WNK1 activates SGK1 by a phosphatidylinositol 3-kinase-dependent and non-catalytic mechanism.
WNK1 (with no lysine (K) 1) is a protein-serine/threonine kinase with a unique catalytic site organization. Deletions in the first intron of the WNK1 gene were found in a group of hypertensive patients with pseudohypoaldosteronism type II. No changes in coding sequence of WNK1 were found, but its expression was increased severalfold. We have been investigating actions of WNK1 and have found that WNK1 activates the serum- and glucocorticoid-induced protein kinase SGK1, which impacts membrane expression of the epithelial sodium channel. Here we explore the role of WNK1 in SGK1 regulation. Activation of SGK1 by WNK1 is blocked by phosphatidylinositol 3-kinase inhibitors. Neither the catalytic activity nor the kinase domain of WNK1 is required; rather the N-terminal 220 residues of WNK1 are necessary and sufficient to activate SGK1. Phosphorylation of WNK1 on Thr-58 contributes to SGK1 activation. Finally, we show that WNK1 is required for the activation of SGK1 by insulin-like growth factor 1.
Xu
Bing-E
BE
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Stippec
Steve
S
Lazrak
Ahmed
A
Huang
Chou-Long
CL
Cobb
Melanie H
MH
D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053503:Epithelial Sodium Channels; D006973:Hypertension / Q000150:complications; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D007668:Kidney / Q000166:cytology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D016297:Mutagenesis, Site-Directed; D009865:Oocytes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology*; D034622:RNA Interference; D015222:Sodium Channels / Q000502:physiology*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D007334:Insulin-Like Growth Factor I; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D015222:Sodium Channels; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099184:Serum-Glucocorticoid Regulated Kinases; C498743:WNK1 protein, human