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Originally published as MBC in Press, 10.1091/mbc.E02-02-0115 on November 18, 2002
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Vol. 14, Issue 1, 156-172, January 2003

A New Identity for MLK3 as an NIMA-related, Cell Cycle-regulated Kinase That Is Localized near Centrosomes and Influences Microtubule Organization

Katherine I. Swenson, Katharine E. Winkler, and Anthony R. Means*

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Although conserved counterparts for most proteins involved in the G2/M transition of the cell cycle have been found in all eukaryotes, a notable exception is the essential but functionally enigmatic fungal kinase NIMA. While a number of vertebrate kinases have been identified with catalytic domain homology to NIMA, none of these resemble NIMA within its extensive noncatalytic region, a region critical for NIMA function in Aspergillus nidulans. We used a bioinformatics approach to search for proteins with homology to the noncatalytic region of NIMA and identified mixed lineage kinase 3 (MLK3). MLK3 has been proposed to serve as a component in MAP kinase cascades, particularly those resulting in the activation of the c-Jun N-terminal kinase (JNK). Here we describe the first in-depth study of endogenous MLK3 and report that, like NIMA, MLK3 phosphorylation and activity are enhanced during G2/M, whereas JNK remains inactive. Coincident with the G2/M transition, a period marked by dramatic reorganization of the cytoplasmic microtubule network, endogenous MLK3 transiently disperses away from the centrosome and centrosomal-proximal sites where it is localized during interphase. Furthermore, when overexpressed, MLK3, like NIMA, localizes to the centrosomal region, induces profound disruption of cytoplasmic microtubules and a nuclear distortion phenotype that differs from mitotic chromosome condensation. Cellular depletion of MLK3 protein using siRNA technology results in an increased sensitivity to the microtubule-stabilizing agent taxol. Our studies suggest a new role for MLK3, separable from its function in the JNK pathway, that may contribute to promoting microtubule instability, a hallmark of M phase entry.

* Corresponding author. E-mail address: means001{at}mc.duke.edu.

Molecular Biology of the Cell
Vol. 14, 156-172, January 2003
Copyright © 2003 by The American Society for Cell Biology


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