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MBC in Press, published online ahead of print April 4, 2007
Mol. Biol. Cell 10.1091/mbc.E06-12-1121

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Submitted on December 15, 2006
Revised on February 14, 2007
Accepted on March 23, 2007

FAK Is Required for TGF{beta}-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix Remodeling Phenotype

Shangxi Liu,*{dagger} Xu Shi-wen,{dagger}{ddagger} Laura Kennedy,* Daphne Pala,* Yunliang Chen,{sect} Mark Eastwood,{sect} David E. Carter,|| Carol M. Black,{ddagger} David J. Abraham,{ddagger} and Andrew Leask*

*Canadian Institutes of Health Research Group in Skeletal Development and Remodeling, Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A 5C1; {ddagger}Centre for Rheumatology, Department of Medicine, Royal Free and University College Medical School, University College London (Royal Free Campus), London, United Kingdom, NW3 2PF; {sect}School of Biosciences, University of Westminster, London, United Kingdom, W1W 6UW; ||London Regional Genomics Centre, London, ON, Canada, N6A 5K8

Monitoring Editor: Carl-Henrik Heldin

Transforming growth factor {beta} (TGF{beta}) 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 TGF{beta} 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. TGF{beta} causes the activation of FAK leading to JNK phosphorylation. TGF{beta} 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 TGF{beta} 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 TGF{beta} signals leading to the control of {alpha}-smooth muscle actin cytoskeleton reorganization, matrix contraction and profibrotic gene expression and hence to the physiological and pathological effects of TGF{beta} on connective tissue remodeling by fibroblasts.

{dagger}These authors contributed equally to this work.

Address correspondence to: Andrew Leask (Andrew.Leask{at}schulich.uwo.ca)




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