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A Study on an Intracellular Signaling Molecule, Phosphinositide 3-Kinase

细胞内信号分子磷酸肌醇 3-激酶的研究

基本信息

批准号：
06672169
负责人：
HAZEKI Osamu
金额：
$ 1.34万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06672169/
关键词：
PI3-KINASE WORTMANNIN NEUTROPHILS CTP -BINDING PROTEIN betagammaSUBUNITS

项目摘要

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.

研究了刺激GTP结合蛋白偶联受体激活细胞磷酸肌醇3-激酶（PI 3-激酶）的机制。已知胰岛素或生长因子受体的刺激通过产生酪氨酸磷酸化肽激活PI 3-激酶，所述酪氨酸磷酸化肽与酶的p85/p110亚型结合并刺激所述酶的p85/p110亚型。然而，在fMLP刺激的中性粒细胞中，尽管可以观察到PI 3-激酶产物PIP_3在细胞中显着积聚，但却没有发现这种酪氨酸磷酸化蛋白。在这项研究的开始，我们发现PI 3 -激酶活性的发生，是不受酪氨酸磷酸化的蛋白质，但刺激的GTP结合蛋白（G β γ）的β γ亚基。其他研究小组也得到了类似的结果，最近克隆了一种对γ-β-γ敏感的PI 3-激酶亚型（p110 γ）。这些研究似乎表明，GTP结合蛋白和酪氨酸激酶独立发挥作用，并刺激不同亚型的PI 3-激酶。然而，我们后来发现，用胰岛素和fMLP共刺激细胞导致PIP_3的协同积累。我们还发现，在无细胞系统的PI 3-激酶，可以协同激活的酪氨酸磷酸化肽和γ射线的发生。我们现在正在研究这种新型调节的生理作用。