TNFR1 signaling kinetics: spatiotemporal control of three phases of IKK activation by posttranslational modification.
TNFR1 signaling kinetics: spatiotemporal control of three phases of IKK activation by posttranslational modification.
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DOI：
10.1016/j.cellsig.2013.04.005
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发表时间：
2013-08
影响因子：
4.8
通讯作者：
Habelhah H
中科院分区：
文献类型：
--
作者：
Workman LM;Habelhah H
TNFα是一种多效性细胞因子，通过激活NF-κB信号通路在炎症反应中发挥核心作用，并且在一系列慢性炎症性疾病中具有靶向作用，强调了了解其潜在分子机制的治疗重要性。尽管TRAF 2/5和cIAP 1/2对RIP 1的K63连接的泛素化被认为是激活NF-κB通路的支架，但最近积累的相互矛盾的结果挑战了这些蛋白在NF-κB激活中的必要性。此外，几种丝氨酸/苏氨酸激酶与TNFα诱导的IKK激活有关;然而，靶向破坏这些激酶对瞬时IKK激活无影响。最近发现的RIP 1依赖性和非依赖性激活的早期和延迟阶段的IKK和TRAF 2磷酸化依赖性激活的长期阶段的IKK提供了一个和解模型的解释矛盾的结果在该领域。值得注意的是，TNFα诱导的炎症反应并非完全由NF-κB通路控制，而是受到NF-κB和其他环境依赖性通路之间的调节串扰的影响。因此，进一步阐明这些时空协调的信号传导机制有可能为NF-κB干预提供新的分子靶点和治疗策略。
TNFα is a pleotropic cytokine that plays a central role in the inflammatory response by activating the NF-κB signaling pathway, and is targeted in a range of chronic inflammatory diseases, underscoring the therapeutic importance of understanding its underlying molecular mechanisms. Although K63-linked ubiquitination of RIP1 by TRAF2/5 and cIAP1/2 was thought to serve as a scaffold to activate the NF-κB pathway, the recent accumulation of conflicting results has challenged the necessity of these proteins in NF-κB activation. In addition, several serine/threonine kinases have been implicated in TNFα-induced IKK activation; however, the targeted disruption of these kinases had no effect on transient IKK activation. The recent discovery of RIP1-dependent and -independent activation of the early and delayed phases of IKK and TRAF2 phosphorylation-dependent activation of the prolonged phase of IKK offers a reconciliatory model for the interpretation of contradictory results in the field. Notably, the TNFα-induced inflammatory response is not exclusively controlled by the NF-κB pathway but is subject to regulatory crosstalk between NF-κB and other context-dependent pathways. Thus further elucidation of these spatiotemporally-coordinated signaling mechanisms has the potential to provide novel molecular targets and therapeutic strategies for NF-κB intervention.
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影响因子：
5.3
作者：
Becker, EBE;Howell, J;Bonni, A
通讯作者：
Bonni, A
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DOI：
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发表时间：
2002-01-21
期刊：
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影响因子：
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作者：
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发表时间：
1999-03-24
影响因子：
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