Proceedings of the National Academy of Sciences · 2005 · 213 citations · 49 references
Life SciencesBiochemistryCell BiologyCell SignalingPathophysiologySignal TransductionIon Channel DisordersIon Channel ExpressionIon Channel PhysiologyIon Channel RegulationIon ChannelsSodium HomeostasisDeletionsE3 Ubiquitin Ligase Substrate RecognitionEpithelial Sodium ChannelsInterstitial DeletionsIon Channel PermeabilityIon PermeabilityRegulation By E3 Ubiquitin LigasesSodium Channel Physiology
WNK (with no lysine [K]) kinases are serine-threonine protein kinases with an atypical placement of the catalytic lysine. Intronic deletions increase the expression of WNK1 in humans and cause pseudohypoaldosteronism type II, a form of hypertension. WNKs have been linked to ion carriers, but the underlying regulatory mechanisms are unknown. Here, we report a mechanism for the control of ion permeability by WNK1. We show that WNK1 activates the serum- and glucocorticoid-inducible protein kinase SGK1, leading to activation of the epithelial sodium channel. Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2. This finding provides compelling evidence that this molecular mechanism contributes to the pathogenesis of hypertension in pseudohypoaldosteronism type II caused by WNK1 and, possibly, in other forms of hypertension.
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Human Hypertension Caused by Mutations in WNK Kinases
Frederick H. Wilson, Sandra Disse-Nicodème, Keith A. Choate et al. · Science · 2001 · 1.5K citations