Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Iκ-B kinase-β-dependent pathway and is required for Tpl2 activation by external signals
Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Iκ-B kinase-β-dependent pathway and is required for Tpl2 activation by external signals
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DOI：
10.1074/jbc.m413554200
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发表时间：
2005-05-27
影响因子：
4.8
通讯作者：
Tsichlis, PN
中科院分区：
文献类型：
--
作者：
Cho, J;Melnick, M;Tsichlis, PN
由肿瘤进展基因座2（Tpl 2）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转导Toll样受体和死亡受体信号。在这里，我们表明，Tp 12在Thr（290）在过表达Tp 12的细胞和在细胞刺激脂多糖（LPS）或肿瘤坏死因子-α和该网站上的磷酸化平行Tp 12激活磷酸化。用野生型Tp 12或Tp 12 T290 D重建Tp 12（-/-）巨噬细胞恢复了LPS对ERK的激活，而用Tp 12 T290 A重建相同的细胞则没有，这表明Thr 290处的磷酸化是外部信号对Tp 12的生理激活所必需的。野生型Tp 12和激酶失活突变体Tp 12 K167 M都经历Thr 290磷酸化，表明Thr 290可能是反式磷酸化而不是自磷酸化的位点。用I κ-B激酶-β（IKK β）抑制剂PS-1145预处理293细胞和原代巨噬细胞阻断了Tp 12在Thr 290的磷酸化，表明磷酸化依赖于IKK β，一种Tp 12的强制性正调节剂。我们得出结论，Tp 12在Thr 290处的磷酸化由LPS诱导，依赖于IKK β，并且是通过外部信号生理激活Tp 12所需的。
The serine-threonine protein kinase encoded by the tumor progression locus 2 ( Tpl2) proto-oncogene transduces Toll-like receptor and death receptor signals in a variety of cell types. Here we show that Tpl2 undergoes phosphorylation at Thr(290) both in cells overexpressing Tpl2 and in cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-alpha and that phosphorylation on this site parallels Tpl2 activation. Reconstitution of Tpl2(-/-) macrophages with wild type Tpl2 or Tpl2 T290D restored ERK activation by LPS, whereas reconstitution of the same cells with Tpl2 T290A did not, suggesting that phosphorylation at Thr290 is required for the physiological activation of Tpl2 by external signals. Both the wild type Tpl2 and the kinase-inactive mutant Tpl2 K167M undergo Thr290 phosphorylation, suggesting that Thr290 may be a site of trans-phosphorylation rather than auto-phosphorylation. Pretreatment of 293 cells and primary macrophages with the I kappa-B kinase-beta (IKK beta) inhibitor PS-1145 blocked Tpl2 phosphorylation at Thr290, suggesting that phosphorylation depends on IKK beta, an obligatory positive regulator of Tpl2. We conclude that Tpl2 phosphorylation at Thr290 is induced by LPS, depends on IKK beta, and is required for the physiological activation of Tpl2 by external signals.