A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress
A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress
复制标题
DOI：
10.1016/s0960-9822(01)00121-x
复制
发表时间：
2001-03-20
期刊：
影响因子：
9.2
通讯作者：
Divecha, N
中科院分区：
文献类型：
--
作者：
Halstead, JR;Roefs, M;Divecha, N
背景：磷脂酰肌醇-3，4，5-三磷酸[PtdIns(3，4，5)P-3]是高等真核细胞中普遍存在的一种重要的第二信使。PtdIns(3，4，5)P-3是一种重要的细胞信号转导事件，与细胞迁移、增殖等下游细胞过程的激活密切相关。尽管许多调节多种生物途径的蛋白质已被证明与PtdIns(3，4，5)P-3结合，但还没有数据表明体内合成PtdIns(3，4，5)P-3的多种机制。结果：在本研究中，我们证明了一种通过小鼠I型α磷脂酰肌醇4-磷酸5-激酶(Type Iα)作用在体内产生PtdIns(3，4，5)P-3的替代途径。PIPKinase)，一种最能调节细胞PtdIns(4，5)P-2水平的酶。通过对细胞膜合成PtdIns(3，4，5)P-3这一新途径的分析，我们得出结论：在体内，I型α-PiPkinase1也作为PtdIns(3，4)P-2 5-激酶发挥作用。我们首次证明了细胞实际上含有内源性的PtdIns(3，4)P-2 5-激酶，并且在氧化应激过程中，这种酶负责PtdIns(3，4，5)P的合成。此外，我们通过过表达研究证明，通过上调过氧化氢诱导的PtdIns(3，4，5)P-3水平，内源性PtdIns(3，4)P-2 5-Kinase很可能是I型αPIPkinase。结论：我们首次描述了TCR型PIPkinaseTCRPIPkinase的体内活性，并为体内合成具有功能的PtdIns(3，4，5)P-3提供了一条新的途径。PtdIns(3，4，5)P-3是调节多种细胞过程的关键脂质第二信使。
Background: Phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P-3] is a key second messenger found ubiquitously in higher eukaryotic cells. The activation of Class I phosphoinositide 3-kinases and the subsequent production of PtdIns(3,4,5)P-3 is an important cell signaling event that has been causally linked to the activation of a variety of downstream cellular processes, such as cell migration and proliferation. Although numerous proteins regulating a variety of biological pathways have been shown to bind PtdIns(3,4,5)P-3, there are no data to demonstrate multiple mechanisms for PtdIns(3,4,5)P-3 synthesis in vivo.Results: In this study, we demonstrate an alternative pathway for the in vivo production of PtdIns(3,4,5)P-3 mediated by the action of murine Type I alpha phosphatidylinositol 4-phosphate 5-kinase (Type I alpha. PIPkinase), an enzyme best characterized as regulating cellular PtdIns(4,5)P-2 levels. Analysis of this novel pathway of PtdIns(3,4,5)P-3 synthesis in cellular membranes leads us to conclude that in vivo, Type I alpha PiPkinase also acts as a PtdIns(3,4)P-2 5-kinase. We demonstrate for the first time that cells actually contain an endogenous PtdIns(3,4)P-2 5-kinase, and that during oxidative stress, this enzyme is responsible for PtdIns(3,4,5)P, synthesis. Furthermore, we demonstrate that by upregulating the H2O2-induced PtdIns(3,4,5)P-3 levels using overexpression studies, the endogenous PtdIns(3,4)P-2 5-kinase is likely to be Type I alpha PIPkinase.Conclusions: We describe for the first time a novel in vivo activity for Type tcr PIPkinase, and a novel pathway for the in vivo synthesis of functional PtdIns(3,4,5)P-3, a key lipid second messenger regulating a number of diverse cellular processes.