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Signaling through surface receptors in immune cells.

通过免疫细胞表面受体发出信号。

基本信息

批准号：
09044263
负责人：
TAKATSU Kiyoshi
金额：
$ 3.46万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044263/
关键词：
IL-5 B cell differentiation Cytokine Cell adhesion Tyrosine kinase Btk JAK2 STAT5 PI 3-kinase チロシンキナーゼアダプター分子 B細胞シグナル伝達 IL-5

项目摘要

The human IL-5R (hIL-5R) consists of two distinct polypeptide chains, alpha and beta which activates JAK1 and JAK2 and STAT5. We analyzed the interaction between hIL-5Ralpha and betac by immuno-precipitation using anti-hIL-5Ralpha and anti-betac mAbs. The binding of JAK1 and JAK2 to each hIL-5R subunit was also evaluated inTF-h5Ralpha. IL-5 stimulation induced the recruitment of betac to hIL-5Ralpha, although in the absence of IL-5 the subunits remained independent. JAK2 and JAK1 were associated with hIL-5Ralpha and betac, respectively. IL-S stimulation resulted in tyrosine phosphoryl-ation of JAK2, JAK1, betac, and STAT5. Moreover, IL-5-induced dimerization of IL-5R subunits caused JAK2 activation and the betac phosphorylation. Furthermore, tyrosine phosphorylation of JAK1 depended on the activation of JAK2. The cytoplasmic stretch at position 346-387, containing the proline-rich region was necessary for JAK2 binding. These observations suggest that activation of hIL-5Ralpha associated JAK2 is indispensable for IL-5 signaling event.Bone-marrow derived mast cells adhered to fibronectin via VLA-5 (alpha5beta1) upon stimulation with steel factor (SLF) and FceRI cross-linking as well as PMA.SLF and PMA, but not FcepsilonRI cross-linking induced a diffusion of VLA-5 as well as drastic morphological changes. In contrast, only FcepsilonRI cross-linking increased affinity of VLA-5. We also showed PI 3-kinase as a critical affinity modulator by a specific inhibitor, wortmannin, and by introduction ofa constitutively active p110 subunit ofPI-3 kinase. Utilization of affinity or spatial modulation of VLA-5 caused differential effects on adhesion in the presence of physiological concentrations of soluble fibronectin. Our findings indicate that adhesion via VLA-5 are regulated physiologically by two mechanisms ; affinity modulation through PI 3-kinase and spatial modulation possibly through protein kinase C.

人IL-5 R（hIL-5 R）由两条不同的多肽链α和β组成，其激活JAK 1和JAK 2以及STAT 5。我们通过使用抗hIL-5 R α和抗betac mAb的免疫沉淀分析了hIL-5 R α和betac之间的相互作用。JAK 1和JAK 2与每个hIL-5 R亚基的结合也在TF-h5 R α中评估。IL-5刺激诱导betac向hIL-5 R α的募集，尽管在不存在IL-5的情况下，亚基保持独立。JAK 2和JAK 1分别与hIL-5 R α和betac相关。IL-S刺激导致JAK 2、JAK 1、betac和STAT 5的酪氨酸磷酸化。此外，IL-5诱导的IL-5 R亚基的二聚化引起JAK 2活化和betac磷酸化。此外，JAK 1的酪氨酸磷酸化依赖于JAK 2的激活。在位置346-387处的细胞质伸展，含有富含脯氨酸的区域是JAK 2结合所必需的。结果表明，hIL-5 R α相关的JAK 2的激活是IL-5信号转导过程中不可或缺的一个环节，骨髓来源的肥大细胞在钢因子（SLF）和FceRI交联以及PMA的刺激下，通过VLA-5（α 5 β 1）粘附于纤维连接蛋白，SLF和PMA可诱导VLA-5的扩散，而FceplonRI交联则不能诱导VLA-5的扩散以及细胞形态学的显著变化。相比之下，仅Fc ε RI交联增加VLA-5的亲和力。我们还表明PI 3激酶作为一个关键的亲和力调节剂的特异性抑制剂，渥曼青霉素，并通过引入一个组成型活性p110亚基的PI 3激酶。在生理浓度的可溶性纤连蛋白存在下，利用VLA-5的亲和力或空间调制对粘附产生不同的影响。我们的研究结果表明，通过VLA-5的粘附在生理上受到两种机制的调节：通过PI 3-激酶的亲和力调节和可能通过蛋白激酶C的空间调节。