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© The Rockefeller University Press, 0021-9525/2003/3/741 $5.00
The Journal of Cell Biology, Volume 160, Number 5, 741-752

Tyrosine-phosphorylated and nonphosphorylated isoforms of -dystrobrevin

R. Mark Grady¹, Mohammed Akaaboune², Alexander L. Cohen², Margaret M. Maimone³, Jeff W. Lichtman² and Joshua R. Sanes²

¹ Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
² Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110
³ Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210

Address correspondence to R. Mark Grady, Dept. of Pediatrics, Washington University School of Medicine, Pediatric Research Bldg., St. Louis, MO 63110. Tel.: (314) 286-2796. Fax: (314) 286-2892. E-mail: grady{at}kids.wustl.edu

-Dystrobrevin (DB), a cytoplasmic component of the dystrophin–glycoprotein complex, is found throughout the sarcolemma of muscle cells. Mice lacking DB exhibit muscular dystrophy, defects in maturation of neuromuscular junctions (NMJs) and, as shown here, abnormal myotendinous junctions (MTJs). In normal muscle, alternative splicing produces two main DB isoforms, DB1 and DB2, with common NH₂-terminal but distinct COOH-terminal domains. DB1, whose COOH-terminal extension can be tyrosine phosphorylated, is concentrated at the NMJs and MTJs. DB2, which is not tyrosine phosphorylated, is the predominant isoform in extrajunctional regions, and is also present at NMJs and MTJs. Transgenic expression of either isoform in DB^-/- mice prevented muscle fiber degeneration; however, only DB1 completely corrected defects at the NMJs (abnormal acetylcholine receptor patterning, rapid turnover, and low density) and MTJs (shortened junctional folds). Site-directed mutagenesis revealed that the effectiveness of DB1 in stabilizing the NMJ depends in part on its ability to serve as a tyrosine kinase substrate. Thus, DB1 phosphorylation may be a key regulatory point for synaptic remodeling. More generally, DB may play multiple roles in muscle by means of differential distribution of isoforms with distinct signaling or structural properties.

Key Words: dystrobrevin; dystrophin; muscular dystrophy; myotendinous junction; neuromuscular junction

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