Abstract
Transforming growth factor beta (TGFbeta) plays a critical role in connective tissue remodeling by fibroblasts during development, tissue repair, and fibrosis. We investigated the molecular pathways in the transmission of TGFbeta signals that lead to features of connective tissue remodeling, namely formation of an alpha-smooth muscle actin (alpha-SMA) cytoskeleton, matrix contraction, and expression of profibrotic genes. TGFbeta causes the activation of focal adhesion kinase (FAK), leading to JNK phosphorylation. TGFbeta induces JNK-dependent actin stress fiber formation, matrix contraction, and expression of profibrotic genes in fak+/+, but not fak-/-, fibroblasts. Overexpression of MEKK1, a kinase acting upstream of JNK, rescues TGFbeta responsiveness of JNK-dependent transcripts and actin stress fiber formation in FAK-deficient fibroblasts. Thus we propose a FAK-MEKK1-JNK pathway in the transmission of TGFbeta signals leading to the control of alpha-SMA cytoskeleton reorganization, matrix contraction, and profibrotic gene expression and hence to the physiological and pathological effects of TGFbeta on connective tissue remodeling by fibroblasts.