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Articles in PresS, published online ahead of print March 18, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00080.2002
Submitted on February 25, 2002
Accepted on March 15, 2002
1 Department of Physiology, University of Otago, Dunedin, Otago, New Zealand
2 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA; Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: fiona.mcdonald{at}stonebow.otago.ac.nz.
The epithelial Na+ channel (ENaC) is a critical component of the pathway maintaining salt and water balance. The channel is regulated by members of the Nedd4 family of ubiquitin-protein ligases, which bind to channel subunits and catalyze channel internalization and degradation. ENaC mutations that abolish this interaction cause Liddle's syndrome, a genetic form of hypertension. Here we test the hypothesis that WWP2, a member of the Nedd4 family of ubiquitin protein ligases, is a candidate to regulate ENaC. Consistent with this hypothesis, we found that WWP2 is expressed in epithelial tissues that express ENaC, as well as in a wide variety of other tissues. WWP2 contains four WW domains, three of which bound differentially to ENaC subunits. In contrast, all four hNedd4-2 WW domains bound to ENaC. WWP2 inhibited ENaC when coexpressed in epithelia, requiring a direct interaction between the proteins; mutation of the ENaC PY motifs abolished inhibition. Thus, expression, binding, and functional data all suggest that WWP2 is a candidate to regulate ENaC-mediated Na+ transport in epithelia.
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