{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:35:35Z","timestamp":1791275735935,"version":"4.1.0"},"reference-count":86,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,1,10]],"date-time":"2014-01-10T00:00:00Z","timestamp":1389312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology of the Cell"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:p>In 2001, with\u2010no\u2010lysine (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\u2010responsive gene 1 (OSR1), Ste20\u2010related proline\u2010alanine\u2010rich kinase (SPAK), and thiazide\u2010sensitive 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\u2013OSR1\/SPAK\u2013NCC 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\u2010causing mutations remain poorly understood. In 2012, two additional genes responsible for PHAII, <jats:italic>Kelch\u2010like 3<\/jats:italic> (<jats:italic>KLHL3<\/jats:italic>) and <jats:italic>Cullin3<\/jats:italic>, 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 <jats:italic>KLHL3<\/jats:italic> and <jats:italic>Cullin3<\/jats:italic>, which provides insight on previously unknown mechanisms of WNK kinase regulation.<\/jats:p>","DOI":"10.1111\/boc.201300069","type":"journal-article","created":{"date-parts":[[2013,12,9]],"date-time":"2013-12-09T03:12:36Z","timestamp":1386558756000},"page":"45-56","source":"Crossref","is-referenced-by-count":29,"title":["Regulation of with\u2010no\u2010lysine kinase signaling by Kelch\u2010like proteins"],"prefix":"10.1111","volume":"106","author":[{"given":"Shinichi","family":"Uchida","sequence":"first","affiliation":[{"name":"Department of Nephrology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University  1\u20105\u201045 Yushima Bunkyo\u2010ku Tokyo 113\u20108519 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