Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress
Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress
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DOI：
10.1093/emboj/20.21.6028
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发表时间：
2001-11-01
期刊：
影响因子：
11.4
通讯作者：
Ichijo, H
中科院分区：
文献类型：
--
作者：
Morita, K;Saitoh, M;Ichijo, H
细胞凋亡信号调节激酶1（ASK 1）是一种MAP激酶（MAPKKK），可激活JNK和p38 MAP激酶级联，并在氧化应激如过氧化氢（H2 O2）时被激活。酵母双杂交筛选鉴定了丝氨酸/苏氨酸蛋白磷酸酶5（PP 5）作为ASK 1的结合伴侣。PP 5直接使ASK 1激酶结构域中的一个必需的磷酸化苏氨酸残基去磷酸化，从而使ASK 1在体外和体内的活性失活。H_2O_2处理诱导了PP_5与ASK_1之间的相互作用，随后ASK_1活性下降。PP 5不仅抑制H2 O2诱导的ASK 1的持续激活，而且抑制ASK 1依赖的凋亡。因此，PP 5似乎通过负反馈作为ASK 1-JNK/p38通路的生理抑制剂。
Apoptosis signal-regulating kinase 1 (ASK1) is a MAP kinase kinase kinase (MAPKKK) that activates the JNK and p38 MAP kinase cascades and is activated in response to oxidative stress such as hydrogen peroxide (H2O2). A yeast two-hybrid screening identified a serine/threonine protein phosphatase 5 (PP5) as a binding partner of ASK1. PP5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ASK1 and thereby inactivated ASK1 activity in vitroandin vivo. The interaction between PP5 and ASK1 was induced by H2O2 treatment and was followed by the decrease in ASK1 activity. PP5 inhibited not only H2O2-induced sustained activation of ASK1 but also ASK1-dependent apoptosis. Thus, PP5 appears to act as a physiological inhibitor of ASK1-JNK/p38 pathways by negative feedback.