Analysis of JAK Pathway Activation in Drosophila

0091535哈里森细胞之间的交流是多细胞生物正常发育和维持的重要因素。 作为信号的分子数量是巨大的，然而细胞对信号做出反应的机制却受到了更多的限制。 有限数量的信号传导途径已经作为启动适当的细胞应答的再利用的细胞内信号传导级联而出现。 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，以调节发育事件。 在从黏菌到人类的生物体中发现的一种保守的细胞内级联是Janus激酶（JAK）信号传导途径。 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应答的主要机制。 果蝇，黑腹果蝇，被选择来研究JAK信号，因为它以与人类相同的方式使用JAK通路，但易于遗传和发育操纵。 在果蝇中唯一已知的JAK信号传导激活剂是未配对（Upd）蛋白。 以前资助的研究（IBN-9723944）集中在upd的分子和生物化学表征。 Upd蛋白与先前鉴定的哺乳动物蛋白没有可识别的相似性，但与来自密切相关的果蝇物种Drosophila ananassae的蛋白相似。 Om（1 E）和updgenes在这两种果蝇中都有发现。 此外，最近公布的果蝇基因组序列已经确定了两个额外的，保守性较低的预测蛋白，具有同源性的Upd。 这三个新基因的功能将被研究，以及这些基因与upd和彼此之间的关系。 对果蝇JAK通路激活的分子和机制的理解将可能为许多多细胞生物的发育信号提供见解。 本研究的主要目的是：（1）从分子、生物化学和表型上表征黑腹果蝇Om（1 E）基因，（2）确定Om（1 E）和upd之间的功能关系，（3）从分子和表型上表征与Upd同源的另外两种蛋白质，（4）使用遗传筛选鉴定JAK信号传导和相关通路的其他组分。

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.