Department of Chemistry, York University, Toronto, Ontario, Canada.
Mol Cell Biol. 2012 Sep;32(18):3695-706. doi: 10.1128/MCB.00232-12. Epub 2012 Jul 16.
Functional redundancy is a pivotal mechanism that supports the robustness of biological systems at a molecular, cellular, and organismal level. The extensive prevalence of redundancy in molecular networks has been highlighted by recent systems biology studies; however, a detailed mechanistic understanding of redundant functions in specific signaling modules is often missing. We used affinity purification of protein complexes coupled to tandem mass spectrometry to generate a high-resolution protein interaction map of the three homologous p38 mitogen-activated protein kinases (MAPKs) in Drosophila and assessed the utility of such a map in defining the extent of common and unique functions. We found a correlation between the depth of integration of individual p38 kinases into the protein interaction network and their functional significance in cultured cells and in vivo. Based on these data, we propose a central role of p38b in the Drosophila p38 signaling module, with p38a and p38c playing more peripheral, auxiliary roles. We also present the first in vivo evidence demonstrating that an evolutionarily conserved complex of p38b with glycogen synthase links stress sensing to metabolic adaptation.
功能冗余是一种关键机制，支持分子、细胞和机体水平上生物系统的稳健性。最近的系统生物学研究强调了分子网络中冗余的广泛存在；然而，对于特定信号模块中冗余功能的详细机制理解往往缺失。我们使用蛋白质复合物的亲和纯化与串联质谱联用，生成了果蝇中三个同源 p38 丝裂原活化蛋白激酶 (MAPK) 的高分辨率蛋白质相互作用图谱，并评估了该图谱在定义共同和独特功能的程度方面的实用性。我们发现单个 p38 激酶整合到蛋白质相互作用网络的深度与其在培养细胞和体内的功能意义之间存在相关性。基于这些数据，我们提出了 p38b 在果蝇 p38 信号模块中的核心作用，而 p38a 和 p38c 则发挥更外围、辅助的作用。我们还提供了第一个体内证据，证明 p38b 与糖原合酶的进化保守复合物将应激感应与代谢适应联系起来。
