Identification and functional characterization of novel phosphorylation sites in TAK1-binding protein (TAB) 1.
Identification and functional characterization of novel phosphorylation sites in TAK1-binding protein (TAB) 1.
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DOI：
10.1371/journal.pone.0029256
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kracht M
中科院分区：
文献类型：
--
作者：
Wolf A;Beuerlein K;Eckart C;Weiser H;Dickkopf B;Müller H;Sakurai H;Kracht M
TAB1被定义为蛋白激酶TAK1的一个调节亚基，它在白介素1、肿瘤坏死因子、Toll样受体和应激物激活的通路的上游发挥作用。然而，Tab1也在TAK1下游的p38MAPK通路中发挥作用。我们发现TAB1的氨基酸(AA)452/453和456/457是被TAK1和p38MAPK在完整细胞和体外细胞中磷酸化的新位点。丝氨酸452/453和456/457在被Calyculin A阻断磷酸酶时被磷酸化，或在IL-1或翻译应激源(如茴香素和山梨醇)的响应下被磷酸化。TAB1基因AA452-457的缺失或模拟磷酸化突变使TAB1和p38MAPK保留在细胞质中。缺失aa452-457的tab1突变体降低了tab1依赖的p38MAPK的磷酸化。它还增加了对IL-1的依赖于TAB1的CCL5的分泌，并增加了一个转录后报告基因的活性，该基因包含CCL5 3‘非翻译区。这些数据表明，TAB1的AA452-457在控制p38MAPK活性和亚细胞定位方面发挥了复杂的作用，并暗示这些残基参与了TAK1或p38MAPK依赖的转录后基因表达控制。
TAB1 was defined as a regulatory subunit of the protein kinase TAK1, which functions upstream in the pathways activated by interleukin (IL)-1, tumor necrosis factor (TNF), toll-like receptors (TLRs) and stressors. However, TAB1 also functions in the p38 MAPK pathway downstream of TAK1. We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro. Serines 452/453 and 456/457 were phosphorylated upon phosphatase blockade by calyculin A, or in response to IL-1 or translational stressors such as anisomycin and sorbitol. Deletion or phospho-mimetic mutations of aa 452–457 of TAB1 retain TAB1 and p38 MAPK in the cytoplasm. The TAB1 mutant lacking aa 452–457 decreases TAB1-dependent phosphorylation of p38 MAPK. It also enhances TAB1-dependent CCL5 secretion in response to IL-1 and increases activity of a post-transcriptional reporter gene, which contains the CCL5 3′ untranslated region. These data suggest a complex role of aa 452–457 of TAB1 in controlling p38 MAPK activity and subcellular localization and implicate these residues in TAK1- or p38 MAPK-dependent post-transcriptional control of gene expression.
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