Epac1 interacts with importin β1 and controls neurite outgrowth independently of cAMP and Rap1
| Autor: | Annemieke Kavelaars, Xiaodong Cheng, Yong Zhou, John F. Hancock, Faiza Baameur, Cobi Jacoba Johanna Heijnen, Pooja Singhmar |
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| Rok vydání: | 2016 |
| Předmět: |
Proteomics
0301 basic medicine Multidisciplinary Neurite Cell Membrane Neuronal Outgrowth Mutant rap1 GTP-Binding Proteins Importin Biology beta Karyopherins Article Cell Line Cell biology 03 medical and health sciences HEK293 Cells 030104 developmental biology DEP domain Cyclic AMP Guanine Nucleotide Exchange Factors Humans CAMP binding Rap1 Beta Karyopherins Guanine nucleotide exchange factor |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep36370 |
| Popis: | 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 β1 (impβ1) is an Epac1 binding partner that prevents PM accumulation of Epac1. We demonstrate that in the absence of impβ1, endogenous as well as overexpressed Epac1 accumulate at the PM. Moreover, agonist-induced PM translocation of Epac1 leads to dissociation of Epac1 from impβ1. Localization of Epac1 at the PM in the absence of impβ1, requires residue R82 in its DEP domain. Notably, the PM accumulation of Epac1 in the absence of impβ1 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 impβ1 controls subcellular localization of Epac1. |
| Databáze: | OpenAIRE |
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