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

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嗜同性细胞黏附(Minami，Tanaka)。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)中起重要作用。研究发现，LAT是一种接头分子，在GEM中被棕榈酰化并隔离，是T淋巴细胞发育和激活所必需的(Samelson)。还阐明了GEM在T细胞参与中的重要性(Kosugi)。在这项研究中，我们建立了一套体外实验系统，旨在检测酪氨酸激酶/磷酸酶抑制剂对体内(Otani)淋巴细胞发育的影响。我们还表明，一种淋巴细胞特异性酪氨酸磷酸酶LC-PTP可以抑制在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。在本研究中，发现Lyn酪氨酸激酶对拓扑异构酶II抑制剂诱导的淋巴细胞(Yamamura)的凋亡具有正向调节作用。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(森山)。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，我们相互交流了成果，并就各自的结果进行了广泛的讨论。我们还讨论了如何规划未来的协作实验。

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.