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Originally published In Press as doi:10.1074/jbc.C100553200 on November 21, 2001

J. Biol. Chem., Vol. 277, Issue 2, 883-886, January 11, 2002
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ACCELERATED PUBLICATION
p21-activated Kinase Links Rac/Cdc42 Signaling to Merlin*

Guang-Hui XiaoDagger , Alexander Beeser§, Jonathan Chernoff§, and Joseph R. TestaDagger §||

From the Dagger  Human Genetics Program and § Tumor Cell Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

The neurofibromatosis type 2 tumor suppressor gene, NF2, is mutated in the germ line of NF2 patients and predisposes affected individuals to intracranial and spinal tumors. Moreover, somatic mutations of NF2 can occur in the sporadic counterparts of these neurological tumor types as well as in certain neoplasms of non-neuroectodermal origin, such as malignant mesothelioma and melanoma. NF2 encodes a 595-amino acid protein, merlin, which exhibits significant homology to the ezrin-radixin-moesin family of proteins. However, the mechanism by which merlin exerts its tumor suppressor activity is not well understood. In this investigation, we show that merlin is phosphorylated in response to expression of activated Rac and activated Cdc42 in mammalian cells. Furthermore, we demonstrate that merlin phosphorylation is mediated by p21-activated kinase (Pak), a common downstream target of both Rac and Cdc42. Both in vivo and in vitro kinase assays demonstrated that Pak can directly phosphorylate merlin at serine 518, a site that affects merlin activity and localization. These biochemical investigations provide insights into the regulation of merlin function and establish a framework for elucidating tumorigenic mechanisms involved in neoplasms associated with merlin inactivation.

* This work was supported by National Institutes of Health Grants CA-45745 (to J. R. T.), GM-54168 (to J. C.), and CA-06927 (to the Fox Chase Cancer Center); American Cancer Society Grant CB-189 (to J. C.); by a gift from the Local No. 14 Mesothelioma Fund of the International Association of Heat and Frost Insulators & Asbestos Workers (to J. R. T.); and by an appropriation from the Commonwealth of Pennsylvania.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Scholar of the Leukemia and Lymphoma Society of America.

|| To whom correspondence should be addressed: Fox Chase Cancer Center, Human Genetics Program, 7701 Burholme Ave., Philadelphia, PA 19111. E-mail: JR_Testa@fccc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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