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J. Biol. Chem., Vol. 282, Issue 32, 23532-23540, August 10, 2007

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Suppression of Tubulin Polymerization by the LKB1-Microtubule-associated Protein/Microtubule Affinity-regulating Kinase Signaling^*

Yasushi Kojima, Hiroyuki Miyoshi, Hans C. Clevers, Masanobu Oshima¹, Masahiro Aoki, and Makoto M. Taketo²

From the Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan and the Hubrecht Laboratory and Utrecht University, 3584 CT Utrecht, The Netherlands

LKB1, a tumor suppressor gene mutated in the Peutz-Jeghers syndrome, encodes a serine/threonine protein kinase. Recent biochemical studies have shown that LKB1 activates 14 AMP-activated protein kinase-related kinases including MARKs (microtubule-associated protein/microtubule affinity-regulating kinases) that regulate microtubule dynamics. Here we show in vitro that LKB1 phosphorylates and activates MARK2, which in turn phosphorylates microtubule-associated protein Tau at the KXGS motif and suppresses tubulin polymerization. In cells, forced expression of LKB1 suppresses microtubule regrowth, whereas LKB1 knockdown accelerates it. We further show that the phosphorylation of Tau by the LKB1-MARK signaling triggers proteasome-mediated degradation of Tau. These results indicate that LKB1 is involved in the regulation of microtubule dynamics through the activation of MARKs.

Received for publication, January 22, 2007 , and in revised form, June 11, 2007.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, 920-0934 Japan.

² To whom correspondence should be addressed: Dept. of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: 81-75-753-4391; Fax: 81-75-753-4402; E-mail: taketo{at}mfour.med.kyoto-u.ac.jp.

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