HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 52, 42685-42693, December 30, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/52/42685    most recent M510042200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moriguchi, T. Articles by Shibuya, H. Search for Related Content PubMed PubMed Citation Articles by Moriguchi, T. Articles by Shibuya, H. Social Bookmarking                      What's this?

WNK1 Regulates Phosphorylation of Cation-Chloride-coupled Cotransporters via the STE20-related Kinases, SPAK and OSR1^*

Tetsuo Moriguchi, Seiichi Urushiyama, Naoki Hisamoto¶, Shun-ichiro Iemura||, Shinichi Uchida**, Tohru Natsume||, Kunihiro Matsumoto¶, and Hiroshi Shibuya1

From the Department of Molecular Cell Biology, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, and CREST, JST, Chiyoda, Tokyo 101-0062, the Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Kanda-Surugadai, Chiyoda, Tokyo 101-0062, the ^¶Department of Molecular Biology, Graduate School of Science, Nagoya University and CREST, JST, Chikusa-ku, Nagoya 464-8602, the ^||National Institutes of Advanced Industrial Science and Technology, Biological Information Research Center (JBIRC), Kohtoh-ku, Tokyo 135-0064, and the ^**Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8519, Japan

The WNK1 and WNK4 genes have been found to be mutated in some patients with hyperkalemia and hypertension caused by pseudohypoaldosteronism type II. The clue to the pathophysiology of pseudohypoaldosteronism type II was its striking therapeutic response to thiazide diuretics, which are known to block the sodium chloride cotransporter (NCC). Although this suggests a role for WNK1 in hypertension, the precise molecular mechanisms are largely unknown. Here we have shown that WNK1 phosphorylates and regulates the STE20-related kinases, Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). WNK1 was observed to phosphorylate the evolutionary conserved serine residue located outside the kinase domains of SPAK and OSR1, and mutation of the OSR1 serine residue caused enhanced OSR1 kinase activity. In addition, hypotonic stress was shown to activate SPAK and OSR1 and induce phosphorylation of the conserved OSR1 serine residue, suggesting that WNK1 may be an activator of the SPAK and OSR1 kinases. Moreover, SPAK and OSR1 were found to directly phosphorylate the N-terminal regulatory regions of cation-chloride-coupled cotransporters including NKCC1, NKCC2, and NCC. Phosphorylation of NCC was induced by hypotonic stress in cells. These results suggested that WNK1 and SPAK/OSR1 mediate the hypotonic stress signaling pathway to the transporters and may provide insights into the mechanisms by which WNK1 regulates ion balance.

Received for publication, September 13, 2005 , and in revised form, October 27, 2005.

Addendum—While this report was in preparation, a study describing WNK1/WNK4 phosphorylation of the same key serine residue, but also identifying an additional threonine residue within the activation loop, was published (36).

^* This work was supported by the Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, grants-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan, and grants provided by the Ichiro Kanehara Foundation, the Naito Foundation, the Yamanouchi Foundation for Research on Metabolic Disorders, and the Center of Excellence Program for Frontier Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure showing the specificity of anti-SPAK/OSR1 and anti-OSR1-P antibodies.

¹ To whom correspondence should be addressed. Tel. and Fax: 81-3-5280-8062, E-mail: shibuya.mcb{at}mri.tmd.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Richardson and D. R. Alessi The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway J. Cell Sci., October 15, 2008; 121(20): 3293 - 3304. [Abstract] [Full Text] [PDF]

				P. San-Cristobal, J. Ponce-Coria, N. Vazquez, N. A. Bobadilla, and G. Gamba WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1199 - F1206. [Abstract] [Full Text] [PDF]

				L. Smith, N. Smallwood, A. Altman, and C. M. Liedtke PKC{delta} Acts Upstream of SPAK in the Activation of NKCC1 by Hyperosmotic Stress in Human Airway Epithelial Cells J. Biol. Chem., August 8, 2008; 283(32): 22147 - 22156. [Abstract] [Full Text] [PDF]

				J. Ponce-Coria, P. San-Cristobal, K. T. Kahle, N. Vazquez, D. Pacheco-Alvarez, P. de los Heros, P. Juarez, E. Munoz, G. Michel, N. A. Bobadilla, et al. Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases PNAS, June 17, 2008; 105(24): 8458 - 8463. [Abstract] [Full Text] [PDF]

