Distinct mechanisms of STAT phosphorylation via the interferon-α/β receptor -: Selective inhibition of STAT3 and STAT5 by piceatannol
Distinct mechanisms of STAT phosphorylation via the interferon-α/β receptor -: Selective inhibition of STAT3 and STAT5 by piceatannol
复制标题
DOI：
10.1074/jbc.275.17.12661
复制
发表时间：
2000-04-28
影响因子：
4.8
通讯作者：
David, M
中科院分区：
文献类型：
--
作者：
Su, L;David, M
干扰素-α可以激活信号转导和转录激活因子家族的几个成员，这一过程需要酪氨酸激酶JAK1和TYK2。在这里，我们提供的证据表明，干扰素α介导的各种STAT蛋白的激活受到不同机制的调节。Piceat注l是一种Syk/ZAP70特异性的激酶抑制剂，选择性地抑制STAT3和STAT5的酪氨酸磷酸化，但不抑制STAT1和STAT5的酪氨酸磷酸化。这种抑制与干扰素α反应中JAK1和IFNAR1酪氨酸磷酸化的丧失平行，而TYK2和IFNAR2酪氨酸磷酸化不受影响。最后，干扰素α诱导的STAT1和STAT3的丝氨酸磷酸化不被Piceatanyl抑制，但对Src激酶特异性抑制剂PP2敏感。因此，我们的结果不仅表明，干扰素α/β受体利用不同的机制来触发特定STAT蛋白的酪氨酸磷酸化，而且它们还表明了导致STAT1和STAT3丝氨酸磷酸化的不同途径。
Interferon-alpha (IFN alpha) can activate several members of the signal transducers and activator of transcription (STAT) transcription factor family, a process that requires the tyrosine kinases Jak1 and Tyk2. Here we provide evidence that IFN alpha-mediated activation of various STAT proteins is regulated by distinct mechanisms. Piceatannol, previously reported as a Syk/ZAP70-specific kinase inhibitor, selectively inhibits the tyrosine phosphorylation of STAT3 and STAT5, but not of STAT1 and STATE. This inhibition is paralleled by the loss of Jak1 and IFNAR1 tyrosine phosphorylation in response to IFN alpha, whereas Tyk2 and IFNAR2 tyrosine phosphorylation is unaffected. Last, the IFN alpha-induced serine phosphorylation of STAT1 and STAT3 is not inhibited by piceatannol but is sensitive to the Src kinase-specific inhibitor PP2. Thus, our results not only demonstrate that the IFN alpha/beta receptor utilizes distinct mechanisms to trigger the tyrosine phosphorylation of specific STAT proteins, but they also indicate a diverging pathway that leads to the serine phosphorylation of STAT1 and STAT3.