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J. Biol. Chem., Vol. 282, Issue 42, 30476-30484, October 19, 2007

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MEKK4 Stimulation of p38 and JNK Activity Is Negatively Regulated by GSK3^*

From the Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7365

The MAPK kinase kinase MEKK4 is required for neurulation and skeletal patterning during mouse development. MEKK4 phosphorylates and activates MKK4/MKK7 and MKK3/MKK6 leading to the activation of JNK and p38, respectively. MEKK4 is believed to be auto-inhibited, and its interaction with other proteins controls its dimerization and activation. TRAF4, GADD45, and Axin each bind and activate MEKK4, with TRAF4 and Axin binding to the kinase domain and GADD45 binding within the N-terminal regulatory domain. Here we show that similar to the interaction with TRAF4 and Axin, the kinase domain of MEKK4 interacts with the multifunctional serine/threonine kinase GSK3. GSK3 binding to MEKK4 blocks MEKK4 dimerization that is required for MEKK4 activation, effectively inhibiting MEKK4 stimulation of the JNK and p38 MAPK pathways. Inhibition of GSK3 kinase activity with SB216763 results in enhanced MEKK4 kinase activity and increased JNK and p38 activation, indicating that an active state of GSK3 is required for binding and inhibition of MEKK4 dimerization. Furthermore, GSK3 phosphorylates specific serines and threonines in the N terminus of MEKK4. Together, these findings demonstrate that GSK3 binds to the kinase domain of MEKK4 and regulates MEKK4 dimerization. However, unlike TRAF4, Axin, and GADD45, GSK3 inhibits MEKK4 activity and prevents its activation of JNK and p38. Thus, control of MEKK4 dimerization is regulated both positively and negatively by its interaction with specific proteins.

Received for publication, July 13, 2007 , and in revised form, August 17, 2007.

^* This work was supported by National Institutes of Health Grant GM30324. 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, 1012 Mary Ellen Jones Bldg., CB 7365 Chapel Hill, NC 27599-7365. Tel.: 919-843-3257; Fax: 919-966-5640; E-mail: amy_abell{at}med.unc.edu.

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