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J. Biol. Chem., Vol. 280, Issue 52, 42984-42993, December 30, 2005

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Cdc42 Induces Activation Loop Phosphorylation and Membrane Targeting of Mixed Lineage Kinase 3^*

Yan Du, Barbara C. Böck1, Karen A. Schachter, Mary Chao, and Kathleen A. Gallo¶2

From the Departments of Physiology and Biochemistry and Molecular Biology and the ^¶Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824

Mixed lineage kinase 3 (MLK3) functions as a mitogen-activated protein kinase kinase kinase to activate multiple mitogen-activated protein kinase pathways. Our current studies demonstrate that lack of MLK3 blocks signaling of activated Cdc42 to c-Jun N-terminal kinase, giving strong support for the idea that Cdc42 is a physiological activator of MLK3. We show herein that Cdc42, in a prenylation-dependent manner, targets MLK3 from a perinuclear region to membranes, including the plasma membrane. Cdc42-induced membrane targeting of MLK3 is independent of MLK3 catalytic activity but depends upon an intact Cdc42/Rac-interactive binding motif, consistent with MLK3 membrane translocation being mediated through direct binding of Cdc42. Phosphorylation of the activation loop of MLK3 requires MLK3 catalytic activity and is induced by Cdc42 in a prenylation-independent manner, arguing that Cdc42 binding is sufficient for activation loop autophosphorylation of MLK3. However, membrane targeting is necessary for full activation of MLK3 and maximal signaling to JNK. We previously reported that MLK3 is autoinhibited through an interaction between its N-terminal SH3 domain and a proline-containing sequence found between the leucine zipper and the CRIB motif of MLK3. Thus we propose a model in which GTP-bound Cdc42/Rac binds MLK3 and disrupts SH3-mediated autoinhibition leading to dimerization and activation loop autophosphorylation. Targeting of this partially active MLK3 to membranes likely results in additional phosphorylation events that fully activate MLK3 and its ability to maximally signal through the JNK pathway.

Received for publication, March 10, 2005 , and in revised form, October 6, 2005.

^* This work was supported by American Cancer Society Research Scholar Grant RSG-03-084 (to K. A. G.). 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 Present address: German Cancer Research Center, Molecular Neuro-Oncology, Heidelberg, Germany.

² To whom correspondence should be addressed: Dept. of Physiology, 4180 Biomedical and Physical Sciences Bldg., Michigan State University, East Lansing, MI 48824. Tel.: 517-355-6475 (ext. 1159); Fax: 517-355-5125; E-mail: gallok{at}msu.edu.

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