Activation of c-Raf-1 kinase signal transduction pathway in alpha(7) integrin-deficient mice

Integrin alpha(7)-deficient mice develop a novel form of muscular dystrophy , Here we report that deficiency of alpha(7) integrin causes an activation of the c-Raf-1/mitogen-activated protein (MAP) 2 kinase signal transduction pathway in muscle cells. The observed activation of c-Raf-1/MAP2 kinases i s a specific effect, because the alpha(7) integrin deficiency does not caus e unspecific stress as determined by measurement of the Hsp72/73 level and activity of the JNK2 kinase, Because an increased level of activated FAK wa s found in muscle of alpha(7)-integrin-deficient mice, the activation of c- Raf-1 kinase is triggered most likely by an integrin-dependent pathway. In accordance with this, in the integrin cu, deficient mice, part of the integ rin beta(1D) variant in muscle is replaced by the beta(1A) variant, which p ermits the FAK activation. A recent report describes that integrin activity can be down-modulated by the c-Raf-1/MAP2 kinase pathway. Specific activat ion of the c-Raf-1/MAP2 kinases by cell-permeable peptides in skeletal musc le of rabbits causes degeneration of muscle fibers, Therefore, we conclude that in alpha(7) integrin deficient mice, the continuous activation of c-Ra f-1 kinase causes a permanent reduction of integrin activity diminishing in tegrin-dependent cell-matrix interactions and thereby contributing to the d evelopment of the dystrophic phenotype.