Fcepsilon RI control of Ras via inositol (1,4,5) trisphosphate 3-kinase and inositol tetrakisphosphate.
Fcepsilon RI control of Ras via inositol (1,4,5) trisphosphate 3-kinase and inositol tetrakisphosphate.
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Fcepsilon RI 通过肌醇 (1,4,5) 三磷酸 3-激酶和肌醇四磷酸控制 Ras。
DOI：
10.1016/j.cellsig.2005.06.003
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发表时间：
2006
影响因子：
4.8
通讯作者：
Turner,Helen
中科院分区：
文献类型：
--
作者：
Stokes,AlexanderJ;Shimoda,LoriMN;Lee,JaeWook;Rillero,Cora;Chang,Young-Tae;Turner,Helen
肌醇（1,4,5）三磷酸3-激酶（ITP3K）磷酸化Ins (1,4,5) P3生成Ins (1,3,4,5) P4。ITP3K的底物InsP3及其产物InsP4都具有调节肥大细胞功能的潜力。在这里，我们探讨了ITP3K的显性抑制在肥大细胞免疫受体Fc / RI抗原交联后对分泌反应和Ras GTPase激活的影响。抑制ITP3K可增强肥大细胞内储存的钙释放和钙依赖性分泌反应。此外，主要抑制ITP3K的肥大细胞显示Ras和某些Ras效应通路的组成性激活。我们提出了ITP3K抑制影响Ras激活的三种机制。ITP3K抑制对InsP3的保护可能导致钙敏感的Ras-GAPs或-GRFs的激活增强。同样，InsP4的缺失可能会改变InsP4受体GAP1IP4BP的行为。我们的数据与钙敏感的Ras-GAP激活是肥大细胞中ITP3K抑制的主要结果不一致。相反，我们观察到在转染显性负GAP1IP4BP的肥大细胞中Ras反应增强。此外，shrna介导的gap1ip4b_1的下调增强了Fc i - RI介导的Ras激活，表明这种结合insp4的GAP蛋白可能被Fc i - RI免疫受体用来调节Ras。
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, FcɛRI. 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 GAP1IP4BP. 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 GAP1IP4BP. Moreover, shRNA-mediated knockdown of GAP1IP4BPpotentiates FcɛRI-mediated Ras activation, indicating that this InsP4-binding GAP protein may be used by the FcɛRI immunoreceptor to regulate Ras.