Regulation of with-no-lysine kinase signaling by Kelch-like proteins.

Abstract

In 2001, with-no-lysine (WNK) kinases were identified as the genes responsible for the human hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). It took a further 6 years to clarify that WNK kinases participate in a signaling cascade with oxidative stress-responsive gene 1 (OSR1), Ste20-related proline-alanine-rich kinase (SPAK), and thiazide-sensitive NaCl cotransporter (NCC) in the kidney and the constitutive activation of this signaling cascade is the molecular basis of PHAII. Since this discovery, the WNK-OSR1/SPAK-NCC signaling cascade has been shown to be involved not only in PHAII but also in the regulation of blood pressure under normal and pathogenic conditions, such as hyperinsulinemia. However, the molecular mechanisms of WNK kinase regulation by dietary and hormonal factors and by PHAII-causing mutations remain poorly understood. In 2012, two additional genes responsible for PHAII, Kelch-like 3 (KLHL3) and Cullin3, were identified. At the time of their discovery, the molecular mechanisms underlying the interaction between these genes and their involvement in PHAII were unknown. Here we review the pathophysiological roles of the WNK signaling cascade clarified to date and introduce a new mechanism of WNK kinase regulation by KLHL3 and Cullin3, which provides insight on previously unknown mechanisms of WNK kinase regulation.

• Authors: Shinichi Uchida, Eisei Sohara, Tatemitsu Rai, Sei Sasaki
• Journal: Biology of the cell (Biol Cell) Vol. 106 Issue 2 Pg. 45-56 (Feb 2014) ISSN: 1768-322X [Electronic] England
• PMID: 24313290 (Publication Type: Journal Article, Review)
• Copyright: © 2013 The Authors. Biology of the Cell published by Wiley-VCH Verlag GmbH & Co. KGaA on behalf of Société de Biologie Cellulaire Francaise.

Chemical References

• Adaptor Proteins, Signal Transducing
• CUL3 protein, human
• Carrier Proteins
• Cullin Proteins
• Intracellular Signaling Peptides and Proteins
• KLHL3 protein, human
• Microfilament Proteins
• Minor Histocompatibility Antigens
• Protein Serine-Threonine Kinases
• STK39 protein, human
• WNK Lysine-Deficient Protein Kinase 1
• WNK1 protein, human

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Carrier Proteins (chemistry, genetics, metabolism)
• Cullin Proteins (chemistry, genetics, metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (chemistry, genetics, metabolism)
• Microfilament Proteins
• Minor Histocompatibility Antigens
• Protein Serine-Threonine Kinases (chemistry, genetics, metabolism)
• Pseudohypoaldosteronism (enzymology, genetics, metabolism)
• Signal Transduction
• WNK Lysine-Deficient Protein Kinase 1