WNK1 activates SGK1 to regulate the epithelial sodium channel.
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.
Xu
Bing-e
BE
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
Stippec
Steve
S
Chu
Po-Yin
PY
Lazrak
Ahmed
A
Li
Xin-Ji
XJ
Lee
Byung-Hoon
BH
English
Jessie M
JM
Ortega
Bernardo
B
Huang
Chou-Long
CL
Cobb
Melanie H
MH
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
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