Regulation of phosphoinositide 3-kinase signaling by oxidants: Hydrogen peroxide selectively enhances immunoreceptor-induced recruitment of phosphatidylinositol(3,4) bisphosphate-binding PH domain proteins
Regulation of phosphoinositide 3-kinase signaling by oxidants: Hydrogen peroxide selectively enhances immunoreceptor-induced recruitment of phosphatidylinositol(3,4) bisphosphate-binding PH domain proteins
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DOI：
10.1016/j.cellsig.2006.10.013
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发表时间：
2007-05-01
影响因子：
4.8
通讯作者：
Marshall, Aaron J.
中科院分区：
文献类型：
--
作者：
Cheung, Samuel M. S.;Kornelson, Jennifer C.;Marshall, Aaron J.
磷脂酰肌醇3 - 激酶（PI3Ks）产生几种不同的脂质第二信使，包括磷脂酰肌醇（3,4,5） - 三磷酸（PIP3）和磷脂酰肌醇（3,4） - 二磷酸PI(3,4)P2。PI(3,4)P2以不同的动力学方式产生，并与不同的PH结构域效应蛋白结合；然而，人们对该信号通路的调节机制了解甚少。过氧化氢等超氧化物在通过各种细胞表面受体激活后会瞬时产生，并在免疫和炎症反应中发挥重要作用。在此，我们利用定量显微镜技术研究过氧化物对B淋巴细胞中PI(3,4)P2介导的信号蛋白动员的影响。研究发现，过氧化物可诱导PI(3,4)P2结合的PH结构域蛋白Bam32、TAPP2和Akt/PKB的膜募集呈剂量依赖性，但不诱导Btk的PIP3结合的PH结构域的膜募集。研究发现，过氧化物诱导的膜募集依赖于PI3K活性，在BJAB人B淋巴瘤模型中，p110δ亚型对该活性贡献较大。令人惊讶的是，过氧化物共刺激增强了抗原受体诱导的Bam32和TAPP2的膜募集，联合刺激的效果超过了单独使用任一刺激所能达到的最大值。脂质磷酸酶PTEN的表达导致抗原受体诱导的TAPP2膜募集减少；然而，过氧化物共刺激能够克服PTEN的抑制作用。抑制NADPH氧化酶导致抗原受体诱导的TAPP2膜募集减少。我们的研究结果表明，外源性和内源性超氧化物可通过选择性地增加PI(3,4)P2依赖性信号传导来调节淋巴细胞中PI3K信号的特性。（c）2006爱思唯尔公司。保留所有权利。
Phosphoinositide 3-kinases (PI3Ks) generate several distinct lipid second messengers including phosphatidylinositol (3,4,5) trisphosphate (PIP3) and phosphatidylinositol (3,4) bisphosphate PI(3,4)P2. PI(3,4)P2 is produced with distinct kinetics and binds to distinct PH domain effector proteins; however, the regulation of this signaling pathway is poorly understood. Superoxides such as hydrogen peroxide are transiently produced after activation through various cell surface receptors and play important roles in immune and inflammatory responses. Here we use quantitative microscopy to examine the effect of peroxide on PI(3,4)P2-mediated mobilization of signaling proteins in B lymphocytes. Peroxide was found to induce dose-dependant membrane recruitment of the PI(3 4)P2 -binding PH domain proteins Bam32, TAPP2 and Akt/PKB but not the PIP3-binding PH domain of Btk. Peroxide-induced membrane recruitment was found to be dependant on PI3K activity, with the p110 delta isoform contributing much of the activity in the BJAB human B lymphoma model. Strikingly, peroxide co-stimulation enhanced antigen receptor-induced membrane recruitment of Bam32 and TAPP2, with combined stimulation exceeding the maximum achievable with either stimulus alone. Expression of the lipid phosphatase PTEN led to reduction of antigen receptor-induced membrane recruitment of TAPP2; however, peroxide costimulation could overcome the inhibitory effect of PTEN. Inhibition of the NADPH oxidase led to reduction of antigen receptor-induced membrane recruitment of TAPP2. Our results indicate that exogenous and endogenous superoxides can modulate the quality of the PI3K signal in lymphocytes by selectively increasing PI(3,4)P2-dependant signaling. (c) 2006 Elsevier Inc. All rights reserved.