Feedback control of the protein kinase TAK1 by SAPK2a/p38α
Feedback control of the protein kinase TAK1 by SAPK2a/p38α
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DOI：
10.1093/emboj/cdg552
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发表时间：
2003-11-03
期刊：
影响因子：
11.4
通讯作者：
Cohen, P
中科院分区：
文献类型：
--
作者：
Cheung, PCF;Campbell, DG;Cohen, P
TAB1是TAK1激酶的一个亚基，在体外被SAPK2a/p38alpha磷酸化Ser423、Thr431和Ser438位点。当细胞暴露于细胞应激或受到肿瘤坏死因子- α (tnf - α)、白细胞介素-1 （IL-1）或脂多糖（LPS）刺激时，TAB1在所有三个位点都发生磷酸化。用SB 203580预孵育细胞可阻止Ser423和Thr431的磷酸化，而PD 184352可部分抑制Ser438的磷酸化。Ser423是SAPK2a/p38alpha磷酸化的第一个没有脯氨酸跟随的残基。在lps刺激的巨噬细胞中，SB 203580增强TAK1的激活，在上皮KB细胞或胚胎成纤维细胞中，促炎细胞因子或渗透休克增强TAK1的激活。在SAPK2a/ p38α缺陷小鼠的胚胎成纤维细胞中，tnf - α、IL-1或渗透休克也能增强TAK1的激活，而与SB 203580孵育这些细胞则没有影响。我们的研究结果表明，TAB1参与了SAPK2a/p38alpha介导的TAK1的反馈控制，这不仅限制了SAPK2a/p38alpha的激活，而且与TAK1下游的其他信号通路（JNK和IKK）同步其活性。
TAB1, a subunit of the kinase TAK1, was phosphorylated by SAPK2a/p38alpha at Ser423, Thr431 and Ser438 in vitro. TAB1 became phosphorylated at all three sites when cells were exposed to cellular stresses, or stimulated with tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or lipopolysaccharide (LPS). The phosphorylation of Ser423 and Thr431 was prevented if cells were pre-incubated with SB 203580, while the phosphorylation of Ser438 was partially inhibited by PD 184352. Ser423 is the first residue phosphorylated by SAPK2a/p38alpha that is not followed by proline. The activation of TAK1 was enhanced by SB 203580 in LPS-stimulated macrophages, and by proinflammatory cytokines or osmotic shock in epithelial KB cells or embryonic fibroblasts. The activation of TAK1 by TNF-alpha, IL-1 or osmotic shock was also enhanced in embryonic fibroblasts from SAPK2a/p38alpha-deficient mice, while incubation of these cells with SB 203580 had no effect. Our results suggest that TAB1 participates in a SAPK2a/p38alpha-mediated feedback control of TAK1, which not only limits the activation of SAPK2a/p38alpha but synchronizes its activity with other signalling pathways that lie downstream of TAK1 (JNK and IKK).