Analysis of JAK Pathway Activation in Drosophila

细胞间的通讯是多细胞生物体正常发育和维持的重要因素。作为信号的分子的数量是巨大的，然而细胞对信号做出反应的机制受到更多的限制。随着重新利用细胞内信号级联启动适当的细胞反应，出现了有限数量的信号通路。这项研究的长期目标是阐明细胞通讯的机制，并了解不同的信号是如何整合和解释来调节发育事件的。从黏菌到人类的生物体中都发现了一个保守的细胞内级联信号通路，即Janus Kinase(JAK)信号通路。在脊椎动物中，JAK信号是细胞对多种细胞因子和生长因子做出反应的主要机制。果蝇被选择来研究JAK信号，因为它使用JAK途径的方式与人类相同，但可以接受遗传和发育操作。果蝇体内唯一已知的JAK信号激活剂是未配对蛋白(UPD)。以前资助的研究(IBN-9723944)侧重于UPD的分子和生化特征。UPD蛋白与以前发现的哺乳动物蛋白没有明显的相似之处，但与密切相关的果蝇物种的蛋白质相似。在这两种果蝇中都发现了Om(1E)和upd基因。此外，最近公布的果蝇基因组序列已经确定了另外两个与UPD同源的较不保守的预测蛋白质。将研究这三个新基因的功能，以及这些基因与UPD和彼此之间的关系。了解果蝇JAK途径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提供深入的认识。这项研究的主要目标是：(1)从分子、生化和表型上鉴定果蝇Om(1E)基因，(2)确定Om(1E)和UPD之间的功能关系，(3)从分子和表型上鉴定另外两种与UPD同源的蛋白质，以及(4)利用遗传筛选鉴定JAK信号转导的其他成分和相关途径。

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.