Tang Liu-Ya, Heller Mary, Meng Zhaojing, Yu Li-Rong, Tang Yi, Zhou Ming, Zhang Ying E
From the Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
the Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland 21702.
J Biol Chem. 2017 Mar 10;292(10):4302-4312. doi: 10.1074/jbc.M116.773085. Epub 2017 Jan 31.
Transforming growth factor-β (TGF-β) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMADs in mediating TGF-β functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGFβRI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-β stimulation. Following the activation of SMADs, TGF-β also induces a second phase of STAT phosphorylation that requires SMADs, protein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-β target genes in hepatic stellate cells, and the cooperation between the JAK1-STAT3 and SMAD pathways is critical to the roles of TGF-β in liver fibrosis.
转化生长因子-β（TGF-β）通过SMAD和非SMAD途径发出信号，以引发广泛的生物学效应。现有数据表明，信号转导和转录激活因子（STATs）与SMADs在介导肝细胞中TGF-β功能方面存在关联和协同作用，但尚不清楚在这些情况下STATs是如何被激活的。在此，我们报告JAK1是一种组成型TGFβRI结合蛋白，在TGF-β刺激后数分钟内，它以不依赖SMAD的方式对STATs的磷酸化绝对必要。在SMADs激活后，TGF-β还会诱导STAT磷酸化的第二阶段，这需要SMADs、蛋白质合成以及JAK1的参与。我们的全基因组表达谱分析表明，非SMAD JAK1/STAT途径对于肝星状细胞中一部分TGF-β靶基因的表达至关重要，并且JAK1-STAT3和SMAD途径之间的协同作用对于TGF-β在肝纤维化中的作用至关重要。
