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Proposed model for the roles of Nedd4-2 and β1Pix in the regulation of ENaC by AMPK. Activation of AMPK promotes AMPK-mediated phosphorylation of Nedd4-2 at Ser-328 (1) and also promotes the binding of β1Pix to the Nedd4-2–14-3-3 complex (2). β1Pix association with Nedd4-2 enhances Nedd4-2 stability by helping to maintain Nedd4-2 phosphorylation at Ser-328 (3), which ultimately enhances the association of Nedd4-2 with ENaC (4) and thereby induces ENaC ubiquitination and degradation.
