Functional analyses of roles of tyrosine kinases/phosphatases in lymhpcyte signaling

酪氨酸激酶/磷酸酶在淋巴细胞信号传导中的作用的功能分析

基本信息

批准号：
10044288
负责人：
MINAMI Yasuhiro
金额：
$ 9.66万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

In this study, we have found that the proto-oncogene products, H-Ras and c-Myc, act co-operatively to induce homophilic cell adhesion of lymphocytes through the induction of VLA-4 activation and of VCAM-1 expression (Minami, Tanaka). It was also shown that Syk tyrosine kinase and SHP-2 tyrosine phosphatase play important roles in IL-2-induced signal transduction (O'Shea). It was found that an adaptor molecule, LAT is palmitoylated and sequestered at GEM, and is required for the development and activation of T lymphocytes (Samelson). An importance of GEM in T cell engagement was also elucidated (Kosugi). In this study, we have established an experimental system using exo utero method, aiming to examine the effects of tyrosine kinase/phosphatase inhibitors on lymphocyte development in vivo (Otani). We have also shown that a lymphocyte-specific tyrosine phosphatase, LC-PTP, inhibits ERK that is activated during T cell activation (Ogata). It was reported that topoisomerase II inhibitors induce apoptosis of lymphocytes. In this study, it was found that Lyn tyrosine kinase regulates positively the topoisomerase II inhibitor-induced apoptosis of lymphocytes (Yamamura). We have also examined a possible role of tyrosine phosphatases in the process of lymphocyte-macrophage interaction (Moriyama). It was shown that engagement of LFA-1 and of TCR results in a synergistic tyrosine phosphorylation of Fak tyrosine kinase (Umehara). In this collaborative study, we have exchanged results mutually, and have discussed about the respective results extensively. We have also discussed to plan our future collaborative experiments.

在这项研究中，我们发现原癌基因产物 H-Ras 和 c-Myc 协同作用，通过诱导 VLA-4 激活和 VCAM-1 表达来诱导淋巴细胞的同种细胞粘附（Minami，田中）。还表明 Syk 酪氨酸激酶和 SHP-2 酪氨酸磷酸酶在 IL-2 诱导的信号转导 (O'Shea) 中发挥重要作用。研究发现，接头分子 LAT 被棕榈酰化并隔离在 GEM 中，并且是 T 淋巴细胞发育和激活所必需的 (Samelson)。 GEM 在 T 细胞参与中的重要性也得到了阐明 (Kosugi)。在本研究中，我们采用宫外方法建立了一个实验系统，旨在检查酪氨酸激酶/磷酸酶抑制剂对体内淋巴细胞发育的影响（Otani）。我们还表明，淋巴细胞特异性酪氨酸磷酸酶 LC-PTP 可以抑制 T 细胞激活过程中激活的 ERK (Ogata)。据报道，拓扑异构酶II抑制剂可诱导淋巴细胞凋亡。在这项研究中，发现 Lyn 酪氨酸激酶正向调节拓扑异构酶 II 抑制剂诱导的淋巴细胞凋亡 (Yamamura)。我们还研究了酪氨酸磷酸酶在淋巴细胞-巨噬细胞相互作用过程中的可能作用（Moriyama）。结果表明，LFA-1 和 TCR 的结合导致 Fak 酪氨酸激酶 (Umehara) 的协同酪氨酸磷酸化。在这次合作研究中，我们相互交换了结果，并对各自的结果进行了广泛的讨论。我们还讨论了计划未来的合作实验。