3B-O1-1050 PDF
Reconstruction of insulin signal flow in global phosphorylation and metabolic network
Cellular functions are realized by a global network of molecular interactions across multiple ‘omic’ layers such as genome, transcriptome, proteome, and metabolome. We designate this global network as a ‘trans-omic’ network. Conventional molecular biological studies and comprehensive measurement of each omic layer have collectively provided clues to elucidate the landscape of the trans-omic network. However, conventional molecular biology has limited comprehensiveness, and in-depth measurement of one particular omic layer does not reveal interaction across multiple omic layers. Consequently, the landscape of the trans-omic network remains unknown. Here we developed an unbiased method to reconstruct trans-omic networks based on time-series phosphoproteome and metabolome data together with public databases. This method was applied to reconstruct a trans-omic network underlying acute insulin action in rat hepatoma FAO cells. We found that the insulin signal flowed through the trans-omic network involving 26 protein kinases, 76 phosphorylated metabolic enzymes, and 80 allosteric effectors, resulting in quantitative changes in 97 metabolites. Kinetic modeling analysis predicted selective control of a subnetwork around phosphofructokinase by specific phosphorylation and allosteric regulation. Thus, we provide an unbiased method that reconstructs the trans-omic network from phosphoproteome and metabolome data, which will be applicable to other cellular responses.