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J. Biol. Chem., Vol. 280, Issue 12, 11790-11797, March 25, 2005

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Erbin Regulates Mitogen-activated Protein (MAP) Kinase Activation and MAP Kinase-dependent Interactions between Merlin and Adherens Junction Protein Complexes in Schwann Cells^*

Reshma Rangwala, Fatima Banine, Jean-Paul Borg¶, and Larry S. Sherman||

From the Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006 and the ^¶Molecular Pharmacology, Institut de Cancérologie de Marseille, UM599, INSERM and Institut Paoli-Calmettes, Marseille 13009, France

Biallelic mutations in the neurofibromatosis 2 (NF2) gene are linked to schwannoma and meningioma tumorigenesis. Cells with NF2 mutations exhibit elevated levels of phosphorylated extracellular signal-regulated kinase (ERK) and aberrant cell-cell and cell-matrix contacts. The NF2 gene product, merlin, associates with adherens junction protein complexes, suggesting that part of its function as a tumor suppressor involves regulating cell junctions. Here, we find that a novel PDZ protein, called erbin, binds directly to the merlin-binding partner, EBP0, and regulates adherens junction dissociation through a MAP kinase-dependent mechanism. Reducing erbin expression using a targeted siRNA in primary cultures of Schwann cells results in altered cell-cell interactions, disruption of E-cadherin adherens junctions, increased cell proliferation, and elevated levels of phosphorylated ERK, all phenotypes observed in cells that lack merlin. Reduction of erbin expression also results in the dissociation of merlin from adherens junction proteins and an increase in the levels of phosphorylated merlin. These phenotypes can be rescued if cells with reduced levels of erbin are treated with a pharmacological inhibitor of ERK kinase. Collectively, these data indicate that erbin regulates MAP kinase activation in Schwann cells and suggest that erbin links merlin to both adherens junction protein complexes and the MAP kinase signaling pathway.

Received for publication, December 16, 2004 , and in revised form, January 18, 2005.

^* This work was supported by Grants NS39550 and RR00163 from the National Institutes of Health and by a University of Cincinnati Functional Genomics Fellowship. 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.

Current address: University of Cincinnati College of Medicine, Physician Scientist Training Program and Graduate Program in Neuroscience, Cincinnati, OH 45267.

^|| To whom correspondence should be addressed: Division of Neuroscience, Oregon National Primate Research Center, 505 NW 185th Ave., Beaverton, OR 97006. Tel.: 503-690-5217; Fax: 503-690-5384; E-mail: shermanl{at}ohsu.edu.

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