Evolution of Signaling Networks

教科书上常见的将蛋白质作为孤立和固定运算符的图解并不能很好地代表现实。大多数蛋白质在物理上和功能上都嵌入到网络中。重要的是，这些对功能至关重要的亲密相互作用可能会限制或促进进化的变化。虽然人们在破译蛋白质序列和功能之间的联系上付出了巨大的努力，但我们仍然在很大程度上忽视了蛋白质序列的变异如何不仅影响特定蛋白质的功能，而且可能更重要的是，影响相互作用蛋白质网络的整体结构、功能和稳定性。我的研究计划的长期目标是解开引导复杂生物网络进化的分子机制。我们的工作集中在激酶介导的信号网络上，因为激酶调节中央细胞过程的活动，它们的多功能可能导致毁灭性的疾病，如癌症。迈向我们长期目标的第一步将是调查简单的突变事件，如氨基酸替换和基因复制，对信号网络的功能和特性的影响。为了解决这一问题，在短期内，我们的工作集中在以下基本问题上：(1)哪些网络组件积累了更多的中性突变？(2)信令网络结构(即所有网络组件之间的功能连接)如何影响信号蛋白的进化能力？以及(3)个体基因的复制和分化如何改变网络的功能？总体而言，通过促进我们对支配信号网络进化的原则的理解，我们的工作将加深我们对生物学基本方面的知识，为与信号相关的人类疾病提供重要的见解，并成为加拿大发展创新生物技术的平台。

The common textbook illustration of proteins as solitary and fixed operators does not fairly represent reality. The majority of proteins are physically and functionally embedded within networks. Importantly, these intimate interactions, fundamental for function, may either constrain or facilitate evolutionary change. While large efforts have gone into decoding the link between protein sequence and function, we are still largely ignorant of how variation in protein sequence affects not just the function of that specific protein, but perhaps more importantly, the overall structure, function and robustness of the network of interacting proteins. The Long Term Goal of my research program is to unravel the molecular mechanisms that guide the evolution of complex biological networks. Our work focuses on kinase-mediated signaling networks, as kinases regulate the activity of central cellular processes and their mulfunction may lead to devastating diseases such as cancer. The first steps towards our long term goal will be to investigate the effects that simple mutational events, such as amino acid substitutions and gene duplication, have on the function and properties of signaling networks. To address this, in the Short Term, our work focuses on the following fundamental questions: (1) which are the network components that accumulate more neutral mutations? (2) How does the structure of the signaling network (that is the functional connections between all network components) affect the ability of signaling proteins to evolve? And (3) how does the duplication and divergence of individual genes alter the function of the network? Overall, by advancing our understanding of the principles that govern the evolution of signaling networks, our work will deepen our knowledge of fundamental aspects of biology, provide important insights into signaling-related human diseases, and serve as a platform for the development of innovative biotechnologies in Canada.