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Merosin‐integrin promotion of skeletal myofiber cell survival: Differentiation state‐distinct involvement of p60Fyn tyrosine kinase and p38α stress‐activated MAP kinase

Myofiber survival and suppression of anoikis depend in large part on the merosin (laminin‐2/‐4)‐integrin α7β1D cell adhesion system; however, the question remains as to the nature of the signaling molecules/pathways involved. In the present study, we investigated this question using the C2C12 cell model of myogenic differentiation and its merosin‐ and laminin‐deficient derivatives. Herein, we report that: 1) of four members of the Src family of tyrosine kinases studied (p60Src, p53/56Lyn, p59Yes, or p60Fyn), the expression and activity of p60Fyn are found in myotubes exclusively; 2) a severe decrease of p60Fyn activity correlates with myotube apoptosis/anoikis induced by pharmocological compounds (herbimycin A or PP2) which inhibit tyrosine kinases of the Src family, by merosin deficiency and by β1 integrin inhibition; 3) myoblast survival depends on Fak and the MEK/Erk pathway, in contrast to myotubes; 4) the PI3‐K pathway is not involved in either myoblast or myotube survival; and 5) p38α SAPK stimulation and activity (but not that of p38β) are required in the progression of myotube apoptosis/anoikis induced by p60Fyn inhibition, merosin deficiency or β1 integrin‐inhibition; however, p38 is not involved in myoblast apoptosis. Taken together, these results suggest that the promotion of myotube survival by the merosin‐α7β1D adhesion system involves p60Fyn, and that disruptions in this cell adhesion system induce myotube apoptosis/anoikis through a p38α SAPK‐dependent pathway. J. Cell. Physiol. 191: 69–81, 2002. © 2002 Wiley‐Liss, Inc.