Reconstruction of Insulin Signal Flow from Phosphoproteome and Metabolome Data
Katsuyuki Yugi,
Hiroyuki Kubota,
Yu Toyoshima,
Rei Noguchi,
Kentaro Kawata,
Yasunori Komori,
Shinsuke Uda,
Katsuyuki Kunida,
Yoko Tomizawa,
Yosuke Funato,
Hiroaki Miki,
Masaki Matsumoto,
Keiichi I. Nakayama,
Kasumi Kashikura,
Keiko Endo,
Kazutaka Ikeda,
Tomoyoshi Soga,
Shinya Kuroda
Affiliations
Katsuyuki Yugi
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Hiroyuki Kubota
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Yu Toyoshima
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Rei Noguchi
Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Kentaro Kawata
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Yasunori Komori
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Shinsuke Uda
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Katsuyuki Kunida
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Yoko Tomizawa
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Yosuke Funato
Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
Hiroaki Miki
Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
Masaki Matsumoto
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812–8582, Japan
Keiichi I. Nakayama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812–8582, Japan
Kasumi Kashikura
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Keiko Endo
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Kazutaka Ikeda
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Tomoyoshi Soga
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Shinya Kuroda
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Cellular homeostasis is regulated by signals through multiple molecular networks that include protein phosphorylation and metabolites. However, where and when the signal flows through a network and regulates homeostasis has not been explored. We have developed a reconstruction method for the signal flow based on time-course phosphoproteome and metabolome data, using multiple databases, and have applied it to acute action of insulin, an important hormone for metabolic homeostasis. An insulin signal flows through a network, through signaling pathways that involve 13 protein kinases, 26 phosphorylated metabolic enzymes, and 35 allosteric effectors, resulting in quantitative changes in 44 metabolites. Analysis of the network reveals that insulin induces phosphorylation and activation of liver-type phosphofructokinase 1, thereby controlling a key reaction in glycolysis. We thus provide a versatile method of reconstruction of signal flow through the network using phosphoproteome and metabolome data.
