WNK1, a Novel Mammalian Serine/Threonine Protein Kinase Lacking the Catalytic Lysine in Subdomain II^*

Bing-e Xu, Jessie M. English, Julie L. Wilsbacher^§, Steve Stippec, Elizabeth J. Goldsmith^¶, and Melanie H. Cobb

From the Departments of Pharmacology and ^¶ Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041

We have cloned and characterized a novel mammalian serine/threonine protein kinase WNK1 (with no lysine (K)) from a rat brain cDNA library. WNK1 has 2126 amino acids and can be detected as a protein of ~230 kDa in various cell lines and rat tissues. WNK1 contains a small N-terminal domain followed by the kinase domain and a long C-terminal tail. The WNK1 kinase domain has the greatest similarity to the MEKK protein kinase family. However, overexpression of WNK1 in HEK293 cells exerts no detectable effect on the activity of known, co-transfected mitogen-activated protein kinases, suggesting that it belongs to a distinct pathway. WNK1 phosphorylates the exogenous substrate myelin basic protein as well as itself mostly on serine residues, confirming that it is a serine/threonine protein kinase. The demonstration of activity was striking because WNK1, and its homologs in other organisms lack the invariant catalytic lysine in subdomain II of protein kinases that is crucial for binding to ATP. A model of WNK1 using the structure of cAMP-dependent protein kinase suggests that lysine 233 in kinase subdomain I may provide this function. Mutation of this lysine residue to methionine eliminates WNK1 activity, consistent with the conclusion that it is required for catalysis. This distinct organization of catalytic residues indicates that WNK1 belongs to a novel family of serine/threonine protein kinases.

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^* This work was supported by National Institutes of Health Grants DK34128 and GM53032.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF227741.

Present address: Dept. of Biological Research-Oncology, Schering-Plough Research Inst., Kenilworth, NJ 07033.

^§ Supported by a predoctoral fellowship from the Howard Hughes Medical Institute. Present address: Dept. of Cell Biology, Harvard Medical School, Boston, MA 02115.

To whom correspondence should be addressed: UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-3627; Fax: 214-648-3811; E-mail: melanie.cobb@email. swmed.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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Familial Hyperkalemic Hypertension.

J. Hadchouel, C. Delaloy, S. Faure, J.-M. Achard, and X. Jeunemaitre (2006)
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Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4.

K. B. E. Gagnon, R. England, and E. Delpire (2006)
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 |  Abstract »  |  Full Text »  |  PDF »

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

T. Moriguchi, S. Urushiyama, N. Hisamoto, S.-i. Iemura, S. Uchida, T. Natsume, K. Matsumoto, and H. Shibuya (2005)
J. Biol. Chem. 280, 42685-42693
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Association of Blood Pressure With Genetic Variation in WNK Kinases in a White European Population.

H. Zhang and J. A. Staessen (2005)
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WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.

J. Rinehart, K. T. Kahle, P. de los Heros, N. Vazquez, P. Meade, F. H. Wilson, S. C. Hebert, I. Gimenez, G. Gamba, and R. P. Lifton (2005)
PNAS 102, 16777-16782
 |  Abstract »  |  Full Text »  |  PDF »

WNK3 modulates transport of Cl- in and out of cells: Implications for control of cell volume and neuronal excitability.

K. T. Kahle, J. Rinehart, P. de los Heros, A. Louvi, P. Meade, N. Vazquez, S. C. Hebert, G. Gamba, I. Gimenez, and R. P. Lifton (2005)
PNAS 102, 16783-16788
 |  Abstract »  |  Full Text »  |  PDF »

WNK1 Activates SGK1 by a Phosphatidylinositol 3-Kinase-dependent and Non-catalytic Mechanism.

B.-e Xu, S. Stippec, A. Lazrak, C.-L. Huang, and M. H. Cobb (2005)
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 |  Abstract »  |  Full Text »  |  PDF »

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L. Y. Lenertz, B.-H. Lee, X. Min, B.-e Xu, K. Wedin, S. Earnest, E. J. Goldsmith, and M. H. Cobb (2005)
J. Biol. Chem. 280, 26653-26658
 |  Abstract »  |  Full Text »  |  PDF »

WNK1 activates SGK1 to regulate the epithelial sodium channel.

B.-e Xu, S. Stippec, P.-Y. Chu, A. Lazrak, X.-J. Li, B.-H. Lee, J. M. English, B. Ortega, C.-L. Huang, and M. H. Cobb (2005)
PNAS 102, 10315-10320
 |  Abstract »  |  Full Text »  |  PDF »

Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study.

S. J. Newhouse, C. Wallace, R. Dobson, C. Mein, J. Pembroke, M. Farrall, D. Clayton, M. Brown, N. Samani, A. Dominiczak, et al. (2005)
Hum. Mol. Genet. 14, 1805-1814
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Identification of WNK1 as a Substrate of Akt/Protein Kinase B and a Negative Regulator of Insulin-stimulated Mitogenesis in 3T3-L1 Cells.

