Merosin (laminin-2/4)-driven survival signaling: Complex modulations of Bcl-2 homologs

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Abstract
We have shown previously that the promotion of myofiber survival by the basement membrane component merosin (laminin-2 [alpha2beta1gamma1]/laminin-4 [alpha2beta2gamma1]) is dependent on the activity of the tyrosine kinase Fyn, whereas myofiber anoikis induced by merosin deficiency is dependent on the stress-activated protein kinase p38alpha. To further understand such merosin-driven survival signaling, we analyzed the expression of five Bcl-2 homologs (Bcl-2, Bcl-X(L), Bax, Bak, Bad) and one non-homologous associated molecule (Bag-1) in normal and merosin-deficient myotubes, with or without pharmacological inhibitors for Fyn and p38. Herein, we report that (1) merosin deficiency induces anoikis and causes decreased Bcl-2, Bcl-X(L), and Bag-1 levels, increased Bax and Bak levels, and decreased Bad phosphorylation; (2) Bcl-2, Bcl-X(L), Bag-1, and Bad phosphorylation are also decreased in anoikis-dying, Fyn-inhibited myotubes; (3) the inhibition of p38alpha in Fyn-inhibited and/or merosin-deficient myotubes protects against anoikis and increases Bcl-2 levels above normal, in addition to restoring Bad phosphorylation and Bag-1 levels to normal; (4) the overexpression of merosin in deficient myotubes also rescues from anoikis and increases Bcl-2 levels and Bad phosphorylation above normal, in addition to restoring Bcl-X(L), Bag-1, Bax, and Bak levels to normal; and (5) Bcl-2 overexpression is sufficient to rescue merosin-deficient myotubes from anoikis, even though the expression/phosphorylation levels of the other homologs analyzed are not restored to normal. These results indicate that merosin-driven myofiber survival signaling affects complex, differential modulations of individual Bcl-2 homologs. These further suggest that Bcl-2 can play a major role in suppressing myofiber anoikis.
Funding Information
  • Canadian Muscular Dystrophy Association (CMDA, to NR and PHV) (PHVNR-1998)
  • Canadian Institutes of Health Research (CIHR, to PHV) (MOP-14468)