SHARK KINASE SIGNALING IN THE ECOTDERMAL EPITHELIUM

外胚层上皮中的鲨鱼激酶信号传导

• 批准号: 2634830
• 负责人: E. RICHARD STANLEY
• 金额: $ 21.94万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2634830
• 关键词: Drosophilidae; biological signal transduction; cell differentiation; cellular polarity; confocal scanning microscopy; ectoderm; epithelioma; fluorescent dye /probe; gene expression; gene interaction; in situ hybridization; ionizing radiation; molecular cloning; nucleic acid hybridization; polymerase chain reaction; protein structure function; protein tyrosine kinase; radionuclides; site directed mutagenesis; southern blotting; western blottings; yeast two hybrid system

We have recently identified a non-receptor tyrosine kinase that, during Drosophila embryogenesis, is exclusively expressed by the ectodermally derived epithelia and is preferentially localized to the apical epithelial surface. It contains, from amino terminus to carboxy terminus, a Src homology (SH2) domain, 5 ankyrin repeats, another SH2 domain, a proline-rich and basic region and a tyrosine kinase domain. We have termed this kinase Shark (SH2 domain ankyrin repeat kinase). The Shark structure and localization pattern suggest that it functions in a signaling pathway for epithelial cell polarity and/or fate of the ectodermally derived epithelium. We propose to: 1. Determine the loss-of-function and gain-of-function phenotypes of shark. 2. Identify proteins that physically interact with Shark. 3. Investigate the role of the functional domains of Shark. 4. Identify and characterize genes interacting with shark. 5. Identify the mouse homologue(s) of Shark. We wish to use these approaches to investigate the action of Shark and identify other components of the signaling pathway(s) in which it functions. Shark is a novel tyrosine kinase that, apart from its kinase domain, contains three different types of domains known to be important in protein-protein interactions in signal transduction. As both tyrosine kinases and ankyrin repeats have been shown to transduce developmental signals and SH2 domains are involved in tyrosine kinase signaling, Shark could lie at an intersection between ankyrin repeat and tyrosine kinase pathways. A Hydra homologue of Shark, HTK16, also expressed in epithelium, has been reported and preliminary data indicate the existence a human homologue(s) suggesting that Shark is involved in regulating fundamental processes in metazoans. Elucidation of the pathways in which Shark functions is therefore expected to yield new information about the development, regulation and maintenance of epithelium.

我们最近确定了一种非受体酪氨酸激酶 果蝇的胚胎发生，仅由外胚层表达 派生的上皮，优先定位于顶端 上皮表面。它包含从氨基终端到羧基 Terminus，SRC同源性（SH2）域，5个Ankyrin重复，另一个SH2 域，富含脯氨酸的碱性区域以及酪氨酸激酶结构域。 我们已经称为这种激酶鲨（SH2结构域Ankyrin重复激酶）。 鲨鱼结构和定位模式表明它的功能 在信号通路中的上皮细胞极性和/或命运 外胚层衍生的上皮。 我们建议： 1。确定功能丧失和功能获得的表型 鲨鱼。 2。确定与鲨鱼物理相互作用的蛋白质。 3。研究鲨鱼功能域的作用。 4。识别和表征与鲨鱼相互作用的基因。 5。识别鲨鱼的小鼠同源物。 我们希望使用这些方法调查鲨鱼的作用和 确定其信号通路的其他组件 功能。 鲨鱼是一种新颖的酪氨酸激酶，除了其激酶域外， 包含三种已知重要的领域 信号转导中的蛋白质蛋白相互作用。作为两个酪氨酸 激酶和氨基林重复已被证明可以传递发育 信号和SH2域参与酪氨酸激酶信号，， 鲨鱼可能位于氨基林重复和酪氨酸之间的交叉点 激酶途径。鲨鱼的Hydra同源物，HTK16，也表示 上皮已有报道，并初步数据表明 存在人类的同源物，表明鲨鱼参与 调节后生动物的基本过程。阐明 因此，预计鲨鱼功能将产生新的途径 有关开发，监管和维护的信息 上皮。