Z. Y. Jiang, Q. L. Zhou, J. Holik, S. Patel, J. Leszyk, K. Coleman, M. Chouinard, and M. P. Czech (2005)
J. Biol. Chem. 280, 21622-21628
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Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters.

G. Gamba (2005)
Physiol Rev 85, 423-493
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Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension.

G. Gamba (2005)
Am J Physiol Renal Physiol 288, F245-F252
 |  Abstract »  |  Full Text »  |  PDF »

The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport.

A. Naray-Fejes-Toth, P. M. Snyder, and G. Fejes-Toth (2004)
PNAS 101, 17434-17439
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Hypercalciuria in Familial Hyperkalemia and Hypertension Accompanies Hyperkalemia and Precedes Hypertension: Description of a Large Family with the Q565E WNK4 Mutation.

H. Mayan, G. Munter, M. Shaharabany, M. Mouallem, R. Pauzner, E. J. Holtzman, and Z. Farfel (2004)
J. Clin. Endocrinol. Metab. 89, 4025-4030
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The Kinase Activity of Kinase Suppressor of Ras1 (KSR1) Is Independent of Bound MEK.

H. R. Xing, L. Campodonico, and R. Kolesnick (2004)
J. Biol. Chem. 279, 26210-26214
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Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins.

K. Yamauchi, T. Rai, K. Kobayashi, E. Sohara, T. Suzuki, T. Itoh, S. Suda, A. Hayama, S. Sasaki, and S. Uchida (2004)
PNAS 101, 4690-4694
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Characterization of OSR1, a Member of the Mammalian Ste20p/Germinal Center Kinase Subfamily.

W. Chen, M. Yazicioglu, and M. H. Cobb (2004)
J. Biol. Chem. 279, 11129-11136
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WNK1 Activates ERK5 by an MEKK2/3-dependent Mechanism.

B.-e Xu, S. Stippec, L. Lenertz, B.-H. Lee, W. Zhang, Y.-K. Lee, and M. H. Cobb (2004)
J. Biol. Chem. 279, 7826-7831
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RhoA Binds to the Amino Terminus of MEKK1 and Regulates Its Kinase Activity.

E. D. Gallagher, S. Gutowski, P. C. Sternweis, and M. H. Cobb (2004)
J. Biol. Chem. 279, 1872-1877
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Multiple Promoters in the WNK1 Gene: One Controls Expression of a Kidney-Specific Kinase-Defective Isoform.

C. Delaloy, J. Lu, A.-M. Houot, S. Disse-Nicodeme, J.-M. Gasc, P. Corvol, and X. Jeunemaitre (2003)
Mol. Cell. Biol. 23, 9208-9221
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WNK kinases, distal tubular ion handling and hypertension.

S. Faure, C. Delaloy, V. Leprivey, J. Hadchouel, D. G. Warnock, X. Jeunemaitre, and J.-M. Achard (2003)
Nephrol. Dial. Transplant. 18, 2463-2467
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Wnk1 kinase deficiency lowers blood pressure in mice: A gene-trap screen to identify potential targets for therapeutic intervention.

B. P. Zambrowicz, A. Abuin, R. Ramirez-Solis, L. J. Richter, J. Piggott, H. BeltrandelRio, E. C. Buxton, J. Edwards, R. A. Finch, C. J. Friddle, et al. (2003)
PNAS 100, 14109-14114
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WNK1, a Gene within a Novel Blood Pressure Control Pathway, Tissue-Specifically Generates Radically Different Isoforms with and without a Kinase Domain.

M. O'Reilly, E. Marshall, H. J.L. Speirs, and R. W. Brown (2003)
J. Am. Soc. Nephrol. 14, 2447-2456
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Identification of E-Box Factor TFE3 as a Functional Partner for the E2F3 Transcription Factor.

P. H. Giangrande, T. C. Hallstrom, C. Tunyaplin, K. Calame, and J. R. Nevins (2003)
Mol. Cell. Biol. 23, 3707-3720
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The Thiazide-Sensitive Na-Cl Cotransporter and Human Disease: Reemergence of an Old Player.

D. H. Ellison (2003)
J. Am. Soc. Nephrol. 14, 538-540
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The Protein Kinase Complement of the Human Genome.

G. Manning, D. B. Whyte, R. Martinez, T. Hunter, and S. Sudarsanam (2002)
Science 298, 1912-1934
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Regulation of WNK1 by an Autoinhibitory Domain and Autophosphorylation.

B.-e Xu, X. Min, S. Stippec, B.-H. Lee, E. J. Goldsmith, and M. H. Cobb (2002)
J. Biol. Chem. 277, 48456-48462
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