Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer
Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer
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DOI：
10.1002/jcp.10080
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发表时间：
2002-04-01
影响因子：
5.6
通讯作者：
Ichijo, H
中科院分区：
文献类型：
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作者：
Tobiume, K;Saitoh, M;Ichijo, H
凋亡信号调节激酶1（Apoptosis signal-regulating kinase 1，ASK 1）是MAPKKK家族成员，其激活c-Jun N-末端激酶（JNK）和p38。在非应激细胞中，ASK 1作为与还原形式的硫氧还蛋白的非活性复合物存在。氧化应激如过氧化氢（H2 O2）通过氧化硫氧还蛋白破坏ASK 1-硫氧还蛋白复合物，从而激活ASK 1。ASK 1从硫氧还蛋白释放后被激活的确切机制尚不清楚。在这里，我们表明，Thr 845在激活环的磷酸化是必不可少的ASK 1被H2 O2激活。在非应激细胞中，ASK 1似乎通过其C-末端卷曲螺旋区域形成沉默的同源寡聚体。H2 O2处理后，预先存在的ASK 1寡聚体发生构象变化，并在寡聚体内产生新的界面，最终导致Thr 845的反式自磷酸化。因此，通过卷曲螺旋区域的直接相互作用是自支架化所需的，但不足以激活ASK 1。重要的是，ASK 1的Thr 845也可以被未鉴定的Thr 845激酶反式磷酸化以响应H2 O2处理。我们认为这种潜在的Thr 845激酶可能是一种点燃激酶，它在寡聚化和有激活能力的ASK 1形式中触发Thr 845磷酸化。J.细胞。191：95-104，2002. (C)2002 Wiley-Liss，Inc.
Apoptosis signal-regulating kinase 1 (ASK1) is a MAPKKK family member which activates c-Jun N-terminal kinase (JNK) and p38. In non-stressed cells, ASK1 exists as an inactive complex with the reduced form of thioredoxin. Oxidative stress such as hydrogen peroxide (H2O2) disrupts the ASK1-thioredoxin complex by oxidization of thioredoxin and thereby activates ASK1. The precise mechanism by which ASK1 is activated after its release from thioredoxin is unknown. Here we show that phosphorylation of Thr845 at the activation loop is essential for ASK1 to be activated by H2O2. ASK1 appears to form a silent homo-oligomer through its C-terminal coiled-coil region in non-stressed cells. Following H2O2 treatment, pre-existing ASK1 oligomer undergoes conformational change and creates a new interface within an oligomer, which ultimately leads to trans-autophosphorylation of Thr845. Thus, direct interaction via the coiled-coil region is required for self-scaffolding but not sufficient for activation of ASK1. Importantly, Thr845 of ASK1 can also be trans-phosphorylated by an unidentified Thr845 kinase in response to H2O2 treatment. We propose that this potential Thr845 kinase may be an ignition kinase that triggers Thr845 phosphorylation in oligomerized and activation-competent forms of ASK1. J. Cell. Physiol. 191: 95-104, 2002. (C) 2002 Wiley-Liss, Inc.