Mechanism of regulation of renal ion transport by WNK kinases.
OBJECTIVE
This review summarizes recent advances in the understanding of the mechanism of regulation of renal ion transport by WNK kinases.


RESULTS
There are four mammalian WNK [with-no-lysine (K)] kinases: WNK1-WNK4. Mutations of WNK1 and WNK4 in humans cause hypertension and hyperkalemia at least partly by altering renal sodium and potassium transport. WNK1 and WNK4 stimulate endocytosis of ROMK1 by recruiting an endocytic scaffold protein, intersectin. The recruitment is independent of the kinase activity and occurs between the PXXP motif of WNKs and the SH3 domain of intersectin. Regulation of cation-chloride-coupled cotransporters, Na+-K+-2Cl(-) cotransporter (NKCC) 1 and NKCC2 [and the Na-Cl co-transporter (NCC), under some conditions] by WNKs requires kinase activity. WNK1 and WNK4 bind with and phosphorylate two Ste20-related protein kinases, OSR1 and SPAK, which in turn bind with and phosphorylate NKCCs and NCC to increase their activity. Binding of OSR1/SPAK to upstream activators (WNKs) and downstream substrates (NKCCs and NCC) are both mediated by a docking site in the C-terminus of OSR1/SPAK and RFX[V/I] motifs present in WNKs or in NKCCs and NCC.


CONCLUSIONS
WNKs regulate ion transport via both catalytic and noncatalytic mechanisms. We discuss hypotheses that WNKs, contrasting with aldosterone, play important roles in dissociating sodium reabsorption from potassium secretion.
Huang
Chou-Long
CL
Department of Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, Texas 75390-8856, USA. chou-long.huang@utsouthwestern.edu
Yang
Sung-Sen
SS
Lin
Shih-Hua
SH
D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D011188:Potassium / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011546:Pseudohypoaldosteronism / Q000503:physiopathology; D012964:Sodium / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1
D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C433806:WNK4 protein, human; D011188:Potassium