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J. Biol. Chem., Vol. 283, Issue 29, 20252-20260, July 18, 2008

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The Endocytic Recycling Protein EHD2 Interacts with Myoferlin to Regulate Myoblast Fusion^*

Katherine R. Doherty¹, Alexis R. Demonbreun¹, Gregory Q. Wallace^¶, Andrew Cave^¶, Avery D. Posey^||, Konstantina Heretis^¶, Peter Pytel^**, and Elizabeth M. McNally^¶||2

From the Department of Molecular Genetics and Cell Biology, Committee on Developmental Biology, ^¶Department of Medicine, ^||Committee on Genetics, ^**Department of Pathology, and Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637

Skeletal muscle is a multinucleated syncytium that develops and is maintained by the fusion of myoblasts to the syncytium. Myoblast fusion involves the regulated coalescence of two apposed membranes. Myoferlin is a membrane-anchored, multiple C2 domain-containing protein that is highly expressed in fusing myoblasts and required for efficient myoblast fusion to myotubes. We found that myoferlin binds directly to the eps15 homology domain protein, EHD2. Members of the EHD family have been previously implicated in endocytosis as well as endocytic recycling, a process where membrane proteins internalized by endocytosis are returned to the plasma membrane. EHD2 binds directly to the second C2 domain of myoferlin, and EHD2 is reduced in myoferlin null myoblasts. In contrast to normal myoblasts, myoferlin null myoblasts accumulate labeled transferrin and have delayed recycling. Introduction of dominant negative EHD2 into myoblasts leads to the sequestration of myoferlin and inhibition of myoblast fusion. The interaction of myoferlin with EHD2 identifies molecular overlap between the endocytic recycling pathway and the machinery that regulates myoblast membrane fusion.

Received for publication, March 24, 2008 , and in revised form, May 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants T32HL007381 (K. R. D. and A. R. D.) and R01NS047726 (to E. M. M.). This work was also supported by the Muscular Dystrophy Association. 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.

¹ These authors contributed equally.

² To whom correspondence should be addressed: 5841 S. Maryland Ave. MC6088, Chicago, IL 60632. Tel.: 773-702-2672; Fax: 773-702-2681; E-mail: emcnally{at}uchicago.edu.

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