Unc119 is an adaptor protein that is involved in the development of the vertebrate nervous system. We have shown that Unc119 stimulates the induction of alpha-smooth muscle actin (alpha-SMA) and myofibroblast differentiation by TGF-beta in human lung fibroblasts. Unc119 increases the kinase activity of Fyn and associates with it in coprecipitation and colocalization studies. Phosphorylation and activation of Fyn in response to TGF-beta and platelet-derived growth factor is delayed in Unc119-deficient cells. This delay translates into suppressed cell proliferation. In Src family kinase-deficient (SYF) cells, Unc119 knockdown does not affect cell proliferation. The result suggests that Unc119 interacts with Fyn in the early stages of signal generation and its presence is essential for conducive signal transduction. Unc119 overexpression does not stimulate alpha-SMA in SYF cells and this defect is restored upon reconstitution with Fyn indicating that Unc119 stimulation of alpha-SMA requires at least Fyn. Unc119 overexpression stimulated p38, but not JNK, phosphorylation. Blocking p38 MAPK resulted in reduced alpha-SMA expression by Unc119 suggesting that the p38 pathway regulates Unc119-induced myofibroblast differentiation. Unc119 stimulates the production of TGF-beta and IL-6, known inducers of myofibroblast differentiation. Thus, Unc119 regulates receptor-mediated signal transduction and myofibroblast differentiation by activating Fyn and the p38 MAPK pathway. Using primary lung fibroblasts from patients with fibrotic lung diseases and control subjects, we show that the expression of alpha-smooth muscle actin is highly correlated with that of Unc119. Taken together, our results suggest that Unc119 plays an important role in fibrotic processes through myofibroblast differentiation.

译文

:Unc119是与脊椎动物神经系统发育有关的衔接蛋白。我们已经显示Unc119刺激人肺成纤维细胞中TGF-β诱导α平滑肌肌动蛋白(α-SMA)和成肌纤维细胞分化。 Unc119增加Fyn的激酶活性,并在共沉淀和共定位研究中与其关联。 Unc119缺陷细胞中,响应于TGF-β和血小板衍生的生长因子的Fyn的磷酸化和激活被延迟。这种延迟转化为抑制的细胞增殖。在Src家族激酶缺陷(SYF)细胞中,Unc119敲低不影响细胞增殖。结果表明,Unc119在信号生成的早期阶段与Fyn相互作用,并且它的存在对于有益的信号转导至关重要。 Unc119的过表达不会刺激SYF细胞中的α-SMA,并且用Fyn重建后该缺陷得以恢复,这表明Unc119刺激α-SMA至少需要Fyn。 Unc119过表达刺激p38磷酸化,但不刺激JNK磷酸化。阻断p38 MAPK导致Unc119降低α-SMA表达,表明p38途径调节Unc119诱导的成肌纤维细胞分化。 Unc119刺激成纤维细胞分化的已知诱导物TGF-β和IL-6的产生。因此,Unc119通过激活Fyn和p38 MAPK通路来调节受体介导的信号转导和成纤维细胞分化。使用来自纤维化性肺病患者和对照对象的原发性肺成纤维细胞,我们显示α-平滑肌肌动蛋白的表达与Unc119的表达高度相关。综上所述,我们的结果表明Unc119在通过成肌纤维细胞分化的纤维化过程中起着重要作用。

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