Coordinate regulation of IκB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-κB-inducing kinase
Coordinate regulation of IκB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-κB-inducing kinase
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DOI：
10.1128/mcb.18.12.7336
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发表时间：
1998-12-01
影响因子：
5.3
通讯作者：
Lin, AN
中科院分区：
文献类型：
--
作者：
Nemoto, S;DiDonato, JA;Lin, AN
I kappa B激酶(ikkα和ikkβ)是IKK复合体的关键组成部分，它介导转录因子NF-kappa B的激活，以响应细胞外刺激，如炎性细胞因子、病毒和细菌感染以及紫外线照射。尽管核因子-kappa B诱导激酶(NIK)与IKK相互作用并激活IKK，但IKK的上游激酶仍然不清楚。我们发现丝裂原活化蛋白激酶1(MEKK1)是IKK复合体的直接上游激酶。MEKK1由肿瘤坏死因子-α(TNF-α)和白介素1激活，可增强肿瘤坏死因子-α对IKK和核因子-kappaB的刺激作用。另一方面，MEKK1的显性负突变部分阻断了肿瘤坏死因子-α对IKK的激活。在HeLa和COS-1细胞中，MEKK1与IKKα和IKKβ相互作用并刺激其活性，并在体外直接磷酸化IKK。此外，MEKK1似乎与Nik平行作用，导致IKK复合体的协同激活。MEKK1-IKK复合体相对于NiK-IKK复合体的形成可能为多种细胞外信号对IKK复合体的调控提供了分子基础。
I kappa B kinases (IKK alpha and IKK beta) are key components of the IKK complex that mediates activation of the transcription factor NF-kappa B in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-kappa B-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-alpha) and interleukin-1 and can potentiate the stimulatory effect of TNF-alpha on IKK and NF-kappa B activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-alpha. MEKK1 interacts with and stimulates the activities of both IKK alpha and IKK beta in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.