Abstract

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Differentiation of skeletal muscle cells into multinucleated myotubes needs several cellular events including shutting off the growth promoting signals mediated by several growth factors. Integrin-mediated growth signal is transduced to the downstream effectors through the higher levels of expression and activity of focal adhesion kinase (FAK), which seems to have strong proliferative signal almost in all tissues that leads to tumorigenesis. During myogenesis, the level of eukaryotic initiation factor 2 (eIF2)-associated glycoprotein p67 gradually increases and its level peaks at the time of fusion of C2C12 myoblasts into myotubes. This increased level binds to extracellular signal-regulated kinases (ERK1/2) to inhibit their activation and activity when C2C12 myoblasts are differentiating into myotubes. To investigate whether p67 is involved in the inactivation of FAK during the differentiation of C2C12 myoblasts, we examined the level of FAK. We found that degradation of FAK peaked at the time of fusion of C2C12 myoblasts into myotubes and at the same time the level of p67 is also high. In addition, p67’s N-terminal lysine-rich domains I & II and acidic residue-rich domain are involved in this degradation of FAK possibly by increasing the cellular concentration of p52 segment of p67 that has intermolecular proteolysis activity. We also found that the level of the Akt1/2 kinase, one of the several downstream effectors of FAK, gradually increased during the differentiation of C2C12 myoblasts, possibly to prevent differentiated C2C12 myoblasts from apoptosis and this process may be independent of FAK.

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