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FAK is required for TGF beta-induced JNK phosphorylation in fibroblasts: Implications for acquisition of a matrix-remodeling phenotype

Liu, SX; Xu, S; Kennedy, L; Pala, D; Chen, Y; Eastwood, M; Carter, DE; ... Leask, A; + view all (2007) FAK is required for TGF beta-induced JNK phosphorylation in fibroblasts: Implications for acquisition of a matrix-remodeling phenotype. MOL BIOL CELL , 18 (6) 2169 - 2178. 10.1091/mbc.E06-12-1121.

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Abstract

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 focal adhesion kinase (FAK), leading to JNK phosphorylation. TGF,6 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-SMA 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.

Type: Article
Title: FAK is required for TGF beta-induced JNK phosphorylation in fibroblasts: Implications for acquisition of a matrix-remodeling phenotype
DOI: 10.1091/mbc.E06-12-1121
Keywords: FOCAL ADHESION KINASE, GROWTH-FACTOR-BETA, MYOFIBROBLAST DIFFERENTIATION, TRANSFORMING GROWTH-FACTOR-BETA-1, SCLERODERMA FIBROBLASTS, FIBROTIC RESPONSE, GENE-EXPRESSION, MAP KINASE, CONTRACTION, MECHANISMS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/93792
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