Hematopoietic Cell Survival by Protein Kinase CISK

描述(申请人提供)：多细胞生物的正常发育依赖于细胞增殖、分化和程序性细胞死亡(PCD或细胞凋亡)之间的平衡。包括癌症在内的许多类型的人类疾病似乎与PCD和增殖的异常调节有关。尽管有丰富的信息，但哺乳动物生存和抗PCD的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IL-3等细胞因子。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。通过一个新开发的基因筛查，我们已经确定了一些新的因子作为生存信号级联反应的新组成部分。其中之一是含有丝氨酸/苏氨酸激酶Cisk(细胞因子依赖的存活激酶)的Phox同源(Px)结构域。Cisk是SGK家族(SGK3)的一个新成员，也是第一个被发现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。Cisk独特的结构域结构、组织表达模式和亚细胞定位也表明Cisk具有不同于Akt和其他SGK家族的作用。本提案的总体目标是了解Cisk信号网络，并确定Cisk在抗细胞凋亡和发育中的功能。 1.通过研究内源性Cisk的存活活性及其对FlII和GCF2功能和活性的调节，阐明体内Cisk调控的信号转导途径。2.通过检测细胞因子和Cisk的独特结构域对其活性的调节，确定控制Cisk激活和亚细胞定位的生化机制。3.通过嵌合和基因敲除小鼠模型研究Cisk对造血细胞发育和存活的影响，探讨Cisk在小鼠细胞存活和发育中的生理作用。

DESCRIPTION (provided by applicant): 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.