Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation.
Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation.
复制标题
Stat4 N 结构域在受体近端酪氨酸磷酸化中的作用。
DOI：
10.1128/mcb.20.19.7121-7131.2000
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发表时间：
2000
影响因子：
5.3
通讯作者：
Murphy,KM
中科院分区：
文献类型：
--
作者：
Murphy,TL;Geissal,ED;Farrar,JD;Murphy,KM
Stat 4被细胞因子白细胞介素12和α干扰素（IFN-α）激活，并在引导幼稚CD 4 +T细胞向Th 1表型发育中起重要作用。信号转导和转录激活因子（STAT）蛋白在保守的酪氨酸残基上进行磷酸化，导致同源和异源二聚化、核转位和DNA结合。Stat 4可以作为二聚体结合单个IFN-γ激活位点（GAS），或者作为一对STAT二聚体或四聚体结合两个串联GAS，通过二聚体之间的N-末端结构域（N结构域）相互作用稳定。我们发现了一个意想不到的效果的Stat 4 N结构域在控制近端激活Stat 4的酪氨酸磷酸化在激活的受体复合物。色氨酸残基W37处的N结构域突变（预计会中断N结构域二聚体形成）意外地阻止了IFN-α诱导的Stat 4单体酪氨酸磷酸化，阻断了二聚体形成和核转位。此外，N结构域似乎发挥私人STAT功能，因为在Stat 1和Stat 4之间互换N结构域在一种情况下阻止了受体介导的酪氨酸磷酸化，在另一种情况下中断了STAT特异性基因激活。最后，用Stat 4的N结构域替换Stat 1的N结构域废除了Stat 1磷酸化的正常Stat 2依赖性，再次表明结构域不等同。因此，除了其在STAT四聚化中的作用外，保守的STAT N结构域似乎参与受体介导的配体诱导的酪氨酸磷酸化的非常接近的步骤。
Stat4 is activated by the cytokines interleukin 12 and alpha interferon (IFN-α) and plays a significant role in directing development of naïve CD4+T cells to the Th1 phenotype. Signal transducers and activators of transcription (STAT) proteins undergo phosphorylation on a conserved tyrosine residue, resulting in homo- and heterodimerization, nuclear translocation, and DNA binding. Stat4 can bind to single IFN-γ-activated sites (GASs) as a dimer or bind two tandem GASs as a pair of STAT dimers, or tetramer, stabilized through N-terminal domain (N domain) interactions between dimers. We uncovered an unexpected effect of the Stat4 N domain in controlling the proximal activation of Stat4 by tyrosine phosphorylation at activated receptor complexes. Mutation of the N domain at tryptophan residue W37, predicted to interrupt N domain dimer formation, unexpectedly prevented IFN-α-induced tyrosine phosphorylation of the Stat4 monomer, blocking dimer formation and nuclear translocation. Furthermore, N domains appear to exert private STAT functions, since interchanging the N domains between Stat1 and Stat4 prevented receptor-mediated tyrosine phosphorylation in one case and interrupted STAT-specific gene activation in another. Finally, replacement of the N domain of Stat1 with that of Stat4 abrogated the normal Stat2 dependence of Stat1 phosphorylation, again suggesting the domains are not equivalent. Thus, in addition to its role in STAT tetramerization, the conserved STAT N domain appears to participate in very proximal steps of receptor-mediated ligand-induced tyrosine phosphorylation.