Systems biology of MAPK signaling in early drosophila embryo

描述(由申请人提供)：丝裂原活化蛋白激酶(MAPK)信号通路是成人和发育中组织细胞过程的关键调节因子。去调控的MAPK信号与许多疾病相关，这使其成为多个治疗领域的关键药物靶点。考虑到这一重要途径中的大量组成部分和调控水平，如果没有定量实验、数学建模和计算分析，理解和控制其功能基本上是不可能的。早期果蝇胚胎的末端模式系统非常适合于这一目的，因为它相对解剖简单，并且可以获得大量的遗传工具来操纵MAPK调节因子和底物。我们已经建立了在体内分析MAPK磷酸化和末端构图系统中的信号传递的定量分析方法。在这些分析的基础上，在我们最近发表的工作中，我们建立了一个模型，根据该模型，MAPK信号在早期胚胎中的空间模式由酶-底物竞争网络控制。具体地说，我们提出了MAPK底物之间以及与MAPK磷酸酶竞争结合激活的MAPK。此外，我们认为MAPK底物竞争不仅影响MAPK通路，而且影响其与其他信号系统的相互作用。本申请中描述的工作将提供底物竞争机制的分子和功能表征。我们建议的主要创新在于综合了建模、遗传和生化方法来进行发育信号转导。通过结合我们在建模、遗传学和生物化学方面的优势，我们在制定和实验测试MAPK信号的系统级描述方面具有独特的优势。超越了果蝇早期胚胎和MAPK途径，我们认为底物竞争在生物分子网络中提供了一种通用的信号整合策略，在生物分子网络中，MAPK等酶与其多个调节器和底物相互作用。

DESCRIPTION (provided by applicant): The Mitogen Activated Protein Kinase (MAPK) signaling pathway is a critical regulator of cellular processes in adult and developing tissues. Deregulated MAPK signaling is associated with a number of diseases, which makes it a key drug target in multiple therapeutic areas. Given a large number of components and levels of regulation within this important pathway, understanding and controlling its function is essentially impossible without quantitative experiments, mathematical modeling, and computational analysis. The terminal patterning system in the early Drosophila embryo is ideally suited for this purpose because of its relative anatomical simplicity and the availability of a large number of genetic tools for the manipulation of MAPK regulators and substrates. We have developed quantitative assays for the in vivo analysis of MAPK phosphorylation and signaling in the terminal patterning system. Based on these assays, in our recently published work we formulated a model according to which the spatial pattern of MAPK signaling in the early embryo is controlled by an enzyme-substrate competition network. Specifically, we proposed that MAPK substrates compete among themselves and with the MAPK phosphatase for binding to the activated MAPK. In addition, we proposed that MAPK substrate competition influences not only the MAPK pathway, but also its interaction with other signaling systems. The work described in this application will provide molecular and functional characterization of the substrate competition mechanism. The main innovation of our proposal is in synthesizing modeling, genetic, and biochemical approaches to developmental signal transduction. By combining our strengths in modeling, genetics, and biochemistry, we are uniquely positioned to formulate and experimentally test systems-level descriptions of MAPK signaling. Going beyond the early Drosophila embryo and MAPK pathway, we propose that substrate competition provides a general signal integration strategy in biomolecular networks where enzymes, such as MAPK, interact with their multiple regulators and substrates.