Analysis of cyto kine signal transduction

细胞因子信号转导分析

• 批准号: 11680626
• 负责人: MATSUDA Tadashi
• 金额: $ 0.64万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680626/
• 关键词: Cyto kine; Signal transduction; Jak Kinase; Tyk2; Cross-talk; サイトカインレセプター; JaKキナーゼ

Janus kinases (Jaks) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. Recently, Jak-binding protein (JAB) was identified as a JAK inhibitor. We demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2, whose phosphorylation is required for activation of kinase activity.Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo. Tyk2-deficient mice show no overt developmental abnormalities, however they display a lack of responsiveness to a small amount of IFNγ, although a high concentration of IFNγ can fully transduce its signal even in the absence of tyk2. Furthermore, IL-12-induced T cell function is defective in these mice. In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro. These observations demonstrate that tyk2 plays only a restricted role in mediating IFNγ-dependent signaling, whilst being required in mediating IL-12-dependent biological responses.One member of the STAT family of proteins is STAT3, which is mainly activated by IL-6 family of cytokines, epidermal growth factor, and leptin. Like other members of the STAT family, STAT3 is tyrosine-phosphorylated by Jak kinases, upon which it dimerizes, and translocates into the nucleus to activate target genes. We provided evidence that the inhibitory action of estrogen receptor on STAT3 activity was due to direct physical interactions between STAT3 and estrogen receptor, which represents a novel form of cross-talk between STAT3 and ER signaling pathways.

Janus激酶（Jaks）通过与细胞因子受体的关联调节细胞生长、分化和转化过程。近年来，JAK结合蛋白（JAK -binding protein， JAB）被鉴定为JAK抑制剂。我们证明JAB特异性结合JAK2激活环中的酪氨酸残基（Y1007），其磷酸化是激活激酶活性所必需的。Tyk2是一种Janus激酶，我们建立了Tyk2缺陷小鼠来研究体内对Tyk2的需求。tyk2缺陷小鼠没有表现出明显的发育异常，但是它们对少量IFNγ缺乏反应性，尽管高浓度IFNγ即使在缺乏tyk2的情况下也能完全转导其信号。此外，il -12诱导的T细胞功能在这些小鼠中存在缺陷。相比之下，这些小鼠对IL-6和IL-10的反应正常，这两种物质在体外都能激活tyk2。这些观察结果表明，tyk2在介导ifn γ依赖性信号传导中仅发挥有限的作用，而在介导il -12依赖性生物反应中则是必需的。STAT3是STAT家族蛋白中的一员，主要被IL-6家族细胞因子、表皮生长因子和瘦素激活。与STAT家族的其他成员一样，STAT3被Jak激酶酪氨酸磷酸化，并在此基础上二聚体化，并易位到细胞核中激活靶基因。我们提供的证据表明，雌激素受体对STAT3活性的抑制作用是由于STAT3和雌激素受体之间的直接物理相互作用，这代表了STAT3和内质网信号通路之间的一种新的串扰形式。

项目成果

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