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首页> 外文期刊>Cellular Signalling >Fc epsilon RI control of Ras via inositol (1,4,5) trisphosphate 3-kinase and inositol tetrakisphosphate
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Fc epsilon RI control of Ras via inositol (1,4,5) trisphosphate 3-kinase and inositol tetrakisphosphate

机译：FcεRI通过肌醇（1,4,5）三磷酸3-激酶和肌醇四磷酸酯控制Ras

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The inositol (1,4,5) trisphosphate 3-kinase (ITP3K) phosphorylates Ins (1,4,5) P3 to produce Ins (1,3,4,5) P4. The ITP3K substrate, InsP3, and its product, InsP4, both have the potential to regulate mast cell function. Here, we explore the effects of dominant inhibition of ITP3K upon secretory responses and Ras GTPase activation following antigenic cross-linking of the mast cell immunoreceptor, Fc epsilon RI. Inhibition of ITP3K potentiates both calcium release from intracellular stores and calcium-dependent secretory responses in mast cells. Moreover, mast cells with dominantly inhibited ITP3K display constitutive activation of Ras and certain Ras effector pathways. We propose three mechanisms by which ITP3K inhibition could influence Ras activation. The protection of InsP3 that results from ITP3K inhibition may lead to enhanced activation of calcium-sensitive Ras-GAPs or -GRFs. Similarly, the deficit in InsP4 may change the behavior of the InsP4 receptor, the GAP1(1P4BP) Our data are inconsistent with calcium-sensitive Ras-GAP activation being the primary consequence of ITP3K, inhibition in mast cells. Rather, we observe potentiation of Ras responses in mast cells transfected with dominant negative GAP1(1P4BP). Moreover, shRNA-mediated knockdown of GAP1(1P4BP) potentiates Fc epsilon RI-mediated Ras activation, indicating that this InsP4-binding GAP protein may be used by the Fc epsilon RI immunoreceptor to regulate Ras. (c) 2005 Elsevier Inc. All rights reserved.
机译：肌醇（1,4,5）三磷酸3激酶（ITP3K）将Ins（1,4,5）P3磷酸化以生成Ins（1,3,4,5）P4。 ITP3K底物InsP3及其产品InsP4都有调节肥大细胞功能的潜力。在这里，我们探讨肥大细胞免疫受体FcεRI的抗原交联后，ITP3K对分泌反应和Ras GTPase活化的显性抑制作用。抑制ITP3K可以增强钙从细胞内储存的释放以及肥大细胞中钙依赖的分泌反应。此外，具有显着抑制作用的ITP3K肥大细胞表现出Ras和某些Ras效应子途径的组成性激活。我们提出了ITP3K抑制可能影响Ras激活的三种机制。由ITP3K抑制引起的InsP3保护可能导致钙敏感性Ras-GAP或-GRF的激活增强。同样，InsP4的缺陷可能会改变InsP4受体GAP1（1P4BP）的行为。我们的数据与钙敏感的Ras-GAP激活（ITP3K的主要后果，肥大细胞的抑制）不一致。而是，我们观察到显性阴性GAP1（1P4BP）转染的肥大细胞中Ras反应的增强。此外，shRNA介导的敲低GAP1（1P4BP）增强FcεRI介导的Ras激活，表明FcεRI免疫受体可使用这种InsP4结合的GAP蛋白来调节Ras。 （c）2005 Elsevier Inc.保留所有权利。

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