Analysis of intracellular signal transduction mediated by the cytokine receptor

白细胞介素（IL-2）在调节活化T细胞增殖中起着关键作用。IL-2通过与靶细胞上的特异性受体（IL-2 R）结合来发挥其生物活性，尽管功能性高亲和力IL-2 R（由α、β和γ链组成）如何将IL-2信号传递到细胞内部仍然是难以捉摸的。先前的研究表明，IL-2 R β和γ链的胞浆区在IL-2诱导的增殖信号传递中起重要作用，并且β链的胞浆区与Src家族蛋白酪氨酸激酶（PTKs）、Lck和Fyn在物理和功能上偶联。在这项研究中，我们发现β和γ链的胞质区域也与一系列非受体PTKs，Syk，Syk/ZAP-70家族PTKs的成员，以及Jak家族PTKs的成员Jak 1和Jak 3在物理和功能上偶联。此外，我们鉴定了一种新的蛋白质丝氨酸/苏氨酸激酶，其与β链的胞质区域物理相关，尽管其在IL-2信号传导中的功能作用仍不清楚。此外，发现具有SH 2区域的蛋白酪氨酸磷酸酶SHP-2在IL-2刺激后被酪氨酸磷酸化。在这项研究中，我们还确定了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-功能分析显示，bcl-2和BAG-1基因的诱导需要β链的胞质“富含丝氨酸”区域。另一方面，LC-PTP基因的诱导需要β链的胞质“富含丝氨酸”和“酸性”区域。我们还获得了提示Bcl-2在IL-2诱导的细胞周期进程中的潜在作用的结果。

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.