TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop
TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop
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DOI：
10.1074/jbc.275.10.7359
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发表时间：
2000-03-10
影响因子：
4.8
通讯作者：
Ninomiya-Tsuji, J
中科院分区：
文献类型：
--
作者：
Kishimoto, K;Matsumoto, K;Ninomiya-Tsuji, J
TAK 1是丝裂原活化激酶激酶家族的一员，在体内可被多种细胞因子激活，包括白细胞介素-1（IL-1），或与TAK 1结合蛋白TAB 1一起异位表达。我们发现内源性TAK 1与TAB 1组成性相关，并在IL-1刺激后磷酸化。此外，当TAB 1异位过表达时，TAK 1被组成性磷酸化。在这两种情况下，TAK 1的去磷酸化使其失活，但它可以通过与ATP预孵育再活化。缺乏激酶活性的TAK 1突变体在IL-1处理后或与TAB 1共表达时均不磷酸化，表明TAK 1磷酸化是由于自磷酸化。此外，在激酶结构域VII和VIII之间的激活环中的保守丝氨酸残基（Ser-192）突变为丙氨酸消除了TAK 1的磷酸化和激活。这些结果表明IL-1和TAB 1的异位表达都通过Ser-192的自磷酸化激活TEK 1。
TAK1, a member of the mitogen-activated kinase kinase kinase family, is activated in vivo by various cytokines, including interleukin-1 (IL-1), or when ectopically expressed together with the TAK1-binding protein TAB1, However, this molecular mechanism of activation is not yet understood. We show here that endogenous TAK1 is constitutively associated with TAB1 and phosphorylated following IL-1 stimulation. Furthermore, TAK1 is constitutively phosphorylated when ectopically overexpressed with TAB1. In both cases, dephosphorylation of TAK1 renders it inactive, but it can be reactivated by preincubation with ATP, A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192.