Possible functions of p94 in connectin-mediated signaling pathways in skeletal muscle cells
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Calpains are intracellular Ca2+-requiring ‘modulator proteases’, which modulate cellular functions by limited and specific proteolysis. p94/calpain3, a skeletal-muscle specific calpain, has been one of the representative calpain species which indicates physiological importance of calpain proteolytic system; a defect of proteolytic activity of p94 causes limb girdle muscular dystrophy type2A (LGMD2A, also called ‘calpainopathy’). Immunohistochemical studies on myofibrils showed that p94 localizes at the Z- and N2-line regions of sarcomeres. It was also identified by the yeast two hybrid studies that p94 binds to the N2A and M-line regions of connectin. Furthermore, genetic studies indicate that p94 is indispensable for skeletal muscles, although its precise functions are still unclear. Interestingly, connectin provides sarcomere not only with elasticity but also with binding sites to various multi-functional proteins such as muscle ankyrin repeat proteins (MARPs), muscle RING finger proteins (MURFs), titin-capping protein (T-cap/telethonin), sarcomeric-α-actinin, p94 etc. Binding sites for these proteins are not randomly placed along connectin but rather accumulated in the Z-, N2-, and/or M-line regions, indicating the existence of ‘signal complexes’ unique to each regions. The concept of these complexes are strongly supported by the facts that mutations of connectin or its binding proteins in these regions severely perturb muscle functions, as in the case of LGMD2A caused by mutations in the p94 gene. Therefore, it is hypothesized that the ‘signal complexes’ in the Z-, N2-, and M-lines modulate muscle cell homeostasis by transducing signals of external stimulations/stresses to trigger appropriate response at various different cellular events such as protein modification and gene expressions. In this article, we performed detailed immunohistochemical analyses of p94 on isolated single myofibers. Together with recent findings about p94, it is suggested that sarcomeric localization of p94, especially its M-line localization, is affected by the combination of cellular contexts such as contractile status of myofibrils, fiber type compositions, sarcomeric maturation, and the composition of the ‘signal complexes’ in each region.
KeywordsMuscular Dystrophy Extensor Digitorum Longus Limb Girdle Muscular Dystrophy Cardiac Ankyrin Repeat Protein PEVK Domain
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We would like to thank Dr Siegfried Labeit and Dr Christian Witt in Universitätsklinikum Mannheim, Dr Carol C. Gregorio in University of Arizona, and Dr Sumiko Kimura in University of Chiba for valuable discussions. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (Cell Cycle) from the Ministry of Education, Science, Sports and Culture, a Grant-in-Aid for Scientific Research and Research Fellowships for Young Scientists from JSPS (the Japan Society for the Promotion of Science), a Research Grant (14B-4) for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare, and ‘Ground-based Research Announcement for Space Utilization’ promoted by the Japan Space Forum. This paper is dedicated to the memory of Prof Koscak Maruyama. We all miss him.
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