Calmodulin-dependent kinase II mediates T cell receptor/CD3-and phorbol ester-induced activation of IκB kinase
Calmodulin-dependent kinase II mediates T cell receptor/CD3-and phorbol ester-induced activation of IκB kinase
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DOI：
10.1074/jbc.m106125200
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发表时间：
2001-09-21
影响因子：
4.8
通讯作者：
Grundström, T
中科院分区：
文献类型：
--
作者：
Hughes, K;Edin, S;Grundström, T
许多基本的生物学过程涉及NF κ B家族的转录因子。因此，调节该蛋白质家族的机制具有广泛的重要性。在大多数细胞中，NF κ B与抑制性I κ B蛋白结合并被隔离在细胞质中。NF κ B诱导信号导致大的多亚基激酶复合物IKK的激活，IKK使I κ B磷酸化。I kappaB随后降解，释放NF kappaB，NF kappaB易位到细胞核。我们以前报道，钙结合蛋白钙调蛋白（CaM）的抑制剂，防止佛波酯诱导的I κ B磷酸化。在这里，我们表明，KN 93，钙调素依赖性激酶（CaMK）的抑制剂，也抑制I κ B的磷酸化。CaM和CaMK抑制剂对I kappaB磷酸化的作用是由于抑制CaMK II的活性，因为当表达对这些抑制剂不敏感的CaMK II衍生物时，两种药物都没有任何作用。当CaMK II被抑制时，佛波酯不再能够激活IKK，将CaMK II置于导致IKK激活的信号通路中。CaM和CaMK抑制剂也阻断T细胞受体/CD 3诱导的活化，但对细胞因子肿瘤坏死因子α或磷酸酶抑制剂calyculin A诱导I κ B降解的能力没有影响。最后，我们表明，一个组成型活性CaMK II的表达结果在NF κ B的激活。结果确定CaMK II作为IKK激活的介体，特异性地响应于T细胞受体/CD 3和佛波酯刺激。
Numerous fundamental biological processes involve the NF kappaB family of transcription factors. The mechanisms by which this family of proteins is regulated are therefore of widespread importance. In most cells, NF kappaB is bound to inhibitory I kappaB proteins and sequestered in the cytoplasm. NF kappaB-inducing signals result in activation of a large multisubunit kinase complex, IKK, which phosphorylates I kappaB. I kappaB is subsequently degraded, releasing NF kappaB, which translocates to the nucleus. We previously reported that inhibitors of the calcium-binding protein calmodulin (CaM) prevent phorbol ester-induced phosphorylation of I kappaB. Here we show that KN93, an inhibitor of CaM-dependent kinases (CaMKs), also inhibits the phosphorylation of I kappaB. The effect of both CaM and CaMK inhibitors on I kappaB phosphorylation is due to the inhibition of the activity of CaMK II because neither drug has any effect when a derivative of CaMK II that is insensitive to these inhibitors is expressed. When CaMK II is inhibited, phorbol ester is no longer able to activate IKK, placing CaMK II in the signaling pathway that leads to IKK activation. CaM and CaMK inhibitors also block T cell receptor/CD3-induced activation but have no effect on the ability of the cytokine tumor necrosis factor alpha or the phosphatase inhibitor calyculin A to induce degradation of I kappaB. Finally we show that expression of a constitutively active CaMK II results in the activation of NF kappaB. The results identify CaMK Il as a mediator of IKK activation specifically in response to T cell receptor/CD3 and phorbol ester stimulation.