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© The Rockefeller University Press, 0021-9525/1999//153 $5.00
The Journal of Cell Biology, Volume 145, Number 1, , 1999 153-165

Regular Articles

Membrane Targeting and Stabilization of Sarcospan Is Mediated by the Sarcoglycan Subcomplex



Rachelle H. Crosbie*, Connie S. Lebakken*, Kathleen H. Holt*, David P. Venzke*, Volker Straub*, Jane C. Lee*, R. Mark Grady{ddagger}, Jeffery S. Chamberlain§, Joshua R. Sanes{ddagger}, and Kevin P. Campbell*

* Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242; {ddagger} Department of Pediatrics and Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110; and § Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109

The dystrophin–glycoprotein complex (DGC) is a multisubunit complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. The proteins of the DGC are structurally organized into distinct subcomplexes, and genetic mutations in many individual components are manifested as muscular dystrophy. We recently identified a unique tetraspan-like dystrophin-associated protein, which we have named sarcospan (SPN) for its multiple sarcolemma spanning domains (Crosbie, R.H., J. Heighway, D.P. Venzke, J.C. Lee, and K.P. Campbell. 1997. J. Biol. Chem. 272:31221–31224). To probe molecular associations of SPN within the DGC, we investigated SPN expression in normal muscle as a baseline for comparison to SPN's expression in animal models of muscular dystrophy. We show that, in addition to its sarcolemma localization, SPN is enriched at the myotendinous junction (MTJ) and neuromuscular junction (NMJ), where it is a component of both the dystrophin– and utrophin–glycoprotein complexes. We demonstrate that SPN is preferentially associated with the sarcoglycan (SG) subcomplex, and this interaction is critical for stable localization of SPN to the sarcolemma, NMJ, and MTJ. Our experiments indicate that assembly of the SG subcomplex is a prerequisite for targeting SPN to the sarcolemma. In addition, the SG– SPN subcomplex functions to stabilize {alpha}-dystroglycan to the muscle plasma membrane. Taken together, our data provide important information about assembly and function of the SG–SPN subcomplex.

Key Words: sarcospan • dystrophin • sarcoglycans • tetraspans • muscular dystrophy

Abbreviations used in this paper: DG, dystroglycan; DGC, dystrophin– glycoprotein complex; EOM, extraocular muscle; LGMD, limb-girdle muscular dystrophy; mdx, murine dystrophin gene; MTJ, myotendinous junction; NMJ, neuromuscular junction; SG, sarcoglycan; Sgca-null, {alpha}-SG deficient mice; SPN, sarcospan; utrn–/–, utrophin deficient; mdx:utrn–/–, utrophin–dystrophin deficient; wt, wild-type.

R.H. Crosbie is supported by the Robert G. Sampson postdoctoral research fellowship from the Muscular Dystrophy Association. C.S. Lebakken is supported by the Iowa Cardiovascular Interdisciplinary Research Fellowship (HL07121). V. Straub was supported by the Deutsche Forschungsgemeinschaft (Str 498/1-1). R.M. Grady was supported by a National Research Service Award. J.R. Sanes was supported by the National Institutes of Health (NIH R01NS1915). This research was also supported by a grant from the Muscular Dystrophy Association to K.P. Campbell and J.R. Sanes. K.P. Campbell is an investigator of the Howard Hughes Medical Institute.


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