title: Kelch-like 3/Cullin 3 ubiquitin ligase complex and WNK signaling in salt-sensitive hypertension and electrolyte disorder.
abstract: Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and thiazide sensitivity. Mutations in with-no-lysine kinase 1 (WNK1) and WNK4 genes are reported to cause PHAII. Rigorous studies have demonstrated that WNK kinases constitute a signaling cascade with oxidative stress-responsive gene 1 (OSR1), Ste20-related proline-alanine-rich kinase (SPAK) and the solute carrier family 12a (SLC12a) transporter, including thiazide-sensitive NaCl cotransporter. The WNK-OSR1/SPAK-SLC12a signaling cascade is present in the kidneys and vascular smooth muscle cells (VSMCs) and regulates salt sensitivity physiologically, i.e. urinary sodium excretion and arterial tone by various hormonal and dietary factors. However, although it was clear that the abnormal activation of this signaling cascade is the molecular basis of PHAII, the molecular mechanisms responsible for the physiological regulation of WNK signaling and the effect of WNK4 mutations on PHAII pathogenesis are poorly understood. Two additional genes responsible for PHAII, Kelch-like 3 (KLHL3) and Cullin 3 (CUL3), were identified in 2012. WNK1 and WNK4 have been shown to be substrates of KLHL3-CUL3 E3 ubiquitin ligase both in vitro and in vivo In PHAII, the loss of interaction between KLHL3 and WNK4 induces increased levels of WNK kinases due to impaired ubiquitination. These results indicate that WNK signaling is physiologically regulated by KLHL3/CUL3-mediated ubiquitination. Here, we review recent studies investigating the pathophysiological roles of the WNK signaling cascade in the kidneys and VSMCs and recently discovered mechanisms underlying the regulation of WNK signaling by KLHL3 and CUL3.
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism*; D004573:Electrolytes / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008840:Microfilament Proteins; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1; D014883:Water-Electrolyte Imbalance / Q000209:etiology / Q000503:physiopathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D004573:Electrolytes; D047908:Intracellular Signaling Peptides and Proteins; C489837:KLHL3 protein, human; D008840:Microfilament Proteins; D015778:Minor Histocompatibility Antigens; D017673:Sodium Chloride, Dietary; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human
keywords: kidney; kinases; membrane transport; salt sensitivity; ubiquitin