title: Bistability of a coupled Aurora B kinase-phosphatase system in cell division.
abstract: Aurora B kinase, a key regulator of cell division, localizes to specific cellular locations, but the regulatory mechanisms responsible for phosphorylation of substrates located remotely from kinase enrichment sites are unclear. Here, we provide evidence that this activity at a distance depends on both sites of high kinase concentration and the bistability of a coupled kinase-phosphatase system. We reconstitute this bistable behavior and hysteresis using purified components to reveal co-existence of distinct high and low Aurora B activity states, sustained by a two-component kinase autoactivation mechanism. Furthermore, we demonstrate these non-linear regimes in live cells using a FRET-based phosphorylation sensor, and provide a mechanistic theoretical model for spatial regulation of Aurora B phosphorylation. We propose that bistability of an Aurora B-phosphatase system underlies formation of spatial phosphorylation patterns, which are generated and spread from sites of kinase autoactivation, thereby regulating cell division.
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Anatoly V
authors.initials: AV
authors.lastname: Zaytsev
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Dario
authors.initials: D
authors.lastname: Segura-Peña
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Maxim
authors.initials: M
authors.lastname: Godzi
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Abram
authors.initials: A
authors.lastname: Calderon
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Ballister
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Rumen
authors.initials: R
authors.lastname: Stamatov
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Mayo
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.|Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Peterson
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Ben E
authors.initials: BE
authors.lastname: Black
authors.affiliation: Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia.|Federal Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Department of Physics, Moscow State University, Moscow, Russia.
authors.forename: Fazly I
authors.initials: FI
authors.lastname: Ataullakhanov
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lampson
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Ekaterina L
authors.identifier: http://orcid.org/0000-0002-9504-4270
authors.initials: EL
authors.lastname: Grishchuk
mesh_terms: D064107:Aurora Kinase B / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002503:Centromere / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008853:Microscopy; D008870:Microtubules / Q000378:metabolism; D061848:Optical Imaging; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D064107:Aurora Kinase B; D010744:Phosphoric Monoester Hydrolases
keywords: cell biology; computational biology; enzyme kinetics; human; kinetochore; mathematical modeling; mitosis; phosphorylation; spatio-temporal dynamics; systems biology