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组织中细胞过程的关键调节因子。MAPK信号失调与许多疾病有关，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成分和调控水平，如果没有定量实验、数学建模和计算分析，基本上不可能理解和控制其功能。早期果蝇胚胎的末端模式系统非常适合这一目的，因为它的解剖结构相对简单，并且可以使用大量的遗传工具来操纵MAPK调节因子和底物。我们已经开发了MAPK磷酸化和终端模式系统中的信号转导的体内定量分析。基于这些实验，在我们最近发表的研究中，我们建立了一个模型，根据该模型，早期胚胎中MAPK信号的空间格局是由酶-底物竞争网络控制的。具体来说，我们提出MAPK底物相互竞争，并与MAPK磷酸酶竞争，以结合活化的MAPK。此外，我们提出MAPK底物竞争不仅影响MAPK通路，还影响其与其他信号系统的相互作用。本应用程序中描述的工作将提供底物竞争机制的分子和功能表征。我们的建议的主要创新是在综合建模，遗传和生化方法发育信号转导。通过结合我们在建模，遗传学和生物化学方面的优势，我们独特地定位于制定和实验测试MAPK信号的系统级描述。除了早期果蝇胚胎和MAPK途径之外，我们提出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，其中酶，如MAPK，与其多种调节因子和底物相互作用。

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.