The dystrophin-glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies.
Mutations of different components of the dystrophin-glycoprotein complex (DGC) cause muscular dystrophies that vary in terms of severity, age of onset, and selective involvement of muscle groups. Although the primary pathogenetic processes in the muscular dystrophies have clearly been identified as apoptotic and necrotic muscle cell death, the pathogenetic mechanisms that lead to cell death remain to be determined. Studies of components of the DGC in muscle and in nonmuscle tissues have revealed that the DGC is undoubtedly a multifunctional complex and a highly dynamic structure, in contrast to the unidimensional concept of the DGC as a mechanical component in the cell. Analysis of the DGC reveals compelling analogies to two other membrane-associated protein complexes, namely integrins and caveolins. Each of these complexes mediates signal transduction cascades in the cell, and disruption of each complex causes muscular dystrophies. The signal transduction cascades associated with the DGC, like those associated with integrins and caveolins, play important roles in cell survival signaling, cellular defense mechanisms, and regulation of the balance between cell survival and cell death. This review focuses on the functional components of the DGC, highlighting the evidence of their participation in cellular signaling processes important for cell survival. Elucidating the link between these functional components and the pathogenetic processes leading to cell death is the foremost challenge to understanding the mechanisms of disease expression in the muscular dystrophies due to defects in the DGC.
Rando
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Department of Neurology and Neurological Sciences, Stanford University Medical Center, Room A-343, Stanford, California 94305-5235, USA. rando@stanford.edu
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D016189:Dystrophin / Q000502:physiology*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D009136:Muscular Dystrophies / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*
D016189:Dystrophin; D006023:Glycoproteins