Protein kinase a (PKA) still activates CFTR chloride channel after mutagenesis of all 10 PKA consensus phosphorylation sites

Xiu Bao Chang, Joseph A. Tabcharani, Yue Xian Hou, Timothy J. Jensen, Norbert Kartner, Noa Alon, John W. Hanrahan, John R. Riordan

Research output: Contribution to journalArticlepeer-review

250 Scopus citations

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) plays a central role in transepithelial ion transport by acting as a tightly regulated apical chloride channel. Regulation is achieved by the concerted action of ATP at conserved nucleotide binding folds and serine phosphorylation at multiple sites by protein kinases A (PKA) and C (PKC). A previous investigation concluded that activation by PKA is critically dependent on phosphorylation at four of the nine predicted PKA sites in the R domain (S660A, S737A, S795A, S813A), because a "Quad" mutant lacking these sites could not be activated. We show in the present work that not only can this mutant be phosphorylated and activated, but a mutant in which all 10 predicted PKA sites have been altered still retains significant PKA-activated function. Potentiation of the PKA response by PKC is also preserved in this mutant. Thus CFTR may be regulated by cryptic PKA sites which also mediate interactions between different kinases. Such hierarchical phosphorylation of CFTR by obvious and cryptic PKA sites could provide a metered response to secretagogues. * This work was supported by grants from the Canadian and American Cystic Fibrosis Foundation and the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Original languageEnglish (US)
Pages (from-to)11304-11311
Number of pages8
JournalJournal of Biological Chemistry
Volume268
Issue number15
StatePublished - May 25 1993

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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