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J Biol Chem, Vol. 275, Issue 19, 14360-14366, May 12, 2000
From the Department of Cell Biology and Physiology, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
The cystic fibrosis transmembrane conductance
regulator (CFTR) is an epithelial Cl
Protein Kinase A Associates with Cystic Fibrosis Transmembrane
Conductance Regulator via an Interaction with Ezrin*
,,
channel whose
activity is controlled by cAMP-dependent protein kinase
(PKA)-mediated phosphorylation. We found that CFTR immunoprecipitates from Calu-3 airway cells contain endogenous PKA, which is capable of
phosphorylating CFTR. This phosphorylation is stimulated by cAMP and
inhibited by the PKA inhibitory peptide. The endogenous PKA that
co-precipitates with CFTR could also phosphorylate the PKA substrate
peptide, Leu-Arg-Arg-Ala-Ser-Leu-Gly (kemptide). Both the catalytic and
type II regulatory subunits of PKA are identified by
immunoblotting CFTR immunoprecipitates, demonstrating that the
endogenous kinase associated with CFTR is PKA, type II (PKA II).
Phosphorylation reactions mediated by CFTR-associated PKA II are
inhibited by Ht31 peptide but not by the control peptide Ht31P,
indicating that a protein kinase A anchoring protein (AKAP) is
responsible for the association between PKA and CFTR. Ezrin may
function as this AKAP, since it is expressed in Calu-3 and T84
epithelia, ezrin binds RII in overlay assays, and RII is
immunoprecipitated with ezrin from Calu-3 cells. Whole-cell patch clamp
of Calu-3 cells shows that Ht31 peptide reduces cAMP-stimulated CFTR
Cl current, but Ht31P does not. Taken together, these
data demonstrate that PKA II is linked physically and functionally to
CFTR by an AKAP interaction, and they suggest that ezrin serves as an
AKAP for PKA-mediated phosphorylation of CFTR.
*
This work was supported by National Institutes of Health
Grant DK56490 and a grant from the Cystic Fibrosis Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to this work.
§
To whom correspondence should be addressed: S362 BST, 3500 Terrace
St., Dept. of Cell Biology and Physiology, University of Pittsburgh
School of Medicine, Pittsburgh, PA 15261. Tel.: 412-648-9498; Fax:
412-648-2004; E-mail: Frizzell+@pitt.edu.
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