Down-Regulating Destruction: Phosphorylation Regulates the E3 Ubiquitin Ligase Nedd4-2

E3 ubiquitin ligases catalyze ubiquitination, which can target specific proteins for degradation. Although a growing number of E3 ubiquitin ligases and their targets have been identified, much less is known about the mechanisms that regulate their activity. A convergence of data indicate that phosphorylation regulates the binding of Nedd4-2, a HECT (homologous to the E6-AP C terminus) domain E3 ubiquitin ligase, to its target, the epithelial Na(+) channel ENaC. Nedd4-2 phosphorylation is emerging as a central convergence point for the regulation of epithelial Na(+) transport.