title: Stochastic ERK activation induced by noise and cell-to-cell propagation regulates cell density-dependent proliferation.
abstract: The extracellular signal-regulated kinase (ERK) plays a central role in the signaling cascades of cell growth. Here, we show that stochastic ERK activity pulses regulate cell proliferation rates in a cell density-dependent manner. A fluorescence resonance energy transfer (FRET) biosensor revealed that stochastic ERK activity pulses fired spontaneously or propagated from adjacent cells. Frequency, but not amplitude, of ERK activity pulses exhibited a bell-shaped response to the cell density and correlated with cell proliferation rates. Consistently, synthetic ERK activity pulses generated by a light-switchable CRaf protein accelerated cell proliferation. A mathematical model clarified that 80% and 20% of ERK activity pulses are generated by the noise and cell-to-cell propagation, respectively. Finally, RNA sequencing analysis of cells subjected to the synthetic ERK activity pulses suggested the involvement of serum responsive factor (SRF) transcription factors in the gene expression driven by the ERK activity pulses.
authors.affiliation: Imaging Platform for Spatio-Temporal Information, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: k-aoki@lif.kyoto-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Atsuro
authors.initials: A
authors.lastname: Sakurai
authors.forename: Naoki
authors.initials: N
authors.lastname: Komatsu
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Fujita
authors.forename: Clara
authors.initials: C
authors.lastname: Shionyu
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Matsuda
mesh_terms: D000465:Algorithms; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002450:Cell Communication; D002452:Cell Count; D002460:Cell Line; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D051381:Rats; D017423:Sequence Analysis, RNA; D013269:Stochastic Processes; D059008:Time-Lapse Imaging; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D007093:Imidazoles; C508204:SB-590885; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases