A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress
| Autor: | Sabine d'Andrea, Nullin Divecha, Jonathan R. Halstead, Chris D. Ellson, Clive D'Santos, Mieke Roefs, Ching Shih Chen |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Cell signaling
COS cells Agricultural and Biological Sciences(all) Phosphatidylinositol (3 4 5)-trisphosphate Biochemistry Genetics and Molecular Biology(all) Cell migration Hydrogen Peroxide Biology General Biochemistry Genetics and Molecular Biology Cell biology Biological pathway chemistry.chemical_compound Mice Oxidative Stress Phosphotransferases (Alcohol Group Acceptor) chemistry Biochemistry Phosphatidylinositol Phosphates In vivo Second messenger system COS Cells Chlorocebus aethiops Animals Phosphatidylinositol General Agricultural and Biological Sciences |
| Zdroj: | Current Biology. (6):386-395 |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/S0960-9822(01)00121-X |
| Popis: | 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 Iα phosphatidylinositol 4-phosphate 5-kinase (Type Iα 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 Iα 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 3 synthesis. Furthermore, we demonstrate that by upregulating the H 2 O 2 -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 Iα PIPkinase. Conclusions: We describe for the first time a novel in vivo activity for Type Iα 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. |
| Databáze: | OpenAIRE |
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