title: WNK1 activates SGK1 to regulate the epithelial sodium channel.
abstract: 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.
authors: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors: Bing-e
authors: BE
authors: Xu
authors: Steve
authors: S
authors: Stippec
authors: Po-Yin
authors: PY
authors: Chu
authors: Ahmed
authors: A
authors: Lazrak
authors: Xin-Ji
authors: XJ
authors: Li
authors: Byung-Hoon
authors: BH
authors: Lee
authors: Jessie M
authors: JM
authors: English
authors: Bernardo
authors: B
authors: Ortega
authors: Chou-Long
authors: CL
authors: Huang
authors: Melanie H
authors: MH
authors: Cobb
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D056827:Endosomal Sorting Complexes Required for Transport; D004789:Enzyme Activation / Q000502:physiology; D053503:Epithelial Sodium Channels; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D000075702:Nedd4 Ubiquitin Protein Ligases; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011546:Pseudohypoaldosteronism / Q000378:metabolism / Q000503:physiopathology*; D015222:Sodium Channels / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D015222:Sodium Channels; D044767:Ubiquitin-Protein Ligases; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099184:Serum-Glucocorticoid Regulated Kinases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; C498743:WNK1 protein, human