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J. Biol. Chem. 278 (3): 1403-1406

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Ubiquitylation of MEKK1 Inhibits Its Phosphorylation of MKK1 and MKK4 and Activation of the ERK1/2 and JNK Pathways*

James A. Witowsky and Gary L. JohnsonDagger

From the Department of Pharmacology, University of Colorado Health Sciences Center and University of Colorado Cancer Center, Denver, Colorado 80262

MEKK1 is a MAPK kinase kinase that is activated in response to stimuli that alter the cytoskeleton and cell shape. MEKK1 phosphorylates and activates MKK1 and MKK4, leading to ERK1/2 and JNK activation. MEKK1 has a plant homeobox domain (PHD) that has been shown to have E3 ligase activity. (Lu, Z., Xu, S., Joazeiro, C., Cobb, M. H., and Hunter, T. (2002) Mol. Cell 9, 945-956). MEKK1 kinase activity is required for ubiquitylation of MEKK1. MEKK1 ubiquitylation is inhibited by mutation of cysteine 441 to alanine (C441A) within the PHD. The functional consequence of MEKK1 ubiquitylation is the inhibition of MEKK1 catalyzed phosphorylation of MKK1 and MKK4 resulting in inhibition of ERK1/2 and JNK activation. The C441A mutation within the PHD of MEKK1 prevents ubiquitylation and preserves the ability of MEKK1 to catalyze MKK1 and MKK4 phosphorylation. MEKK1 ubiquitylation represents a mechanism for inhibiting the ability of a protein kinase to phosphorylate substrates and regulate downstream signaling pathways.

* This work was supported by National Institutes of Health Grant DK37871.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.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology, Rm. 2809, SOM, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262. Fax: 303-315-1022; E-mail:

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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