1995 Fiscal Year Final Research Report Summary
A Study on an Intracellular Signaling Molecule, Phosphinositide 3-Kinase
| Project/Area Number |
06672169
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
HAZEKI Osamu University of Tokyo Faculty of Pharmaceutical Sciences Lecturer, 薬学部, 講師 (80142751)
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| Project Period (FY) |
1994 – 1995
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| Keywords | PI3-KINASE / WORTMANNIN / NEUTROPHILS / CTP -BINDING PROTEIN / betagammaSUBUNITS |
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| Research Abstract |
The mechanism by which stimulation of GTP-binding protein-coupled receptors activates cellular phosphoinositide 3-kinase (PI 3-kinase) was examined. It is known that stimulation of insulin or growth factor receptors activates PI 3-kinase by producing tyrosine-phosphorylated peptide that associates with and stimulates the p85/p110 subtype of the enzyme. However, such a tyrosine-phosphorylated protein can not be found in the neutrophils stimulated by fMLP,in spite that a marked accumulation of PIP_3, a product of PI 3-kinase, can be observed in the cells. At the beginning of this study, we found the occurrence of PI 3 -kinase activity that is unaffected by tyrosine-phosphorylated proteins but is stimulated by betagamma subunits of GTP-binding proteins (Gbetagamma). Similar results were obtained by other groups and more recently one subtype of Gbetagamma-sensitive PI 3-kinase (p110gamma) was cloned. These studies seemed to indicate that GTP-binding proteins and tyrosine kinases act independently and stimulate the different subtypes of PI 3-kinase. We found later, however, that co-stimulation of cells with insulin and fMLP causes synergistic accumulation of PIP_3. We also found in cell-free systems the occurrence of PI 3-kinase that can be synergistically activated by tyrosine-phosphorylated peptide and Gbetagamma. We are now examining for a physiological role of this novel type of regulation.
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Research Products
(17 results)
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[Publications] Ninomiya, N., Hazaki, K., Fukui, Y., Seya, T., Okada, T., Hazeki, O., and Ui, M.: "Involvement of phosphatidylinositol 3-kinase in Fcgamma receptor signaling." J.Biol.Chem. 269. 22732-22737 (1994)
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「研究成果報告書概要(欧文)」より
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[Publications] Kurosu, H., Hazeki, O., Kukimoto, I., Honzawa, S., Shibasaki, M., Nakada, M., Ui, M., and Katada, T.: "Radiolabeling of catalytic subunits of PI 3-kinases with 17beta-hydroxy-16alpha- [^<125>I] iodowortmannin : Identification of the Gbetagamma-sensitive isoform as a complex composed of 46-kDa and 100-kDa subunits." Biochem.Biophys.Res.Commun. 216. 655-661 (1995)
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「研究成果報告書概要(欧文)」より
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[Publications] Honzawa, S., Nakada, M., Kurosu, H., Hazeki, O., Katada, T., and Shibasaki, M: "17beta-Hydroxy-16-alpha-[^<125>I] idodowortmannin, a sensitive labeling agent for PI 3-kinases." Chem.Phar.Bull. 43. 2276-2278 (1995)
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「研究成果報告書概要(欧文)」より
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[Publications] Kontani, K., Kukimoto, I., Nishina, H., Hoshino, S., Hazeki, O., Kanaho, Y., and Katada, T.: "Tyrosine phosphorylation of the c-cbl protooncogene product mediated by cell surface antigen CD38 in HL-60 cells." J.Biol.Chem. 271. 1534-1537 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Matsuo, T., Hazeki, K., Hazeki, O., Katada, T., and Ui, M.: "Activation of phosphatidylinositol 3-kinase by concanavalin A through dual signaling pathways, G protein-coupled and phosphotyrosine-related, and an essential role of the G protein-coupled signals for the lectin-induced respiratory burst in human monocytic THP-1 cells." Biochem.J. (in press).
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