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	Am. J. Physiol. Renal Physiol. Sep (2002); 283(3):F431-6
Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel.
McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM
Department of Physiology, University of Otago, Dunedin 9100, New Zealand. fiona.mcdonald@stonebow.otago.ac.nz
Abstract: 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 WW domain-containing protein 2 (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 human Nedd4-2 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.
[PUBMED: 12167593]