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J. Biol. Chem., Vol. 279, Issue 9, 7826-7831, February 27, 2004

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WNK1 Activates ERK5 by an MEKK2/3-dependent Mechanism^*

Bing-e Xu, Steve Stippec, Lisa Lenertz, Byung-Hoon Lee, Wei Zhang, Youn-Kyoung Lee, and Melanie H. Cobb

From the Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041

WNK1 belongs to a unique protein kinase family that lacks the catalytic lysine in its normal position. Mutations in human WNK1 and WNK4 have been implicated in causing a familial form of hypertension. Here we report that overexpression of WNK1 led to increased activity of cotransfected ERK5 in HEK293 cells. ERK5 activation was blocked by the MEK5 inhibitor U0126 and expression of a dominant negative MEK5 mutant. Expression of dominant negative mutants of MEKK2 and MEKK3 also blocked activation of ERK5 by WNK1. Moreover, both MEKK2 and MEKK3 coimmunoprecipitated with endogenous WNK1 from cell lysates. WNK1 phosphorylated both MEKK2 and -3 in vitro, and MEKK3 was activated by WNK1 in 293 cells. Finally, ERK5 activation by epidermal growth factor was attenuated by suppression of WNK1 expression using small interfering RNA. Taken together, these results place WNK1 in the ERK5 MAP kinase pathway upstream of MEKK2/3.

Received for publication, December 9, 2003

^* This work was supported by Grant GM53032 from the National Institutes of Health and Grant I1243 from the Welch Foundation. 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.

Submitted in partial fulfillment of the requirements for a Ph.D.

To whom correspondence should be addressed: University of Texas, Southwestern Medical Ctr., 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-3627; Fax: 214-648-3811; E-mail: mcobb{at}mednet.swmed.edu.

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