Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway
Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway
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DOI：
10.1128/mcb.19.3.2416
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发表时间：
1999-03-01
影响因子：
5.3
通讯作者：
Feng, GS
中科院分区：
文献类型：
--
作者：
You, M;Yu, DH;Feng, GS
Shp-2是一种含有SH 2结构域的蛋白酪氨酸磷酸酶。虽然其机制仍有待确定，但大量的实验数据表明，Shp-2主要是细胞生长和发育的正调控因子。我们在这里提出的证据表明，Shp-2，而采取行动，以促进有丝分裂信号，也作为一个负效应干扰素（IFN）诱导的生长抑制和凋亡途径。与野生型细胞相比，用IFN-α或IFN-γ处理缺乏功能性Shp-2的小鼠成纤维细胞导致细胞活力的抑制增强。为了剖析分子机制，我们研究了干扰素诱导的信号转导和转录激活因子（STAT）的电泳迁移率变动分析，使用特定的DNA探针（hSIE）的激活。在IFN-α或IFN-γ刺激后，与hSIE结合的STAT蛋白质的量在Shp-2（-/-）细胞中显著增加。一致的是，在IFN-γ处理后，以及在较小程度上，在IFN-α刺激后，Stat 1的酪氨酸磷酸化水平在突变细胞中显著升高。此外，IFN-γ在Shp-2（-/-）细胞中诱导了比野生型细胞更高水平的半胱天冬酶1表达。野生型Shp-2蛋白的重新引入逆转了Shp-2（-/-）成纤维细胞对IFN-α和IFN-γ的细胞毒性作用的超敏性。在重新引入Shp-2的突变细胞中，IFN对STAT的过度激活也减少了。总之，这些结果确定Shp-2作为Jak/STAT途径的负调节剂发挥作用。我们认为Shp-2通过两种机制促进细胞生长和存活，即刺激生长、因子启动的促有丝分裂途径和抑制细胞因子（如IFN）引起的细胞毒性作用。
Shp-2 is an SH2 domain-containing protein tyrosine phosphatase. Although the mechanism remains to be defined, substantial experimental data suggest that Shp-2 is primarily a positive regulator in cell growth and development. We present evidence here that Shp-2, while acting to promote mitogenic signals, also functions as a negative effector in interferon (IFN)-induced growth-inhibitory and apoptotic pathways. Treatment of mouse fibroblast cells lacking a functional Shp-2 with IFN-alpha or IFN-gamma resulted in an augmented suppression of cell viability compared to that of wild-type cells. To dissect the molecular mechanism, we examined IFN-induced activation of signal transducers and activators of transcription (STATs) by electrophoretic mobility shift assay, using a specific DNA probe (hSIE). The amounts of STAT proteins bound to hSIE upon IFN-alpha or IFN-gamma stimulation were significantly increased in Shp-2(-/-) cells. Consistently, tyrosine phosphorylation levels of Stat1 upon IFN-gamma treatment and, to a lesser extent, upon IFN-alpha stimulation were markedly elevated in mutant cells. Furthermore, IFN-gamma induced a higher level of caspase 1 expression in Shp-2(-/-) cells than in wild-type cells. Reintroduction of wild-type Shp-2 protein reversed the hypersensitivity of Shp-2(-/-) fibroblasts to the cytotoxic effect of IFN-alpha and IFN-gamma. Excessive activation of STATs by IFNs was also diminished in mutant cells in which Shp-2 had been reintroduced. Together, these results establish that Shp-2 functions as a negative regulator of the Jak/STAT pathway. We propose that Shp-2 acts to promote cell growth and survival through two mechanisms, i.e, the stimulation of growth, factor-initiated mitogenic pathways and the suppression of cytotoxic effect elicited by cytokines, such as IFNs.