonstrate that in the absence of imp?1, endogenous as well as overexpressed Epac1 accumulate at the PM. Moreover, agonist-induced PM translocation of Epac1 leads to dissociation of Epac1 from imp?1. Localization of Epac1 at the PM in the absence of imp?1, requires residue R82 in its DEP domain. Notably, the PM accumulation of Epac1 in the absence of imp?1 does not require binding of cAMP to Epac1 and does not result in Rap1 activation. Functionally, PM accumulation of Epac1, an Epac1 mutant deficient in cAMP binding, or an Epac1 mutant tethered to the PM, is sufficient to inhibit neurite outgrowth. In conclusion, we uncover a cAMP-independent function of Epac1 at the PM and demonstrate that imp?1 controls subcellular localization of Epac1.

SUBMITTER: Baameur F 

PROVIDER: S-EPMC5093460 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature