TAK1 is recruited to the tumor necrosis factor-α (TNF-α) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-κB activation
TAK1 is recruited to the tumor necrosis factor-α (TNF-α) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-κB activation
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DOI：
10.1074/jbc.m507807200
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Lin, X
中科院分区：
文献类型：
--
作者：
Blonska, M;Shambharkar, PB;Lin, X
受体相互作用蛋白（RIP）在肿瘤坏死因子- α (tnf - α)诱导的I κ B激酶（IKK）激活和随后转录因子NF-kappa B的激活中起着关键作用。然而，RIP介导tnf - α诱导的NF-kappa B激活的分子机制尚不完全明确。在本研究中，我们发现在tnf - α受体1 （TNF-R1）的刺激下，TAK1以rip依赖的方式被募集到tnf - α受体复合体中。此外，在没有RIP的情况下，TAK1向TNF-R1的强制募集足以介导tnf - α诱导的NF-kappa B激活，这表明RIP的主要功能是将其下游激酶募集到TNF-R1复合体中。有趣的是，我们还发现TAK1和MEKK3形成一个功能复合物，其中TAK1调节MEKK3的自磷酸化。TAK1介导的MEKK3磷酸化调控依赖于TAK1的激酶活性。虽然TAK1-MEKK3的相互作用不受TAB1过表达的影响，但TAB1是TAK1激活和随后的MEKK3磷酸化所必需的。总之，我们得出结论，TAK1通过RIP被招募到TNF-R1复合体中，并可能与MEKK3合作激活tnf - α信号传导中的NF-kappa B。
Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-alpha (TNF-alpha)-induced I kappa B kinase (IKK) activation and subsequent activation of transcription factor NF-kappa B. However, the molecular mechanism by which RIP mediates TNF-alpha-induced NF-kappa B activation is not completely defined. In this study, we have found that TAK1 is recruited to the TNF-alpha receptor complex in a RIP-dependent manner following the stimulation of TNF-alpha receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-alpha-induced NF-kappa B activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-kappa B in TNF-alpha signaling.