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J. Biol. Chem., Vol. 279, Issue 7, 6196-6203, February 13, 2004

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Regulation of Microtubule Destabilizing Activity of Op18/Stathmin Downstream of Rac1^*

Torsten Wittmann, Gary M. Bokoch¶, and Clare M. Waterman-Storer||

From the Department of Cell Biology, and the ^¶Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

In the leading edge of migrating cells, a subset of microtubules exhibits net growth in a Rac1- and p21-activated kinase-dependent manner. Here, we explore the possibility of whether phosphorylation and inactivation of the microtubule-destabilizing protein Op18/stathmin could be a mechanism regulating microtubule dynamics downstream of Rac1 and p21-activated kinases. We find that, in vitro, Pak1 phosphorylates Op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit Op18/stathmin in vitro. In cells, the microtubule-destabilizing effect of an excess of Op18/stathmin can be partially overcome by expression of constitutively active Rac1(Q61L), which is dependent on Pak activity, suggesting that the microtubule cytoskeleton can be regulated through inactivation of Op18/stathmin downstream of Rac1 and Pak in vivo. However, in vivo, Pak1 activity alone is not sufficient to phosphorylate Op18, indicating that additional pathways downstream of Rac1 are required for Op18 regulation.

Received for publication, July 7, 2003 , and in revised form, November 4, 2003.

^* This work was funded by National Institutes of Health Grants GM61804 (to C. M. W.-S.) and GM39434 (to G. M. B.) and an EMBO Long Term Fellowship (to T. W.). 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.

The on-line version of this article (available at http://www.jbc.org) contains video files.

To whom correspondence may be addressed: Dept. of Cell Biology, Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-9244; Fax: 858-784-9779; E-mail: twittman{at}scripps.edu.

^|| To whom correspondence may be addressed: Dept. of Cell Biology, Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-9764; Fax: 858-784-9779; E-mail: waterman{at}scripps.edu.

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