Analysis of JAK Pathway Activation in Drosophila

0091535Harrison细胞之间的通讯是多细胞生物体正常发育和维持的重要因素。 充当信号的分子数量巨大，但细胞响应信号的机制却受到更多限制。 有限数量的信号通路已作为重复利用的细胞内信号级联出现，可启动适当的细胞反应。 这项研究的长期目标是阐明细胞通讯的机制，并了解如何整合和解释不同的信号来调节发育事件。 Janus 激酶 (JAK) 信号通路是在从粘菌到人类的生物体中发现的一种保守的细胞内级联反应。 在脊椎动物中，JAK 信号传导是细胞对多种细胞因子和生长因子做出反应的主要机制。 选择果蝇（Drosophila melanogaster）来研究 JAK 信号传导，是因为它以与人类相同的方式使用 JAK 通路，但易于进行遗传和发育操作。 果蝇中唯一已知的 JAK 信号激活剂是不配对 (Upd) 蛋白。 先前资助的研究 (IBN-9723944) 重点关注 upd 的分子和生化特征。 Upd 蛋白与之前鉴定的哺乳动物蛋白没有明显的相似性，但与密切相关的果蝇物种 Drosophila ananassae 的蛋白相似。 Om(1E) 和 updgenes 均在这两种果蝇物种中发现。 此外，最近发布的果蝇基因组序列还鉴定出另外两种与 Upd 具有同源性的不太保守的预测蛋白。 我们将研究这三个新基因的功能，以及这些基因与 upd 以及彼此之间的关系。 了解果蝇中 JAK 通路激活的分子和机制可能会为许多多细胞生物体的发育信号传导提供见解。 本研究的主要目标是：(1) 从分子、生化和表型方面表征果蝇 Om(1E) 基因，(2) 确定 Om(1E) 和 upd 之间的功能关系，(3) 从分子和表型方面表征与 Upd 具有同源性的另外两种蛋白质，以及 (4) 使用遗传筛选鉴定 JAK 信号传导和相关通路的其他成分。

0091535HarrisonCommunication between cells is a vital factor in proper development and maintenance of multicellular organisms. The number of molecules that serve as signals is enormous, yet the mechanisms by which cells can respond to signals are much more restricted. A finite number of signaling pathways have emerged as reutilized intracellular signaling cascades that initiate appropriate cellular responses. The long term objectives of this research are to elucidate mechanisms of cellular communication and to understand how different signals are integrated and interpreted to regulate developmental events. One conserved intracellular cascade that has been found in organisms from slime mold to human is the Janus kinase (JAK) signaling pathway. In vertebrates, JAK signaling is the primary mechanism for response of cells to a wide array of cytokines and growth factors. The fruit fly, Drosophila melanogaster, was chosen to study JAK signaling because it uses the JAK pathway in the same manner as humans, yet is amenable to genetic and developmental manipulation. The only known activator of JAK signaling in Drosophila is the Unpaired (Upd) protein. Previously funded research (IBN-9723944) focused on the molecular and biochemical characterization of upd. The Upd protein bears no recognizable similarity to previously identified mammalian proteins, but is similar to a protein from a closely related fruit fly species, Drosophila ananassae. Both Om(1E) and updgenes are found in both of these Drosophila species. Furthermore, the recent release of the Drosophila genome sequence has identified two additional, less conserved predicted proteins that have homology to Upd. The functions of these three new genes will be investigated, as well as the relationships of these genes to upd and to one another. Understanding of the molecules and mechanisms of JAK pathway activation in Drosophila will likely provide insights into developmental signaling in many multicellular organisms. The primary goals of this research are to: (1) characterize, molecularly, biochemically, and phenotypically, the Drosophila melanogaster Om(1E) gene, (2) determine the functional relationships between Om(1E) and upd, (3) characterize, molecularly and phenotypically, two other proteins with homology to Upd, and (4) identify additional components of JAK signaling and related pathways using genetic screens.