FAK is required for TGFβ-induced JNK phosphorylation in fibroblasts:: Implications for acquisition of a matrix-remodeling phenotype
FAK is required for TGFβ-induced JNK phosphorylation in fibroblasts:: Implications for acquisition of a matrix-remodeling phenotype
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DOI：
10.1091/mbc.e06-12-1121
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发表时间：
2007-06-01
影响因子：
3.3
通讯作者：
Leask, Andrew
中科院分区：
文献类型：
--
作者：
Liu, Shangxi;Xu Shi-wen;Leask, Andrew
转化生长因子β（TGF β）在发育、组织修复和纤维化期间通过成纤维细胞的结缔组织重塑中起关键作用。我们研究了导致结缔组织重塑特征的TGF β信号传递的分子途径，即α-平滑肌肌动蛋白（α-SMA）细胞骨架的形成、基质收缩和促纤维化基因的表达。TGF β引起粘着斑激酶（FAK）的活化，导致JNK磷酸化。TGF β 6诱导JNK依赖性肌动蛋白应力纤维形成、基质收缩和fak+/+成纤维细胞中促纤维化基因的表达，但不诱导fak-/-成纤维细胞中促纤维化基因的表达。MEKK 1（JNK上游激酶）的过表达可挽救FAK缺陷成纤维细胞中JNK依赖性转录物的TGF β反应性和肌动蛋白应力纤维形成。因此，我们提出了一个FAK-MEKK 1-JNK通路在TGF β信号的传输，导致控制α-SMA细胞骨架重组，基质收缩，和促纤维化基因的表达，并因此TGF β对结缔组织重塑成纤维细胞的生理和病理作用。
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.