Phosphorylation at Thr-290 regulates Tpl2 binding to NF-κB1/p105 and Tpl2 activation and degradation by lipopolysaccharide
Phosphorylation at Thr-290 regulates Tpl2 binding to NF-κB1/p105 and Tpl2 activation and degradation by lipopolysaccharide
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DOI：
10.1073/pnas.0409856102
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发表时间：
2005-02-15
影响因子：
11.1
通讯作者：
Tsichlis, PN
中科院分区：
文献类型：
--
作者：
Cho, JH;Tsichlis, PN
Tp12原癌基因编码的丝氨酸-苏氨酸蛋白激酶在多种细胞类型中传递Toll样受体和死亡受体信号，在先天免疫和炎症中发挥重要作用。Tp12 mRNA的差异翻译起始导致58 kDa(P58)和52 kDa(P52)亚型。在未经刺激的细胞中，这两种异构体都通过与核因子-kappaB1/p105的化学计量结合而稳定和失活。在脂多糖或肿瘤坏死因子-α刺激后，p105优先释放p58，而不是p52。释放的p58是活性的，但不稳定，并通过蛋白酶体快速降解。最近的研究表明，Tp12在Thr-290处经历了磷酸化，激活需要在这个位置进行。在此，我们提出的证据表明，p58亚型优先在Thr-290处被磷酸化，并且当p58与p52络合时，磷酸化更有效。由于p58在刺激后优先从p105释放，我们研究了该位点的Tp12磷酸化是否控制了这两个蛋白质在外界信号和随后导致Tp12激活的事件中的解离。结果表明，脂多糖诱导巨噬细胞Tp12在Thr-290处的磷酸化促进了P105中Tp12的释放，有助于Tp12激酶的酶激活，并且是通过蛋白酶体降解Tp12所必需的。
The serine-threonine protein kinase encoded by the Tp12 protooncogene transduces Toll-like and death receptor signals in a variety of cell types and plays an important role in innate immunity and inflammation. Differential translational initiation of the Tp12 mRNA gives rise to 58-kDa (p58) and 52-kDa (p52) isoforms. In unstimulated cells, both isoforms are stabilized and inactivated by stoichiometric binding to NF-kappaB1/p105. After lipopolysaccharide or TNF-alpha stimulation, p58 is released from p105 preferentially relative to p52. The released p58 is active but unstable and undergoes rapid degradation via the proteasome. Recent studies revealed that Tp12 undergoes phosphorylation at Thr-290 and that phosphorylation at this site is required for activation. Here, we present evidence showing that it is the p58 isoform that is preferentially phosphorylated at Thr-290 and that phosphorylation is more efficient when p58 is complexed to p52. Because p58 is preferentially released from p105 after stimulation, we examined whether Tp12 phosphorylation at this site controls the dissociation of the two proteins in response to external signals and the subsequent events leading to the activation of Tp12. The results showed that lipopolysaccharide-induced Tp12 phosphorylation at Thr-290 in macrophages promotes the release of Tp12 from p105, contributes to the enzymatic activation of the Tp12 kinase, and is required for the degradation of Tp12 via the proteasome.