Scaffold蛋白介导细胞信号转导专一性的定量分析

THE QUANTITATIVE ANALYSIS OF SPECIFICITY IN SCAFFOLD-MEDIATED CELL SIGNALING

细胞使用相对有限的蛋白质组分传递大量的信号,因此不同的信号通常由相同的蛋白质组分传递。这些蛋白质组分是如何选择性地参与不同的信号通路,“高保真”地传递不同的刺激,从而产生特定的细胞应答,是目前细胞生物学领域中的研究热点和难点之一。鉴于Scaffold蛋白在确保信号转导专一性和保真性中的关键作用,作者基于酵母S.cerevisiae的生物学实验数据,建立了由Scaffold介导的丝裂原活化蛋白激酶(mitogenactivatedproteinkinase,MAPK)级联信号转导网络的数学模型。并对已报道的工作进行扩展,给出了多条信号级联网络的“专一性(specificity)”和“保真性(fidelity)”的精确数学定义,计算了MAPK信号网络的专一性和保真性的解析解。用这些解定量分析细胞信号转导的专一性和保真性与信号通路各种动力学参数(输入信号的强度和时间、反应率、磷酸化和去磷酸化系数、降解系数等)之间的关系,从理论上阐述Scaffold蛋白通过隔离(sequestration)和选择性激活(selectiveactivation)等机制增强信号转导网络的专一性和保真性。从而有助于加深对细胞信号转导及其调控过程的系统理解,为揭示某些因细胞信号转导异常所致疾病的发生机理,寻找治疗药物提供新的思路。

Cells use only a relatively limited number of component proteins to transmit a plethora of signals. Accordingly pathways that transduce distinct signals can share protein components. An important yet poorly understood problem in cell and developmental biology is how these component proteins selectively perceive different signaling pathways to transmit different stimuli with ＂high fidelity＂ so that distinct signals produce specific cellular response. Current data indicate that scaffold proteins play key roles in the maintenance of specificity and fidelity, hence, based on experimental data, the mathematical models of the yeast mating, invasive growth and stress-responsive MAPK cascades for scaffolding-mediated were developed. Literature （Komarova NL, Zou XF, Nie Q, Bardwell L. A theoretical framework for specificity in cell signaling, Molecular Systems Biology, 2005, doi： 10.1038/msb4100031： El-E5） was extended to include multipathways, and the precise mathematical definition of ＂specificity＂ and ＂fidelity＂ was proposed. The authors calculated the analytic solutions of MAPK cascade networks and used these results to quantitatively analyze the relationship between ＂specificity＂ , ＂fidelity＂ and kinetic parameters in signaling pathways. It may help to understand cell signaling mechanisms and regulatory processes, and provide a rationale for revealing mechanisms of diseases caused by abnormalities of signal transduction, and novel tools for the prevention and treatment of disease.