EXTRACELLULAR SIGNAL-REGULATED KINASE AND C-JUN NH2-TERMINAL KINASE ACTIVATION BY MECHANICAL STRETCH IS INTEGRIN-DEPENDENT AND MATRIX-SPECIFIC IN RAT CARDIAC FIBROBLASTS

Integrins, which connect the cytoskeleton to the extracellular matrix and mediate a variety of signaling cascades, may transduce mechanical stimuli into biochemical signals. We studied integrin-and matrix-depen dent activation of extracellular signal-regulated kinase (ERK2), c-Jun NH2-terminal kinase (JNK1), and p38 in response to 4% static biaxial stretch in rat cardiac fibroblasts. ERK2 and JNK1, but not p38, were r apidly activated by stretch when the fibroblasts were allowed to synth esize their own matrices. When the cells were limited to specific matr ix substrates, ERK2 and JNK1 were differentially activated: ERK2 was o nly activated when the cells were plated on fibronectin, while JNK1 wa s activated when the cells were plated on fibronectin, vitronectin, or laminin. Plating cells on collagen before stretching did not activate either kinase. Adhesion to all matrices was integrin-dependent becaus e it could be blocked by inhibitors of specific integrins. ERK2 activa tion could be blocked with a combination of anti-alpha 4 and -alpha 5 antibodies and an arginine-glycine-aspartic acid (RGD) peptide, while the antibodies or peptide used separately failed to block ERK2 activat ion. This result suggests that at least two integrins, alpha 4 beta 1 and an RGD-directed, non-alpha 5 beta 1 integrin, activate ERK2 in res ponse to mechanical stimulation. Activation of JNK1 could not be block ed with the inhibitors, suggesting that an RGD-independent integrin or integrins other than alpha 4 beta 1 can activate JNK1 in cells adhere nt to fibronectin. This study demonstrates that integrins act as mecha notransducers, providing insight into potential mechanisms for in vivo responses to mechanical stimuli.