Growth Regulatory and Survival Functions of the SRC-CAS Protein Complex

SRC-CAS 蛋白复合物的生长调节和生存功能

• 批准号: 0078022
• 负责人: Amy Bouton
• 金额: $ 30万
• 依托单位: University of Virginia Main Campus
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0078022&HistoricalAwards=false
• 关键词: Growth; Regulatory; Survival; Functions; SRC

Homeostasis in multicellular organisms is achieved through a complex process involving the integration of environmental signals for survival, proliferation, and differentiation. The genetic makeup of a cell, as well as the nature of other cells and factors in its environment, dictates how it will respond at any given moment in time. The complex regulation of these processes is perhaps most apparent from the observation that molecules functioning in pathways leading to one type of response may also play a role in generating completely different, and often opposing, outcomes. Moreover, pathways that become activated through distinct mechanisms may functionally merge to produce a common outcome. These fundamental issues of regulation and integration are at the core of this project. Specifically, the project focuses on a newly identified function of the SRC-CAS protein complex as a modulator of cell proliferation and survival. The research plan that is described in this project is designed to test the hypothesis that the activity of this complex has unique signaling functions that arise from a number of potential factors, including 1) altered temporal and/or potency of enzymatic activity; 2) substrate selection; 3) molecular targeting to distinct subcellular compartments; and 4) protein stabilization. Ultimately, the regulated activation of these functions within the proper setting of time (for example, within a particular phase of the cell cycle) and space (for example, within a specific cellular microenvironment) is proposed to play a critical role in pathways leading to proliferation and cell survival . In order to address this hypothesis, C3H10T-one half murine fibroblast cell lines will be generated that over-express various c-SRC and CAS molecules. Preliminary studies in this system have shown that constitutive association of wild-type CAS and c-SRC may circumvent the need for normal positive regulators of growth and survival. Based on these initial studies, it is clear that this model will serve as an excellent tool with which to probe the requisite molecular features of SRC-CAS complex, the specific functions of the complex that contribute to its activity, and its overall impact on cellular growth and survival. Once the mechanism and biological consequences of SRC-CAS activities are better understood, this knowledge will then be applied to more physiological conditions with the goal of understanding how the SRC-CAS complex may signal in space and time.

多细胞生物体的动态平衡是通过一个复杂的过程实现的，该过程涉及到为生存、增殖和分化而整合的环境信号。细胞的基因组成，以及其他细胞的性质和环境中的因素，决定了它在任何给定的时刻将如何做出反应。这些过程的复杂调控可能最明显的是观察到，在导致一种类型反应的途径中发挥作用的分子也可能在产生完全不同的、往往是相反的结果方面发挥作用。此外，通过不同机制激活的通路可能会在功能上合并，产生共同的结果。监管和整合的这些基本问题是该项目的核心。具体地说，该项目侧重于新发现的SRC-CAS蛋白复合体作为细胞增殖和存活调节器的功能。本项目中描述的研究计划旨在检验这样一个假设，即该复合体的活性具有独特的信号功能，这些功能源于许多潜在因素，包括1)酶活性的时间和/或效力的改变；2)底物选择；3)分子靶向不同的亚细胞间隔；以及4)蛋白质的稳定性。最终，在适当的时间(例如，在细胞周期的特定阶段)和空间(例如，在特定的细胞微环境)内，这些功能的调节激活被认为在导致增殖和细胞生存的途径中发挥关键作用。为了解决这一假设，将产生C3H10T-一半的小鼠成纤维细胞系，过表达各种c-SRC和CAS分子。对该系统的初步研究表明，野生型CAS和c-SRC的结构性结合可能绕过了正常的正向生长和生存调节因子的需要。基于这些初步研究，很明显，这个模型将是一个很好的工具，用来探索SRC-CAS复合体所需的分子特征，该复合体对其活性的特定功能，以及它对细胞生长和生存的整体影响。一旦更好地了解了SRC-CAS活动的机制和生物学后果，这些知识将被应用于更多的生理条件，目标是了解SRC-CAS复合体如何在空间和时间上发出信号。