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.

我们最近发现了一种非受体酪氨酸激酶，在 果蝇胚胎发生仅由外胚层表达 衍生上皮细胞并优先定位于顶端 上皮表面。它包含从氨基末端到羧基 末端，一个 Src 同源 (SH2) 结构域，5 个锚蛋白重复序列​​，另一个 SH2 结构域、富含脯氨酸和碱性区域以及酪氨酸激酶结构域。 我们将这种激酶称为 Shark（SH2 结构域锚蛋白重复激酶）。 鲨鱼的结构和定位模式表明它的功能 在上皮细胞极性和/或命运的信号通路中 外胚层衍生的上皮。 我们建议： 1. 确定功能丧失和功能获得表型 鲨鱼。 2. 识别与鲨鱼发生物理相互作用的蛋白质。 3. 研究Shark功能域的作用。 4. 识别并表征与鲨鱼相互作用的基因。 5. 鉴定Shark 的小鼠同源物。 我们希望使用这些方法来调查鲨鱼的行为 识别信号通路中的其他成分 功能。 Shark 是一种新型酪氨酸激酶，除了其激酶结构域外， 包含已知重要的三种不同类型的域 信号转导中的蛋白质-蛋白质相互作用。由于两者都是酪氨酸 激酶和锚蛋白重复序列​​已被证明可以转导发育 信号和 SH2 结构域参与酪氨酸激酶信号传导， 鲨鱼可能位于锚蛋白重复序列​​和酪氨酸之间的交叉点 激酶途径。鲨鱼的水螅同源物 HTK16，也表达于 上皮细胞，已被报道，初步数据表明 人类同源物的存在表明鲨鱼参与了 调节后生动物的基本过程。阐明 因此，鲨鱼发挥作用的途径预计会产生新的 有关开发、监管和维护的信息 上皮。