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 alpha7beta1 D 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: I) of four members of the Src family of tyrosine kinases studied (p60(Src), p53/56(Lyn), p59(Yes), or p60(Fyn)), the expression and activity of p60(Fyn) are found in myotubes exclusively; 2) a severe decrease of p60(Fyn) 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 beta1 integrin inhibition; 3) myoblast survival depends on Fak and the MEK/Erk pathway, in contrast to myotubes; 4) the P13-K pathway is not involved in either myoblast or myotube survival; and 5) p38alpha SAPK stimulation and activity (but not that of p38beta) are required in the progression of myotube apoptosis/anoikis induced by p60(Fyn), inhibition, merosin deficiency or 31 integrin-inhibition; however, p38 is not involved in myoblast apoptosis. Taken together, these results suggest that the promotion of myotube survival by the merosin-alpha7beta1 D adhesion system involves p60(Fyn), and that disruptions in this cell adhesion system induce myotube apoptosis/anoikis through a p38a SAPK-dependent pathway. J. Ce I I. Physio L 191: 69-81, 2002. (C) 2002 Wiley-Liss, Inc.