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J. Biol. Chem., Vol. 280, Issue 29, 26653-26658, July 22, 2005

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Properties of WNK1 and Implications for Other Family Members^*

Lisa Y. Lenertz, Byung-Hoon Lee, Xiaoshan Min¶, Bing-e Xu, Kyle Wedin, Svetlana Earnest, Elizabeth J. Goldsmith¶, and Melanie H. Cobb||

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

WNKs are large serine/threonine protein kinases structurally distinct from all other members of the protein kinase superfamily. Of the four human WNK family members, WNK1 and WNK4 have been linked to a hereditary form of hypertension, pseudohypoaldosteronism type II. We characterized the biochemical properties and regulation of WNK1 that may contribute to its physiological activities and abnormal function in disease. We showed that WNK1 is activated by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines. In addition, hypotonic stress also led to a modest increase in WNK1 activity. Gel filtration suggested that WNK1 exists as a tetramer, and yeast two-hybrid data showed that the N terminus of WNK1 (residues 1–222) interacts with residues 481–660, which includes the WNK1 autoinhibitory domain and a C-terminal coiled-coil domain. Although cell biological studies have suggested a functional interaction between WNK1 and WNK4, we found no evidence of stable interactions between these kinases. However, WNK1 phosphorylated both WNK4 and WNK2. In addition, the WNK1 autoinhibitory domain inhibited the catalytic activity of these WNKs. These findings suggest potential mechanisms for interconnected regulation of WNK family members.

Received for publication, March 9, 2005 , and in revised form, May 2, 2005.

^* This work was supported by National Institutes of Health Grant GM53032, Welch Foundation Grants I1243 (to M. H. C.) and I1128 (to E. J. G.), and Department of Defense Graduate Fellowship W81XWH-04-1-0308 (to L. Y. L.). 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.

In partial fulfillment of the requirements for a Ph.D.

^|| To whom correspondence should be addressed: Dept. of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041. Tel.: 214-645-6122; Fax: 214-645-6124; E-mail: Melanie.Cobb{at}UTSouthwestern.edu.

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