Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways
Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways
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DOI：
10.1128/mcb.26.6.2408-2418.2006
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发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Clark, AR
中科院分区：
文献类型：
--
作者：
Brook, M;Tchen, CR;Clark, AR
p38 丝裂原激活蛋白激酶 (MAPK) 信号通路通过下游激酶 MK2 发挥作用，调节许多促炎 mRNA 的稳定性；含有富含腺苷/尿苷的元素 (ARE)。据认为，这是通过调节 ARE 结合蛋白的表达或活性来实现的，这些蛋白可调节 mRNA 的周转。 MK2 在丝氨酸 52 和 178 处磷酸化 ARE 结合和 mRNA 不稳定蛋白 tristetraprolin (TTP)。在这里，我们表明 p38 MAPK 通路调节 TTP 蛋白的亚细胞定位和稳定性。 p38 MAPK 抑制剂导致 TTP 快速去磷酸化、从细胞质重新定位到细胞核，并被 20S/26S 蛋白酶体降解。因此，需要 p38 MAPK 途径的持续活性来维持 TTP 蛋白的磷酸化状态、细胞质定位和稳定性。亚细胞定位和蛋白质稳定性的调节取决于 NIK2 以及丝氨酸 52 和 178 的完整性。此外，细胞外信号调节激酶 (ERK) 通路与 p38 MAPK 通路协同调节 TTP 的稳定性和定位。这种效应与已知由 ERK 和 p38 MAPK 协同激活的激酶无关。我们提出了 TTP 和 p38 MAPK 通路在炎症反应不同阶段的作用模型。
The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs; that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on NIK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.