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J. Biol. Chem., Vol. 279, Issue 18, 18559-18566, April 30, 2004

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Cyclic AMP-dependent Protein Kinase Phosphorylates Merlin at Serine 518 Independently of p21-activated Kinase and Promotes Merlin-Ezrin Heterodimerization^*

Kaija Alfthan, Leena Heiska, Mikaela Grönholm, G. Herma Renkema¶, and Olli Carpén||

From the Biomedicum Helsinki, Department of Anatomy and Pathology, Neuroscience Program, University of Helsinki and Helsinki University Hospital, FIN-00014 Helsinki, Finland and ^¶Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33014 Tampere, Finland

Mutations in the NF2 tumor suppressor gene encoding merlin induce the development of tumors of the nervous system. Merlin is highly homologous to the ERM (ezrin-radixin-moesin) family of membrane/cytoskeleton linker proteins. However, the mechanism for the tumor suppressing activity of merlin is not well understood. Previously, we characterized a novel role for merlin as a protein kinase A (PKA)-anchoring protein, which links merlin to the cAMP/PKA signaling pathway. In this study we show that merlin is also a target for PKA-induced phosphorylation. In vitro [-³³P]ATP labeling revealed that both the merlin N and C termini are phosphorylated by PKA. Furthermore, both in vitro and in vivo phosphorylation studies of the wild-type and mutated C termini demonstrated that PKA can phosphorylate merlin at serine 518, a site that is phosphorylated also by p21-activated kinases (PAKs). Merlin was phosphorylated by PKA in cells in which PAK activity was suppressed, indicating that the two kinases function independently. Both in vitro and in vivo interaction studies indicated that phosphorylation of serine 518 promotes heterodimerization between merlin and ezrin, an event suggested to convert merlin from a growth-suppressive to a growth-permissive state. This study provides further evidence on the connection between merlin and cAMP/PKA signaling and suggests a role for merlin in the cAMP/PKA transduction pathway.

Received for publication, December 19, 2003 , and in revised form, February 3, 2004.

^* This work was supported by United States Army Neurofibromatosis Research Grant DAMD17-00-0550 and by grants from the Academy of Finland and the Finnish Cancer Organizations. 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.

Present address: VTT Biotechnology, Tietotie 2, P. O. Box 1500, FIN-02044 VTT, Finland.

^|| To whom correspondence should be addressed: Neuroscience Program, Rm. C524, Biomedicum, P. O. Box 63, Haartmaninkatu 8, University of Helsinki, FIN-00014 Helsinki, Finland. Tel.: 358-9-19125650; Fax: 358-9-47171964; E-mail: olli.carpen{at}helsinki.fi.

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