| 19116914 |
Shi-wen X, Parapuram SK, Pala D, Chen Y, Carter DE, Eastwood M, Denton CP, Abraham DJ, Leask A: Requirement of transforming growth factor beta-activated kinase 1 for transforming growth factor beta-induced alpha-smooth muscle actin expression and extracellular matrix contraction in fibroblasts. J Cell Commun Signal. 2009 Nov 15.
OBJECTIVE: Fibrosis is believed to occur through normal tissue remodeling failing to terminate. Tissue repair intimately involves the ability of fibroblasts to contract extracellular matrix (ECM), and enhanced ECM contraction is a hallmark of fibrotic cells in various conditions, including scleroderma. Some fibrogenic transcriptional responses to transforming growth factor beta (TGFbeta), including alpha-smooth muscle actin (alpha-SMA) expression and ECM contraction, require focal adhesion kinase/Src (FAK/Src). The present study was undertaken to assess whether TGFbeta-activated kinase 1 (TAK1) acts downstream of FAK/Src to mediate fibrogenic responses in fibroblasts. METHODS: We used microarray, real-time polymerase chain reaction, Western blot, and collagen gel contraction assays to assess the ability of wild-type and TAK1-knockout fibroblasts to respond to TGFbeta1. RESULTS: The ability of TGF to induce TAK1 was blocked by the FAK/Src inhibitor PP2. JNK phosphorylation in response to TGFbeta1 was impaired in the absence of TAK1. TGFbeta could not induce matrix contraction or expression of a group of fibrotic genes, including alpha-SMA, in the absence of TAK1. CONCLUSION: These results suggest that TAK1 operates downstream of FAK/Src in mediating fibrogenic responses and that targeting of TAK1 may be a viable antifibrotic strategy in the treatment of certain disorders, including scleroderma. |
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