Serine phosphorylation and negative regulation of Stat3 by JNK
Serine phosphorylation and negative regulation of Stat3 by JNK
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DOI：
10.1074/jbc.274.43.31055
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发表时间：
1999-10-22
影响因子：
4.8
通讯作者：
Cao, XM
中科院分区：
文献类型：
--
作者：
Lim, CP;Cao, XM
STATs通过酪氨酸磷酸化被各种细胞因子和生长因子激活，从而导致序列二聚体的形成、核转位、与特定DNA序列的结合以及基因表达的调节。最近，在表皮生长因子(EGF)的作用下，ERK发现Ser-727上STAT3的丝氨酸磷酸化。在这里，我们报告了JNK也可以诱导STAT3的Ser727磷酸化，并被应激或其上游的激酶激活，并且各种应激处理诱导STAT3的丝氨酸磷酸化，而不是酪氨酸磷酸化。ERK和p38的抑制剂不能抑制紫外线诱导的STAT3丝氨酸磷酸化，表明它们都不参与其中。我们进一步证明，JNK1被其上游的MKK7激活，负向调节EGF刺激的STAT3的酪氨酸磷酸化、DNA结合和转录活性。相应地，紫外线对细胞的预处理降低了EGF刺激的STAT3的酪氨酸磷酸化和磷酸酪氨酸依赖的活性。未观察到对STAT1的抑制作用，我们的结果表明，STAT3是JNK的靶点，可能通过Ser-727磷酸化依赖和非依赖机制来调节STAT3的活性。
STATs are activated by various cytokines and growth factors via tyrosine phosphorylation, which leads to sequential dimer formation, nuclear translocation, binding to specific DNA sequences, and regulation of gene expression. Recently, serine phosphorylation of Stat3 on Ser-727 by ERK has been identified in response to epidermal growth factor (EGF). Here, we report that Ser727 phosphorylation of Stat3 can also be induced by JNK and activated either by stress or by its upstream kinase and that various stress treatments induce serine phosphorylation of Stat3 in the absence of tyrosine phosphorylation. Inhibitors of ERK and p38 did not inhibit UV-induced Stat3 serine phosphorylation, suggesting that neither of them is involved. We further demonstrate that JNK1, activated by its upstream kinase MKK7, negatively regulated the tyrosine phosphorylation and DNA binding and transcriptional activities of Stat3 stimulated by EGF. Correspondingly, pretreatment of cells with UV reduced the EGF-stimulated tyrosine phosphorylation and phosphotyrosine-dependent activities of Stat3. The inhibitory effect was not observed for Stat1, Our results suggest that Stat3 is a target of JNK that may regulate Stat3 activity via both Ser-727 phosphorylation-dependent and -independent mechanisms.