3-Phosphoinositide-dependent protein kinase-1-mediated IκB kinase β (IKKB) phosphorylation activates NF-κB signaling
3-Phosphoinositide-dependent protein kinase-1-mediated IκB kinase β (IKKB) phosphorylation activates NF-κB signaling
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DOI：
10.1074/jbc.m506235200
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发表时间：
2005-12-09
影响因子：
4.8
通讯作者：
Tsuruo, T
中科院分区：
文献类型：
--
作者：
Tanaka, H;Fujita, N;Tsuruo, T
I-kappa B激酶(IKK)/核因子-kappaB和磷脂酰肌醇3-羟基-激酶/3-磷酸肌醇依赖的蛋白激酶-1(PDK1)/Akt信号通路调节多种细胞功能，尤其是细胞存活。这两条通路在许多肿瘤中经常被激活，被认为与肿瘤的进展有关。然而，他们之间的相互作用仍不清楚。在这里，我们表明，除了Akt信号外，PDK1还可以激活IKK/NF-kappa B信号来促进细胞存活。筛选能够调节核因子-kappaB活性的激酶表明，上游Akt激酶PDK1的表达上调了核因子-kappa B的转录活性。我们发现，PDK1直接在激活环的Ser(181)残基上磷酸化ikkβ，导致核转录因子-kappaB的核转位和依赖于核因子-kappaB的抗凋亡基因的表达。由于在IKKα(-/-)小鼠胚胎成纤维细胞(MEF)和野生型MEF细胞中观察到了NF-kappa B的激活，因此IKKα不是PDK1介导的NF-kappa B激活所必需的。先前报道激活IKKα的AKT不参与依赖PDK1的IKKβ或核因子-kappaB的激活。SiRNA介导的PDK1基因沉默减弱了NF-kappaB的活性，增加了TRAIL介导的细胞毒作用。此外，结构性活性IKKβ的表达克服了PDK1 siRNA介导的TRAIL敏感性。这些结果表明，除了Akt通路外，PDK1还通过调节IKK/NF-kappa B通路对细胞存活起着关键的调节作用。
The I kappa B kinase (IKK)/NF-kappa B and phosphatidylinositol 3-OH-kinase/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt pathways regulate various cellular functions, especially cell survival. These two pathways are often activated in many tumors and are thought to be associated with tumor progression. However, the cross-talk between them remains unclear. Here we show that PDK1 can activate IKK/NF-kappa B signaling in addition to Akt signaling to promote cell survival. Screening kinases that could modulate NF-kappa B activity revealed that expression of an upstream Akt kinase PDK1 up-regulates NF-kappa B transcriptional activity. We found that PDK1 directly phosphorylates IKK beta at the Ser(181) residue in the activation loop, leading to NF-kappa B nuclear translocation and NF-kappa B-dependent anti-apoptotic gene expression. IKK alpha is not required for PDK1-mediated NF-kappa B activation because NF-kappa B activation was observed in IKK alpha(-/-) mouse embryonic fibroblast (MEF) cells as in wild type MEF cells. Akt, which was previously reported to activate IKK alpha, did not participate in the PDK1-dependent IKK beta or NF-kappa B activation. The siRNA-mediated PDK1 gene silencing attenuated NF-kappa B activity and increased TRAIL-mediated cytotoxicity. Moreover, expression of constitutively active IKK beta overcame the PDK1 siRNA-mediated susceptibility to TRAIL. These results indicate that PDK1 is a critical regulator of cell survival by modulating the IKK/NF-kappa B pathway in addition to the Akt pathway.