The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus.
The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus.
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DOI：
10.1126/stke.1999.5.re1
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发表时间：
1999-10-26
期刊：
影响因子：
--
通讯作者：
Karin, M
中科院分区：
文献类型：
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作者：
Rothwarf, D M;Karin, M
核因子κ B（NF-κ B）/Rel蛋白是二聚体的序列特异性转录因子，其参与响应于炎症、病毒和细菌感染以及需要基因表达的快速重编程的其它应激情况的异常大量基因的活化。在未受刺激的细胞中，NF-κ B以非活性形式被隔离在细胞质中，与抑制性IkappaB蛋白结合。刺激导致IkappaB的快速磷酸化、泛素化和最终的蛋白水解降解，其释放NF-κ B以易位到细胞核并激活其靶基因的转录。多亚基IkappaB激酶（IKK）负责IkappaB的诱导磷酸化似乎是大多数激活NF-κ B的刺激的起始点。IKK含有两个催化亚基，IKK α和IKK β，它们都在体内磷酸化的位点磷酸化IkappaB。基因敲除研究表明，IKK β主要负责NF-κ B的激活，以响应促炎刺激，而IKK α是角质形成细胞分化所必需的。IKK的活性受磷酸化调节。IKK含有一个调节亚基IKK γ，它对IKK的激活至关重要，被认为是上游激活物的识别位点。当磷酸化时，IkappaB α上的IKK识别位点作为Skp 1-Cullin-F-box型E3泛素蛋白连接酶的kappa-TrCP样组分的特异性识别位点。多种其他信号传导事件，包括NF-κ B的磷酸化、IKK的磷酸化、IkappaB的新合成和NF-κ B前体的加工，提供了调节NF-κ B活性的量和持续时间的机制。
Nuclear factor kappa B (NF-kappaB)/Rel proteins are dimeric, sequence-specific transcription factors involved in the activation of an exceptionally large number of genes in response to inflammation, viral and bacterial infections, and other stressful situations requiring rapid reprogramming of gene expression. In unstimulated cells, NF-kappaB is sequestered in an inactive form in the cytoplasm bound to inhibitory IkappaB proteins. Stimulation leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus and activate the transcription of its target genes. The multisubunit IkappaB kinase (IKK) responsible for the inducible phosphorylation of IkappaB appears to be the initial point of convergence for most stimuli that activate NF-kappaB. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which phosphorylate IkappaB at sites phosphorylated in vivo. Gene knockout studies indicate that IKKbeta is primarily responsible for the activation of NF-kappaB in response to proinflammatory stimuli, whereas IKKalpha is essential for keratinocyte differentiation. The activity of IKK is regulated by phosphorylation. IKK contains a regulatory subunit, IKKgamma, which is critical for activation of IKK and is postulated to serve as a recognition site for upstream activators. When phosphorylated, the IKK recognition site on IkappaBalpha serves as a specific recognition site for the kappa-TrCP-like component of a Skp1-Cullin-F-box-type E3 ubiquitin-protein ligase. A variety of other signaling events, including phosphorylation of NF-kappaB, phosphorylation of IKK, new synthesis of IkappaBs, and the processing of NF-kappaB precursors provide mechanisms of modulating the amount and duration of NF-kappaB activity.