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Regulation of development of type I allergy by the signal transducer specific for the high-affinity IgE receptor

高亲和力 IgE 受体特异性信号转导器对 I 型过敏发展的调节

基本信息

批准号：
11460139
负责人：
RYO Goitsuka
金额：
$ 9.54万
依托单位：
Tokyo University of Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11460139/
关键词：
Allergy Signal transduction IgE receptor Mast cells

项目摘要

MIST is the third member of SLP-76/BASH family signaling proteins, acting downstream of the immunoreceptors. These adaptor proteins are differentially expressed among hematopoietic cells, and very uniquely MIST is only expressed in mast cell lines and cytokine-dependent cell lines. We have demonstrated in this project that MIST is tyrosine phosphorylated upon high-affinity IgE receptor cross linking in mast cells, which is mainly mediated by Lyn kinase. Tyrosine-phosphorylated MIST can inter act with other signaling proteins including PLCy, Vav and Grb 2.The significant reduction of IgE recep-tor-mediated degranulation response was observed when the tyrosine phosphorylation-deficient MIST mutant was expressed in RBL-2H3 rat mast cell line, suggesting that MIST functions as an important scaffold protein for IgE receptor-degranulation. To understand MIST functions in vivo, we generated MIST-deficient mice by gene targeting using ES cell lines. MIST homozygous mice expressed no MIST protein in IL-3-induced bone marrow-derived mast cells and IL-2-induced spleen NK cells. IgE recep tor-mediated degranulation responses as well as cytokine production were profoundly reduced in MIST deficient mast cells, as compared with those in wild-type mast cells. Furthermore, IgE-mediated passive and systemic anaphylaxis in vivo were also attenuated in MIST-deficient mice, indicating that MIST is indeed involved in IgE receptor-mediated mast cell functions in vivo. Based on these findings, we be lieve that MIST would be an excellent target for anti-allergic drugs.

MIST是SLP-76/BASH家族信号传导蛋白的第三个成员，作用于免疫受体的下游。这些衔接蛋白在造血细胞中差异表达，并且非常独特地，MIST仅在肥大细胞系和精氨酸依赖性细胞系中表达。我们在这个项目中已经证明，MIST是酪氨酸磷酸化的高亲和力IgE受体交联在肥大细胞，这主要是由林恩激酶介导的。酪氨酸磷酸化的MIST可与PLC γ、Vav和Grb 2等信号蛋白相互作用。当酪氨酸磷酸化缺陷的MIST突变体在大鼠肥大细胞系RBL-2 H3中表达时，可显著降低IgE受体介导的脱颗粒反应，提示MIST是IgE受体脱颗粒的重要支架蛋白。为了了解MIST在体内的功能，我们使用ES细胞系通过基因靶向产生了MIST缺陷小鼠。MIST纯合子小鼠在IL-3诱导的骨髓源性肥大细胞和IL-2诱导的脾NK细胞中不表达MIST蛋白。与野生型肥大细胞相比，MIST缺陷型肥大细胞中IgE受体介导的脱颗粒反应以及细胞因子产生显著减少。此外，IgE介导的被动和全身过敏反应在体内也减弱了MIST缺陷小鼠，表明MIST确实参与IgE受体介导的肥大细胞功能在体内。基于这些发现，我们相信MIST将是抗过敏药物的一个很好的靶点。