EPAC1 activation by cAMP stabilizes CFTR at the membrane by promoting its interaction with NHERF1

Journal article

Cyclic AMP (cAMP) activates protein kinase A (PKA) but also the guanine nucleotide exchange factor EPAC1 (exchange protein directly activated by cAMP). While phosphorylation by PKA is known to regulate CFTR channel gating, the protein defective in cystic fibrosis (CF), the contribution of EPAC1 to CFTR regulation remains largely undefined. Here we demonstrate that in human airway epithelial cells cAMP signaling through EPAC1 promotes CFTR stabilization at the PM by attenuating its endocytosis, independently of PKA activation. EPAC1 and CFTR co-localize and interact through protein adaptor NHERF1. This interaction is promoted by EPAC1 activation triggering its translocation to the PM and binding to NHERF1. Our findings identify a novel CFTR interacting protein and demonstrate that cAMP activates CFTR through two different but complementary pathways – the well-known PKA-dependent channel gating and a novel regulatory mechanism of endocytosis involving EPAC1. The latter may constitute a novel therapeutic target for CF.

Authors: Zaccolo, M; Lobo, M; Amaral, M; Farinha, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Company of Biologists
• Journal: Journal of Cell Science
• Publication date: 2016-05-20
• Acceptance date: 2016-05-17
• DOI: 10.1242/jcs.185629
• EISSN: 1477-9137
• ISSN: 0021-9533
• Keywords: cAMP; CFTR; protein trafficking; membrane stability; EPAC1