Journal
JOURNAL OF CELL SCIENCE
Volume 129, Issue 13, Pages 2599-2612Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.185629
Keywords
CFTR; cAMP; EPAC1; Membrane stability; Protein trafficking
Categories
Funding
- Fundacao para a Ciencia e a Tecnologia [UID/MULTI/04046/2013, EXPL/BIM-MEC/1451/2013]
- European Respiratory Society (Romain Pauwels Research Award)
- British Heart Foundation [PG/15/5/31110, RG/12/3/29423]
- British Heart Foundation [RG/12/3/29423, PG/15/5/31110] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [EXPL/BIM-MEC/1451/2013] Funding Source: FCT
Ask authors/readers for more resources
Cyclic AMP (cAMP) activates protein kinase A (PKA) but also the guanine nucleotide exchange factor 'exchange protein directly activated by cAMP' (EPAC1; also known as RAPGEF3). Although phosphorylation by PKA is known to regulate CFTR channel gating the protein defective in cystic fibrosis -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 plasma membrane by attenuating its endocytosis, independently of PKA activation. EPAC1 and CFTR colocalize and interact through protein adaptor NHERF1 (also known as SLC9A3R1). This interaction is promoted by EPAC1 activation, triggering its translocation to the plasma membrane and binding to NHERF1. Our findings identify a new CFTR-interacting protein and demonstrate that cAMP activates CFTR through two different but complementary pathways\-the well-known PKA-dependent channel gating pathway and a new mechanism regulating endocytosis that involves EPAC1. The latter might constitute a novel therapeutic target for treatment of cystic fibrosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available