ANNEXIN PHOSPHORYLATION: CAUSES AND CONSEQUENCES

说明（申请人摘要）：膜联蛋白是钙依赖性的， 磷脂结合蛋白是主要的外周蛋白， 响应细胞中的钙信号事件而在膜上和膜外。 有证据表明，它们调节细胞膜上的许多酶活性， 作为蛋白激酶和磷脂酶，它们充当受体和停靠位点 对于膜上的其他蛋白质，它们可以介导膜-膜 相互作用的基础胞吐，胞吞作用，和细胞器trafficking。一 许多膜联蛋白响应于细胞刺激而被磷酸化， 促分泌素、生长因子和致癌激酶。本项目谋求 通过识别膜联蛋白的最重要功能， 它们被磷酸化的生理和病理条件， 参与的蛋白激酶，以及磷酸化的后果， 调节细胞活动的术语。Annexin VI的结构 模拟磷酸化的突变将通过X射线 结晶学天然和突变膜联蛋白VI在脂质上的构象 单层将通过二维晶体的电子显微镜来确定。 停靠在膜联蛋白磷酸化位点上的蛋白质， 表征了磷酸化对细胞定位和运动的影响 膜联蛋白在细胞中的运动，包括膜联蛋白的运动， 进入细胞核。这些关于组织的基本研究 膜及其相关的蛋白质应该可以更好地理解 激素释放的细胞信号事件， 神经递质和调节细胞生长在正常和 病理条件。

DESCRIPTION (Applicant's abstract): The annexins are calcium-dependent, phospholipid-binding proteins that are the major peripheral proteins that move on and off membranes in response to calcium signalling events in cells. Evidence suggests they regulate a number of enzyme activities on membranes such as protein kinases and phospholipases, they act as receptors and docking sites for other proteins on the membrane, and they may mediate membrane-membrane interactions underlying exocytosis, endocytosis, and organelle tra.fficking. A number of annexins are phosphorylated in response to cell stimulation by secretogogues, growth factors, and oncogenic kinases. This project seeks to understand the most important ftinctions of annexins by identifying the physiological and pathological conditions under which they are phosphorylated, the protein kinases involved, and the consequences of the phosphorylation in terms of the regulation of cellular activities. The structure of annexin VI with a mutation that mimics phosphorylation will be determined by X-ray crystallography. The conformation of native and mutant annexin VI on lipid monolayers will be determined by electron microscopy of 2 dimensional crystals. Proteins that dock onto the phosphorylation sites on annexins will be characterized. The influence of phosphorylation on the locations and movements of annexins in cells will be determined, including the movements of annexins into the nucleus of the cell. These fundamental studies on the organization of membranes and their associated proteins should lead to a better understanding of cell signalling events that underlie the release of hormones and neurotransmitters and the regulation of cell growth under normal and pathological conditions.