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 und...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 29; pp. 10315 - 10320
Main Authors Bing-e Xu, Stippec, Steve, Chu, Po-Yin, Lazrak, Ahmed, Li, Xin-Ji, Lee, Byung-Hoon, English, Jessie M., Ortega, Bernardo, Huang, Chou-Long, Cobb, Melanie H., Garbers, David L.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 19.07.2005
National Acad Sciences
Subjects
Animals
Biological Sciences
Blood pressure
Cells, Cultured
CHO Cells
Cricetinae
Cricetulus
Endosomal Sorting Complexes Required for Transport
Enzyme Activation - physiology
Epithelial Sodium Channels
Gene expression
Gene expression regulation
HEK293 cells
Humans
Hypertension
Immediate-Early Proteins - metabolism
Immunoblotting
Immunoprecipitation
Intracellular Signaling Peptides and Proteins
Ions
Minor Histocompatibility Antigens
Nedd4 Ubiquitin Protein Ligases
Oocytes
Patch-Clamp Techniques
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Proteins
Pseudohypoaldosteronism - metabolism
Pseudohypoaldosteronism - physiopathology
Sodium
Sodium channels
Sodium Channels - metabolism
Two-Hybrid System Techniques
Ubiquitin-Protein Ligases - metabolism
WNK Lysine-Deficient Protein Kinase 1
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Communicated by David L. Garbers, University of Texas Southwestern Medical Center, Dallas, TX, May 27, 2005
Author contributions: B.-e.X., C.-L.H., and M.H.C. designed research; B.-e.X., S.S., P.-Y.C., A.L., X.-J.L., B.-H.L., J.M.E., and B.O. performed research; B.-e.X., S.S., P.-Y.C., A.L., X.-J.L., B.-H.L., J.M.E., B.O., C.-L.H., and M.H.C. analyzed data; and B.-e.X., C.-L.H., and M.H.C. wrote the paper.
Abbreviations: CHO, Chinese hamster ovary; ENaC, epithelial sodium channel; KD, kinase-dead; NCC, sodium chloride cotransporter; PHA II, pseudohypoaldosteronism type II.
To whom correspondence may be addressed. E-mail: melanie.cobb@utsouthwestern.edu or chou-long.huang@utsouthwestern.edu.
Present address: Pfizer Research and Technology, 620 Memorial Drive, Cambridge, MA 02139.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0504422102