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Originally published In Press as doi:10.1074/jbc.M204934200 on September 25, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49105-49110, December 20, 2002
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Stimulus-specific Requirements for MAP3 Kinases in Activating the JNK Pathway*

Wei Chen, Michael A. WhiteDagger , and Melanie H. Cobb§

From the Departments of Pharmacology and Dagger  Cell Biology and Neuroscience, the University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041

Mitogen-activated protein kinases (MAPKs) are activated by numerous ligands typically through a protein kinase cascade minimally composed of the MAPK in series with a MAP2 kinase (MAP2K) and a MAP3K. This arrangement is thought to confer specificity and appropriate kinetic properties on the activation of MAPKs in response to physiological stimuli. Surprisingly, more than a dozen MAP3Ks have been identified that activate the c-Jun N-terminal kinases (JNKs) when overexpressed, but there is no clear understanding of which kinases actually mediate JNK activation by ligands. Here, we use double-stranded RNA-mediated interference of gene expression to reveal the explicit participation of discrete MAP3Ks in controlling JNK activity by multiple stimuli. Maximal activation of JNK by lipopolysaccharide requires the MAP3K TAK1. On the other hand, sorbitol requires expression of four MAP3Ks to cause maximal JNK activation. Thus, we demonstrate that specific stimuli use different mechanisms to recruit distinct MAP3Ks to regulate the JNK pathway.

* This work was supported by National Institutes of Health Grants GM53032, GM56498 (to M. H. C.), and CA71443 (to M. A. W.) and Welch Foundation Grants I1243 and I1414.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.

§ To whom correspondence should be addressed: Dept. of Pharmacology, the University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-3627; Fax: 214-648-3811; E-mail: mcobb@mednet.swmed.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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