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J. Biol. Chem., Vol. 279, Issue 7, 5915-5923, February 13, 2004

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MARK4 Is a Novel Microtubule-associated Proteins/Microtubule Affinity-regulating Kinase That Binds to the Cellular Microtubule Network and to Centrosomes^*

Bernhard Trinczek, Miro Brajenovic¶, Andreas Ebneth||, and Gerard Drewes¶**

From the Department of Medicinal Chemistry, University of Kansas, Malott Hall, Lawrence, Kansas 66045, ^¶Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany, and ^||EVOTEC NeuroSciences GmbH, Schnackenburgallee 114, 22525 Hamburg, Germany

The MARK protein kinases were originally identified by their ability to phosphorylate a serine motif in the microtubule-binding domain of tau that is critical for microtubule binding. Here, we report the cloning and expression of a novel human paralog, MARK4, which shares 75% overall homology with MARK1-3 and is predominantly expressed in brain. Homology is most pronounced in the catalytic domain (90%), and MARK4 readily phosphorylates tau and the related microtubule-associated protein 2 (MAP2) and MAP4. In contrast to the three paralogs that all exhibit uniform cytoplasmic localization, MARK4 colocalizes with the centrosome and with microtubules in cultured cells. Overexpression of MARK4 causes thinning out of the microtubule network, concomitant with a reorganization of microtubules into bundles. In line with these findings, we show that a tandem affinity-purified MARK4 protein complex contains -, -, and -tubulin. In differentiated neuroblastoma cells, MARK4 is localized prominently at the tips of neurite-like processes. We suggest that although the four MARK/PAR-1 kinases might play multiple cellular roles in concert with different targets, MARK4 is likely to be directly involved in microtubule organization in neuronal cells and may contribute to the pathological phosphorylation of tau in Alzheimer's disease.

Received for publication, April 30, 2003 , and in revised form, September 12, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY057448 and AF465413.

This work contains part of the doctoral thesis of M. B. at the University of Heidelberg.

^* This work was supported in part by the Max-Planck Gesellschaft and the Human Frontier Science Program. 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany. Tel.: 49-6221-13757350; Fax: 49-6221-13757206; E-mail: Gerard.Drewes{at}Cellzome.com.

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