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首页> 外文期刊>Molecular biology of the cell >A mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type IIFN-induced apoptosis
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A mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type IIFN-induced apoptosis

机译：STAT2的SH2结构域的突变延长了STAT1的酪氨酸磷酸化并促进IIFN诱导的细胞凋亡

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摘要

Type I interferons (IFN-alpha/beta) induce apoptosis in certain tumor cell lines but not others. Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN-alpha stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-alpha could account for one difference between tumor cell lines that undergo IFN-alpha-induced apoptosis compared with those that display an antiproliferative response but do not die.
机译：I型干扰素（IFN-alpha /β）诱导某些肿瘤细胞系中的细胞凋亡，但不是其他肿瘤细胞系。在这里，我们描述了STAT2中的突变，响应于I IFNS，赋予肿瘤细胞中的凋亡效应。该突变被引入位于STAT SH2结构域中的保守基序，PyTK，其由Stat1，Stat2和Stat3共享。为了测试该基序中的酪氨酸是否可能磷酸化并影响信号传导，STAT2的Y631突变为苯丙氨酸（Y631F）。尽管确定Y631未磷酸化，但Y631F突变赋予持续的信号和IFN刺激基因的诱导。这种延长的IFN响应与STAT1和Stat2的持续酪氨酸磷酸化有关，其相互关联作为异二聚体，这是由核酪氨酸磷酸酶TCPT的抗性抗磷酸化。最后，与野生型STAT2相比，在IFN-α刺激后，载入Y631F突变的细胞在IFN-α刺激后进行了细胞凋亡。因此，这种突变显示，与IFN-α-诱导的细胞凋亡的肿瘤细胞系之间的肿瘤细胞系与显示抗增法反应的肿瘤细胞凋亡相比但不会死亡的突变。

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