Disabled-2 (Dab2) mediates transforming growth factor β (TGFβ)-stimulated fibronectin synthesis through TGFβ-activated kinase 1 and activation of the JNK pathway
Disabled-2 (Dab2) mediates transforming growth factor β (TGFβ)-stimulated fibronectin synthesis through TGFβ-activated kinase 1 and activation of the JNK pathway
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DOI：
10.1074/jbc.m501150200
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发表时间：
2005-07-08
影响因子：
4.8
通讯作者：
Howe, PH
中科院分区：
文献类型：
--
作者：
Hocevar, BA;Prunier, C;Howe, PH
多功能细胞因子转化生长因子β通过调节细胞外基质成分发挥多种作用，包括纤维连接蛋白(FN)。尽管转化生长因子β和纤维连接蛋白的表达对成人胚胎发育和创面愈合是必不可少的，但过度表达会导致细胞外基质过度沉积，在许多纤维增生性疾病中观察到。我们先前已经证明，转化生长因子β刺激的纤维连接蛋白的诱导需要激活c-jun氨基末端激酶(JNK)通路；然而，连接转化生长因子β受体与JNK通路的信号分子仍不清楚。在此，我们发现胞浆接头蛋白失活2(DAB2)直接刺激JNK活性，而稳定的小干扰RNA介导的DAB2在NIH3T3小鼠成纤维细胞和A10大鼠主动脉平滑肌细胞中的消融表明其表达是转化生长因子β介导的FN诱导所必需的。我们证明，转化生长因子β治疗刺激DAB2与丝裂原激活的蛋白激酶激酶，TAK1的联系。瞬时双链RNA寡核苷酸转染降低了细胞中TAK1的水平，并过表达了激酶缺陷的TAK1，导致了转化生长因子β刺激的FN诱导的取消。此外，细胞迁移，另一种依赖JNK的反应，在表达NIH3T3-siDab2的克隆中被减弱。因此，我们描绘了一条从转化生长因子β受体到DAB2和TAK1的信号通路，导致转化生长因子β刺激的JNK激活、FN表达和细胞迁移。
The multifunctional cytokine transforming growth factor beta ( TGF beta) exerts many of its effects through its regulation of extracellular matrix components, including fibronectin ( FN). Although expression of both TGF beta and FN are essential for embryonic development and wound healing in the adult, overexpression leads to excessive deposition of extracellular matrix observed in many fibroproliferative disorders. We previously have demonstrated that TGF beta- stimulated FN induction requires activation of the c- Jun N- terminal kinase ( JNK) pathway; however, the signaling molecules that link the TGF beta receptors to the JNK pathway remain unknown. We show here that the cytosolic adaptor protein disabled2 ( Dab2) directly stimulates JNK activity, whereas stable small interfering RNA- mediated ablation of Dab2 in NIH3T3 mouse fibroblasts and A10 rat aortic smooth muscle cells demonstrates that its expression is required for TGF beta- mediated FN induction. We demonstrate that TGF beta treatment stimulates the association of Dab2 with the mitogen- activated protein kinase kinase kinase, TAK1. Attenuation of cellular TAK1 levels by transient double- stranded RNA oligonucleotide transfection as well as overexpression of kinase- deficient TAK1 leads to abrogation of TGF beta- stimulated FN induction. Furthermore, cell migration, another JNK- dependent response, is attenuated in NIH3T3- siDab2- expressing clones. We, therefore, delineate a signaling pathway proceeding from the TGF beta receptors to Dab2 and TAK1, leading to TGF beta- stimulated JNK activation, FN expression, and cell migration.