Journal article
Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator
Proceedings of the National Academy of Sciences - PNAS, Vol.94(20), pp.11055-11060
09/30/1997
DOI: 10.1073/pnas.94.20.11055
PMCID: PMC23594
PMID: 9380758
Abstract
cAMP-dependent phosphorylation activates the cystic fibrosis transmembrane conductance regulator (CFTR) in epithelia. However, the protein phosphatase (PP) that dephosphorylates and inactivates CFTR in airway and intestinal epithelia, two major sites of disease, is not certain. We found that in airway and colonic epithelia, neither okadaic acid nor FK506 prevented inactivation of CFTR when cAMP was removed. These results suggested that a phosphatase distinct from PP1, PP2A, and PP2B was responsible. Because PP2C is insensitive to these inhibitors, we tested the hypothesis that it regulates CFTR. We found that PP2Cα is expressed in airway and T84 intestinal epithelia. To test its activity on CFTR, we generated recombinant human PP2Cα and found that it dephosphorylated CFTR and an R domain peptide in vitro. Moreover, in cell-free patches of membrane, addition of PP2Cα inactivated CFTR Cl− channels; reactivation required readdition of kinase. Finally, coexpression of PP2Cα with CFTR in epithelia reduced the Cl− current and increased the rate of channel inactivation. These results suggest that PP2C may be the okadaic acid-insensitive phosphatase that regulates CFTR in human airway and T84 colonic epithelia. It has been suggested that phosphatase inhibitors could be of therapeutic value in cystic fibrosis; our data suggest that PP2C may be an important phosphatase to target.
Details
- Title: Subtitle
- Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator
- Creators
- Sue M Travis - Departments of Internal Medicine and Physiology and Biophysics andHerbert A Berger - Departments of Internal Medicine and Physiology and Biophysics andMichael J Welsh - Departments of Internal Medicine and Physiology and Biophysics and
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.94(20), pp.11055-11060
- DOI
- 10.1073/pnas.94.20.11055
- PMID
- 9380758
- PMCID
- PMC23594
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 09/30/1997
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Neurosurgery; Internal Medicine
- Record Identifier
- 9984020861202771
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