Jak/STAT訊息鏈在哺乳動物中受到cytokines及生長因子的活化，在血液生成及免疫反應扮演重要的角色。哺乳動物中有四個Jaks及七個STATs，在果蠅中只有一個Jak和一個STAT，具有演化高度保留性及基因不重複特性，因此我們利用果蠅來研究來Jak/STAT訊息鏈在個體發育過程中扮演的角色。Jak/STAT訊息鏈在果蠅參與許多發育過程，例如：調控免疫反應、胚胎體節生長、眼睛大小、血球生成及維持幹細胞的特性。此訊息鏈在果蠅中可能的配體(ligand)為： Unpaired-like 蛋白質(Upd ， Upd2 及Upd3) ； 可能的受體為： Domeless(Dome) 及CG14225 (Dome-like)。先前研究證明Upd和Upd2會透過Dome來活化Jak/STAT訊息鏈，然而Upd3和 Dome-like在此訊息鏈的角色仍未清楚。在未來三年的計畫，我們(1)將驗證Upd3及Dome-like是否為Jak/STAT訊息鏈的配體和受體，並了解它們在果蠅複眼發育過程扮演的角色。(2)且Upd-like蛋白質是否會和Dome或 Dome-like有交互作用。另一方面，我們對於Jak/STAT這個簡單的訊息鏈(一個Jak和STAT)為何可以調控多種不同發育過程感到興趣，我們推測不同配體之間及受體之間可能會形成雙體或異雙體，進而引起多種不同的發育過程。我們(3)將利用雙分子螢光互補技術及共同免疫沉澱法，在果蠅及S2細胞株中測試不同配體間和受體間是否會形成雙體。(4)研究Jak/STAT訊息鏈的不同的配體組合和受體組合，是否在果蠅複眼發育過程中會引發不同作用。希望利用我們的研究能釐清Jak/STAT訊息鏈的配體和受體在果蠅發育過程中作用的分子機制。 The Janus kinase (Jak)/Signal Transducers and Activators of Transcription (STAT) signaling plays important roles in immune responses and hematopoiesis in mammals. This signaling transduces signals for cytokines and growth factors. Four Jaks and seven STATs are identified in mammals and only one Jak and one STAT exist in Drosophila. Fly provides a simple and “complete” Jak/STAT signaling to study the roles of the Jak/STAT signaling during development. This signaling participates in multiple developmental processes, including segmentation of embryos, eye development, haematopoiesis, immune response and stem cell renewal in Drosophila. There are three potential ligands, 3 Unpaired-like proteins (Upd, Upd2, Upd3), and two putative receptors, Domeless (Dome) and Dome-like in the Drosophila Jak/STAT signaling. It still is unclear how such a simple Jak/STAT pathway (one Jak and one STAT) can mediate multiple developmental processes in Drosophila? Based on our preliminary results, we propose that different combination of Jak/STAT ligands (homo- and hetero-dimers) and ligand-receptor can induce distinct biological processes. These preliminary results, if further verified, will drastically increase the complexity of the Jak/STAT signaling in Drosophila. In this three-year grant, we will use a variety of genetic and biochemical methods to study this problem both in vivo and in vitro.
