Diao Yarui, Wang Xi, Wu Zhenguo
Department of Biochemistry, Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China.
Mol Cell Biol. 2009 Sep;29(18):5084-93. doi: 10.1128/MCB.00267-09. Epub 2009 Jul 20.
We recently showed that a leukemia inhibitory factor (LIF)-engaged signaling pathway consisting of JAK1, STAT1, and STAT3 plays dual roles in myogenic differentiation: while it participates in myoblast proliferation, it also actively represses differentiation. Downregulation of this pathway is required at the onset of differentiation. However, it remained unclear how this is achieved mechanistically. We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. We further demonstrated that the SUMO E3-ligase activity of PIAS1 is dispensable for its role in myogenic differentiation. Collectively, our current study revealed a molecular mechanism that explains how the LIF-induced JAK1/STAT1/STAT3 pathway is downregulated upon myogenic differentiation.
我们最近发现，由JAK1、STAT1和STAT3组成的白血病抑制因子（LIF）参与的信号通路在肌源性分化中发挥双重作用：它在成肌细胞增殖中发挥作用，同时也积极抑制分化。在分化开始时，该信号通路的下调是必需的。然而，其机制仍不清楚。我们现在发现，SOCS1、SOCS3和PIAS1通过不同靶点特异性抑制LIF诱导的JAK1/STAT1/STAT3信号通路，从而促进肌源性分化；SOCS1和SOCS3分别选择性结合并抑制JAK1和gp130，而PIAS1主要作用于激活的STAT1并阻止其与DNA结合。我们进一步证明，PIAS1的SUMO E3连接酶活性对其在肌源性分化中的作用并非必需。总之，我们目前的研究揭示了一种分子机制，解释了在肌源性分化过程中LIF诱导的JAK1/STAT1/STAT3信号通路是如何被下调的。
