Identification of Op18/stathmin as a potential target of ASK1-p38 MAP kinase cascade
Identification of Op18/stathmin as a potential target of ASK1-p38 MAP kinase cascade
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DOI：
10.1002/jcp.20465
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发表时间：
2006-02-01
影响因子：
5.6
通讯作者：
Ichijo, H
中科院分区：
文献类型：
--
作者：
Mizumura, K;Takeda, K;Ichijo, H
凋亡信号调节激酶1（Apoptosis Signal-Regulating Kinase 1，ASK 1）是一种丝裂原活化蛋白激酶（mitogen-activated protein kinase kinase kinase kin然而，发挥这种活性的ASK 1-MAP激酶级联的效应分子尚未完全鉴定。在这里，我们已经确定了癌蛋白18（Op 18）/stathmin作为一个潜在的目标的ASK 1-p38级联。通过双向电泳，发现在PC 12细胞中表达组成型活性ASK 1（ASK 1 Delta N）后，Op 18/stathmin的磷酸化增加。SB 203580处理减弱了Asp 1依赖性的Op 18/stathmin磷酸化增加，表明p38 α和/或p38 β有助于Op 18/stathmin的磷酸化。一致地，我们发现，所有四种异构体的p38直接磷酸化Op 18/stathmin主要在丝氨酸25在体外。结合定量RT-PCR数据表明p38 a是PC 12细胞中主要表达的同种型，ASK 1诱导的Op 18/stathmin磷酸化似乎主要通过p38 a介导。鉴于Op 18/stathmin的微管去稳定活性受其磷酸化调节，ASK 1-p38级联可能通过Op 18/stathmin调节微管动力学。
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein (MAP) kinase kinase kinase that activates the JNK and p38 MAP kinase cascades and has a broad range of biological activities including cell differentiation and stress-induced apoptosis. However, effector molecules of ASK1-MAP kinase cascades that exert Such activities have not been fully identified. Here we have identified oncoprotein 18 (Op18)/stathmin as a potential target of the ASK1-p38 cascade. By two-dimensional electrophoresis, phosphorylation of Op18/stathmin was found to be increased upon the expression Of Constitutively active ASK1 (ASK1 Delta N) in PC12 cells. The ASK1-dependent increase in the phosphorylation of Op18/stathmin was attenuated by the treatment with SB203580, suggesting that p38 alpha and/or p38 beta contribute to the phosphorylation of Op18/stathmin. Consistently, we found that all four isoforms of p38 directly phosphorylated Op18/stathmin primarily at serine 25 in vitro. Taken together with the quantitative RT-PCR data indicating that p38a was the dominantly expressed isoform in PC12 cells, ASK1-induced phosphorylation of Op18/stathmin appears to be mediated mainly through p38a in these cells. Given that the microtubule-destabilizing activity of Op18/stathmin is regulated by its phosphorylation, the ASK1-p38 cascade may regulate microtubule dynamics through Op18/stathmin.