Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal
Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal
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DOI：
10.1038/sj.cdd.4401238
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发表时间：
2003-07-01
影响因子：
12.4
通讯作者：
Nakashima, I
中科院分区：
文献类型：
--
作者：
Liu, W;Akhand, AA;Nakashima, I
我们研究了 Jurkat 细胞中丝氨酸/苏氨酸蛋白激酶 Akt 的信号通路调节，这些细胞已用 4-羟基壬烯醛 (HNE) 处理，以诱导 caspase 依赖性细胞凋亡。用 HNE 处理细胞会导致 Akt 活性水平下降，这是由于 Ser473（主要调节磷酸化位点）的去磷酸化所致。 HNE 介导的 Akt 去磷酸化可被蛋白磷酸酶 2A (PP2A) 抑制剂冈田酸和 caspase-3 抑制剂 DEVD-CHO 阻止。 HNE 处理导致 PP2A 活性总水平增加、细胞骨架中活性酪氨酸去磷酸化 PP2A 的释放以及 PP2A-Akt 关联的增加，这些都依赖于 caspase-3 的激活。这些结果表明，PP2A 活性水平至少部分由其酪氨酸磷酸化决定，酪氨酸磷酸化由冈田酸敏感磷酸酶和蛋白酪氨酸激酶双重控制。 HNE 处理可能导致 Src 激酶活性下调，这可能是 caspase 介导的 PP2A 激活机制的基础，Src 激酶是一种代表性的 caspase 敏感激酶，可在酪氨酸处磷酸化 PP2A。此外，激活的 caspase-3 在细胞凋亡的后期部分切割 Akt。这些结果表明存在两种不同的 caspase 依赖性信号通路来下调 Akt，Akt 是 HNE 触发的细胞凋亡信号的正反馈调节机制。
We studied the signal pathways for regulation of serine/threonine protein kinase Akt in Jurkat cells that had been treated with 4-hydroxynonenal (HNE) for caspase-dependent apoptosis induction. Treatment of cells with HNE led to a decrease in the level of Akt activity due to the dephosphorylation at Ser473, a major regulatory phosphorylation site. HNE-mediated dephosphorylation of Akt was prevented by a protein phosphatase 2A (PP2A) inhibitor, okadaic acid, and by a caspase-3 inhibitor, DEVD-CHO. HNE treatment resulted in an increase in the total level of PP2A activity, release of active tyrosine-dephosphorylated PP2A from the cytoskeleton and PP2A-Akt association, which were all dependent on caspase-3 activation. These results suggest that the level of PP2A activity is at least in part determined by its tyrosine phosphorylation, which is dually controlled by okadaic acid-sensitive phosphatases and protein-tyrosine kinases. Possibly underlying the mechanism of caspase-mediated activation of PP2A, HNE treatment resulted in downregulation of the activity of Src kinase, as a representative caspase-sensitive kinase to phosphorylate PP2A at tyrosine. In addition, activated caspase-3 partially cleaved Akt at a late stage of the apoptosis. These results indicate the existence of two distinct caspase-dependent signal pathways for downregulation of Akt that works as a mechanism of positive feedback regulation for HNE-triggered apoptotic signals.