Hematopoietic Cell Survival by Protein Kinase CISK

多细胞生物的正常发育有赖于细胞增殖、 分化和程序性细胞死亡(PCD或细胞凋亡)。许多类型的人类疾病包括 癌症似乎与PCD和增殖的异常调节有关。尽管拥有丰富的 有关生存和抗PCD的信息、哺乳动物信号通路仍然知之甚少。 造血细胞的生存和生长以及造血细胞的发育依赖于细胞因子 比如IL-3。我们一直在使用IL-3信号作为模型系统来研究细胞生存途径。 通过新开发的基因筛查，我们已经确定了一些新的因素 生存信号中的组成部分级联。其中之一是包含的Phox同源(PX)结构域 丝氨酸/苏氨酸激酶Cisk(细胞因子非依赖性生存激酶)。CSK是SGK的新成员 家族激酶(SGK3)，也是第一个被证明能够支持细胞生存的蛋白。我们的研究表明 Cisk可能在PI-3激酶下游发挥作用，调节非飞行同系物和GCF2的活性。 独特的结构域结构、组织表达模式和亚细胞定位也提示 Cisk与Akt和其他SGK家族的激酶具有不同的作用。这项提案的总体目标是 目的是了解Cisk信号网络，明确Cisk在抗细胞凋亡和细胞周期调控中的作用 发展。 这项建议的具体目的是： 1.通过研究Cisk在体内的存活活性，阐明Cisk在体内的信号转导途径。 内源性Cisk及其对FlII和GCF2功能和活性的调节 2.通过以下方式确定控制Cisk激活和亚细胞定位的生化机制 检测细胞因子和Cisk的独特结构域对其活性的调节。 3.通过研究Cisk在小鼠细胞生存和发育中的作用，探讨Cisk在细胞生存和发育中的生理作用 Cisk通过嵌合和基因敲除的小鼠模型影响造血细胞的发育和存活。

Normal development of multi-cellular organisms relies on the balance between cell proliferation, differentiation and programmed cell death (PCD or apoptosis). Many types of human diseases including cancer appear to be associated with aberrant regulation of PCD and proliferation. Despite the wealth of information, mammalian-signaling pathways for survival and anti-PCD remain poorly understood. Survival and growth of hematopoietic cells as well as hematopoietic development depend on cytokines such as IL-3. We have been studying cell survival pathways using IL-3 signaling as a model system. Through a newly developed genetic screen, we have identified a number of novel factors as new components in survival signaling cascades. One of them is the Phox-homology (PX) domain containing serine/threonine kinase CISK (Cytokine-lndependent Survival Kinase). CISK is a new member of the SGK family kinases (SGK3), and the first to be shown capable of supporting cell survival. Our studies suggest that CISK may function downstream of PI-3 kinase and regulate Flightless homologue and GCF2 activities. The unique domain structure, tissue expression pattern, and subcellular localization of CISK also suggest that CISK plays a distinct role from Akt and other SGK family kinases. The overall objective of this proposal is to understand CISK signaling networks and to define the function of CISK in anti-apoptosis and development. The specific aims of this proposal are to: 1. Elucidate the signaling pathways modulated by CISK in vivo, by investigating the survival activity of endogenous CISK and its regulation of FLII and GCF2 function and activities. 2. Determine the biochemical mechanisms that control CISK activation and subcellular localization, by examining the regulation of its activities by cytokines and the unique domains of CISK. 3. Investigate the physiological role of CISK in cell survival and development in mice, by studying how CISK affects hematopoietic cell development and survival using chimeric and knock-out mouse models.