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J. Biol. Chem., Vol. 281, Issue 28, 19134-19144, July 14, 2006

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Dynamic Positive Feedback Phosphorylation of Mixed Lineage Kinase 3 by JNK Reversibly Regulates Its Distribution to Triton-soluble Domains^*

Karen A. Schachter, Yan Du, Anning Lin^¶, and Kathleen A. Gallo^||1

From the Departments of Biochemistry and Molecular Biology and Physiology, and the ^||Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824 and the ^¶Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637

MLK3 (mixed lineage kinase 3) is a widely expressed, mammalian serine/threonine protein kinase that activates multiple MAPK pathways. Previously our laboratory used in vivo labeling/mass spectrometry to identify phosphorylation sites of activated MLK3. Seven of 11 identified sites correspond to the consensus motif for phosphorylation by proline-directed kinases. Based on these results, we hypothesized that JNK, or another proline-directed kinase, phosphorylates MLK3 as part of a feedback loop. Herein we provide evidence that MLK3 can be phosphorylated by JNK in vitro and in vivo. Blockade of JNK results in dephosphorylation of MLK3. The hypophosphorylated form of MLK3 is inactive and redistributes to a Triton-insoluble fraction. Recovery from JNK inhibition restores MLK3 solubility and activity, indicating that the redistribution process is reversible. This work describes a novel mode of regulation of MLK3, by which JNK-mediated feedback phosphorylation of MLK3 regulates its activation and deactivation states by cycling between Triton-soluble and Triton-insoluble forms.

Received for publication, April 7, 2006

^* This work was supported by an 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 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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