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J. Biol. Chem., Vol. 280, Issue 13, 12517-12522, April 1, 2005

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The NF2 Tumor Suppressor Merlin and the ERM Proteins Interact with N-WASP and Regulate Its Actin Polymerization Function^*

Nitasha Manchanda, Anna Lyubimova¶, Hsin-Yi Henry Ho||, Marianne F. James, James F. Gusella, Narayanaswamy Ramesh**, Scott B. Snapper¶, and Vijaya Ramesh

From the Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the Department of Genetics, ^||Department of Cell Biology, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, the ^¶Gastrointestinal Unit (Medical Services) and the Center for Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts 02114, and the ^**Division of Immunology, Children's Hospital, Boston, Massachusetts 02115

The function of the NF2 tumor suppressor merlin has remained elusive despite increasing evidence for its role in actin cytoskeleton reorganization. The closely related ERM proteins (ezrin, radixin, and moesin) act as linkers between the cell membrane and cytoskeleton, and have also been implicated as active actin reorganizers. We report here that merlin and the ERMs can interact with and regulate N-WASP, a critical regulator of actin dynamics. Merlin and moesin were found to inhibit N-WASP-mediated actin assembly in vitro, a function that appears independent of their ability to bind actin. Furthermore, exogenous expression of a constitutively active ERM inhibits N-WASP-dependent Shigella tail formation, suggesting that the ERMs may function as inhibitors of N-WASP function in vivo. This novel function of merlin and the ERMs illustrates a mechanism by which these proteins directly exert their effects on actin reorganization and also provides new insight into N-WASP regulation.

Received for publication, December 15, 2004 , and in revised form, February 3, 2005.

^* This work was supported by National Institutes of Health Grants NS24279 (to N. M., M. F. J., J. F. G., and V. R.) and AI052354 and HL59561 (to S. B. S.) and Department of Defense Grant DAMD17-02-0647. 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 supplemental Figs. S1 and S2.

To whom correspondence should be addressed: Molecular Neurogenetics Unit, Bldg. 149, 13th St., Rm. 6222, Massachusetts General Hospital-East, Charlestown, MA 02129. Tel.: 617-724-9733; Fax: 617-726-3655; E-mail: ramesh{at}helix.mgh.harvard.edu.

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