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Analysis of intracellular signal transduction mediated by the cytokine receptor

细胞因子受体介导的细胞内信号转导分析

基本信息

批准号：
06670351
负责人：
MINAMI Yasuhiro
金额：
$ 1.22万
依托单位：
Kobe University (1995-1996)Osaka University (1994)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

Interleukin (IL-2) plays a crrucial role in regulating proliferation of activated T cells. IL-2 exerts its biological activities through the binding to its specific receptor (IL-2R) on target cells, although it remained elusive how the functional high-affinity IL-2R (consisting of alpha, beta, and gamma chains) transduce IL-2 signals to cell interior. Previous studies demonstrate that the cytyoplasmic regions of both the IL-2Rbeta and gamma chains play important roles in IL-2-induced proliferative signal transmission, and that the cytoplasmic region of the beta chain couples physically and functionally with the Src-family protein tyrosine kinases (PTKs), Lck and Fyn. In this study we found that the sytoplasmic regions of beta and gamma chains also couple both physically and functionally with a series of non-receptor PTKs, Syk, a member of the Syk/ZAP-70-family PTKs, and Jak1 and Jak3, members of the Jak-family PTKs. In addition, we identified a novel protein serine/threonine kinase(s) that associates physically with the cytoplasmic region of the beta chain, although its functional role in IL-2 signaling is still unclear. Furthermore, it was found that protein tyrosine phosphatase, SHP-2, that possesses an SH2 region, is tyrpsine phosphorylated upon IL-2 stimulation. In this study we also identified target genes of IL-2 signals ; i.e.bcl-2 proto-oncogene, a gene encoding the protein tyrosine phosphatase LC-PTP,and BAG-1 gene. Structure-function analyzes of the beta chain revealed that induction of both bcl-2 and BAG-1 genes requires the cytoplasmic "serine-rich" region of the beta chain. On the other hand, the induction of LC-PTP gene requies both the cytoplasmic "serine-rich" and "acidic" regions of the beta chain. We also obtained the results suggesting potential role of Bcl-2 in IL-2-induced cell cycle progression.

白细胞介素 (IL-2) 在调节活化 T 细胞的增殖中发挥着至关重要的作用。 IL-2 通过与其靶细胞上的特异性受体 (IL-2R) 结合来发挥其生物活性，尽管功能性高亲和力 IL-2R（由 α、β 和 γ 链组成）如何将 IL-2 信号转导至细胞内部仍不清楚。先前的研究表明，IL-2Rβ 和 γ 链的细胞质区域在 IL-2 诱导的增殖信号传递中发挥着重要作用，并且 β 链的细胞质区域与 Src 家族蛋白酪氨酸激酶 (PTK)、Lck 和 Fyn 在物理和功能上耦合。在这项研究中，我们发现 β 链和 γ 链的胞质区域也在物理和功能上与一系列非受体 PTK、Syk（Syk/ZAP-70 家族 PTK 成员）以及 Jak1 和 Jak3（Jak 家族 PTK 成员）耦合。此外，我们还发现了一种新的蛋白丝氨酸/苏氨酸激酶，它与 β 链的细胞质区域物理相关，但其在 IL-2 信号传导中的功能作用仍不清楚。此外，还发现具有SH2区域的蛋白酪氨酸磷酸酶SHP-2在IL-2刺激下被酪氨酸磷酸化。在本研究中我们还鉴定了IL-2信号的靶基因；即bcl-2原癌基因、编码蛋白酪氨酸磷酸酶LC-PTP的基因和BAG-1基因。 β 链的结构功能分析表明，bcl-2 和 BAG-1 基因的诱导需要 β 链的细胞质“富含丝氨酸”区域。另一方面，LC-PTP基因的诱导需要β链的细胞质“富含丝氨酸”和“酸性”区域。我们还获得了表明 Bcl-2 在 IL-2 诱导的细胞周期进展中潜在作用的结果。