				C. Richardson, F. H. Rafiqi, H. K. R. Karlsson, N. Moleleki, A. Vandewalle, D. G. Campbell, N. A. Morrice, and D. R. Alessi Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1 J. Cell Sci., March 1, 2008; 121(5): 675 - 684. [Abstract] [Full Text] [PDF]

				J. A. McCormick, C.-L. Yang, and D. H. Ellison WNK Kinases and Renal Sodium Transport in Health and Disease: An Integrated View Hypertension, March 1, 2008; 51(3): 588 - 596. [Full Text] [PDF]

				A. S. Galanopoulou Dissociated Gender-Specific Effects of Recurrent Seizures on GABA Signaling in CA1 Pyramidal Neurons: Role of GABAA Receptors J. Neurosci., February 13, 2008; 28(7): 1557 - 1567. [Abstract] [Full Text] [PDF]

				H. Mayan, D. Attar-Herzberg, M. Shaharabany, E. J Holtzman, and Z. Farfel Increased urinary Na-Cl cotransporter protein in familial hyperkalaemia and hypertension Nephrol. Dial. Transplant., February 1, 2008; 23(2): 492 - 496. [Abstract] [Full Text] [PDF]

				J.-B. Peng and D. G. Warnock WNK4-mediated regulation of renal ion transport proteins Am J Physiol Renal Physiol, October 1, 2007; 293(4): F961 - F973. [Abstract] [Full Text] [PDF]

				K. P. Choe and K. Strange Evolutionarily conserved WNK and Ste20 kinases are essential for acute volume recovery and survival after hypertonic shrinkage in Caenorhabditis elegans Am J Physiol Cell Physiol, September 1, 2007; 293(3): C915 - C927. [Abstract] [Full Text] [PDF]

				T. Garzon-Muvdi, D. Pacheco-Alvarez, K. B. E. Gagnon, N. Vazquez, J. Ponce-Coria, E. Moreno, E. Delpire, and G. Gamba WNK4 kinase is a negative regulator of K+-Cl- cotransporters Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1197 - F1207. [Abstract] [Full Text] [PDF]

				H. Dimke, A. Flyvbjerg, S. Bourgeois, K. Thomsen, J. Frokiaer, P. Houillier, S. Nielsen, and S. Frische Acute growth hormone administration induces antidiuretic and antinatriuretic effects and increases phosphorylation of NKCC2 Am J Physiol Renal Physiol, February 1, 2007; 292(2): F723 - F735. [Abstract] [Full Text] [PDF]

				A. Zagorska, E. Pozo-Guisado, J. Boudeau, A. C. Vitari, F. H. Rafiqi, J. Thastrup, M. Deak, D. G. Campbell, N. A. Morrice, A. R. Prescott, et al. Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress J. Cell Biol., January 1, 2007; 176(1): 89 - 100. [Abstract] [Full Text] [PDF]

				K. T. Kahle, J. Rinehart, A. Ring, I. Gimenez, G. Gamba, S. C. Hebert, and R. P. Lifton WNK Protein Kinases Modulate Cellular Cl- Flux by Altering the Phosphorylation State of the Na-K-Cl and K-Cl Cotransporters. Physiology, October 1, 2006; 21: 326 - 335. [Abstract] [Full Text] [PDF]

				D. Pacheco-Alvarez, P. S. Cristobal, P. Meade, E. Moreno, N. Vazquez, E. Munoz, A. Diaz, M. E. Juarez, I. Gimenez, and G. Gamba The Na+:Cl- Cotransporter Is Activated and Phosphorylated at the Amino-terminal Domain upon Intracellular Chloride Depletion J. Biol. Chem., September 29, 2006; 281(39): 28755 - 28763. [Abstract] [Full Text] [PDF]

				M. O'Reilly, E. Marshall, T. MacGillivray, M. Mittal, W. Xue, C. J. Kenyon, and R. W. Brown Dietary Electrolyte-Driven Responses in the Renal WNK Kinase Pathway In Vivo J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2402 - 2413. [Abstract] [Full Text] [PDF]

				A. N. Anselmo, S. Earnest, W. Chen, Y.-C. Juang, S. C. Kim, Y. Zhao, and M. H. Cobb WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells PNAS, July 18, 2006; 103(29): 10883 - 10888. [Abstract] [Full Text] [PDF]

				G. Gamba TRPV4: a new target for the hypertension-related kinases WNK1 and WNK4 Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1303 - F1304. [Full Text] [PDF]