Raf kinase inhibitor protein interacts with NF-κB-inducing kinase and TAK1 and inhibits NF-κ13 activation
Raf kinase inhibitor protein interacts with NF-κB-inducing kinase and TAK1 and inhibits NF-κ13 activation
复制标题
DOI：
10.1128/mcb.21.21.7207-7217.2001
复制
发表时间：
2001-11-01
影响因子：
5.3
通讯作者：
Sedivy, JM
中科院分区：
文献类型：
--
作者：
Yeung, KC;Rose, DW;Sedivy, JM
Raf激酶抑制蛋白（RKIP）作为由Raf-1启动的丝裂原活化蛋白（MAP）激酶（MAPK）级联反应的负调节剂。RKIP通过破坏这两种激酶之间的相互作用来抑制Raf-1对MAP/细胞外信号调节激酶1（MEK 1）的磷酸化。我们在这里表明，RKIP也拮抗信号转导途径，介导的激活的转录因子核因子κ B（NF-κ B）在响应刺激与肿瘤坏死因子α（TNF-α）或白细胞介素1 β。RKIP表达水平的调节影响NF-κ B信号传导，而不依赖于MAPK通路。涉及在NF-κ B通路中起作用的激酶的异位表达的遗传上位性分析表明，RKIP在激酶复合物的上游起作用，所述激酶复合物介导NF-κ B抑制剂（I κ B）的磷酸化和失活。体外激酶试验表明，RKIP拮抗TNF-α引起的I κ B激酶（IKK）活性的激活。RKIP与NF-κ B活化途径的四种激酶（NF-κ B诱导激酶、转化生长因子β活化激酶1、IKK α和IKK β）发生物理相互作用。这种作用模式与MAPK途径中RKIP与Raf-1和MEK 1的相互作用具有惊人的相似性。来自不同生物体的新兴数据表明，RKIP和RKIP相关蛋白代表了一个新的和进化上高度保守的蛋白激酶调节剂家族。由于MAPK和NF-κ B通路在生理学上具有不同的作用，因此RKIP的功能可能部分是协调这些通路的调节。
The Raf kinase inhibitor protein (RKIP) acts as a negative regulator of the mitogen-activated protein (MAP) kinase (MAPK) cascade initiated by Raf-1. RKIP inhibits the phosphorylation of MAP/extracellular signal-regulated kinase 1 (MEK1) by Raf-1 by disrupting the interaction between these two kinases. We show here that RKIP also antagonizes the signal transduction pathways that mediate the activation of the transcription factor nuclear factor kappa B (NF-kappaB) in response to stimulation with tumor necrosis factor alpha (TNF-alpha) or interleukin 1 beta. Modulation of RKIP expression levels affected NF-kappaB signaling independent of the MAPK pathway. Genetic epistasis analysis involving the ectopic expression of kinases acting in the NF-kappaB pathway indicated that RKIP acts upstream of the kinase complex that mediates the phosphorylation and inactivation of the inhibitor of NF-kappaB (I kappaB). In vitro kinase assays showed that RKIP antagonizes the activation of the I kappaB kinase (IKK) activity elicited by TNF-alpha. RKIP physically interacted with four kinases of the NF-KB activation pathway, NF-kappaB-inducing kinase, transforming growth factor beta-activated kinase 1, IKK alpha, and IKK beta. This mode of action bears striking similarities to the interactions of RKIP with Raf-1 and MEK1 in the MAPK pathway. Emerging data from diverse organisms suggest that RKIP and RKIP-related proteins represent a new and evolutionarily highly conserved family of protein kinase regulators. Since the MAPK and NF-kappaB pathways have physiologically distinct roles, the function of RKIP may be, in part, to coordinate the regulation of these pathways.