title: Utilization of extracellular information before ligand-receptor binding reaches equilibrium expands and shifts the input dynamic range.
abstract: Cell signaling systems sense and respond to ligands that bind cell surface receptors. These systems often respond to changes in the concentration of extracellular ligand more rapidly than the ligand equilibrates with its receptor. We demonstrate, by modeling and experiment, a general "systems level" mechanism cells use to take advantage of the information present in the early signal, before receptor binding reaches a new steady state. This mechanism, pre-equilibrium sensing and signaling (PRESS), operates in signaling systems in which the kinetics of ligand-receptor binding are slower than the downstream signaling steps, and it typically involves transient activation of a downstream step. In the systems where it operates, PRESS expands and shifts the input dynamic range, allowing cells to make different responses to ligand concentrations so high as to be otherwise indistinguishable. Specifically, we show that PRESS applies to the yeast directional polarization in response to pheromone gradients. Consideration of preexisting kinetic data for ligand-receptor interactions suggests that PRESS operates in many cell signaling systems throughout biology. The same mechanism may also operate at other levels in signaling systems in which a slow activation step couples to a faster downstream step.
authors.affiliation: Institute of Physiology, Molecular Biology, and Neuroscience (IFIBYNE), University of Buenos Aires (UBA)-National Scientific and Technical Research Council (CONICET), Department of Physiology, Molecular, and Cell Biology, School of Exact and Natural Sciences (FCEN).
authors.forename: Alejandra C
authors.initials: AC
authors.lastname: Ventura
authors.affiliation: Institute of Physiology, Molecular Biology, and Neuroscience (IFIBYNE), University of Buenos Aires (UBA)-National Scientific and Technical Research Council (CONICET), Department of Physiology, Molecular, and Cell Biology, School of Exact and Natural Sciences (FCEN).
authors.forename: Alan
authors.initials: A
authors.lastname: Bush
authors.affiliation: Institute of Physiology, Molecular Biology, and Neuroscience (IFIBYNE), University of Buenos Aires (UBA)-National Scientific and Technical Research Council (CONICET), Department of Physiology, Molecular, and Cell Biology, School of Exact and Natural Sciences (FCEN).
authors.forename: Gustavo
authors.initials: G
authors.lastname: Vasen
authors.affiliation: Institute of Physiology, Molecular Biology, and Neuroscience (IFIBYNE), University of Buenos Aires (UBA)-National Scientific and Technical Research Council (CONICET), Department of Physiology, Molecular, and Cell Biology, School of Exact and Natural Sciences (FCEN).
authors.forename: Matías A
authors.initials: MA
authors.lastname: Goldín
authors.affiliation: Institute of Physiology, Molecular Biology, and Neuroscience (IFIBYNE), University of Buenos Aires (UBA)-National Scientific and Technical Research Council (CONICET), Department of Physiology, Molecular, and Cell Biology, School of Exact and Natural Sciences (FCEN).
authors.forename: Brianne
authors.initials: B
authors.lastname: Burkinshaw
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195; and.
authors.forename: Nirveek
authors.initials: N
authors.lastname: Bhattacharjee
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195; and.
authors.forename: Albert
authors.initials: A
authors.lastname: Folch
authors.affiliation: Fundación Instituto Leloir, C1405BWE Buenos Aires, Argentina;
authors.forename: Roger
authors.initials: R
authors.lastname: Brent
authors.affiliation: Physics Institute of Buenos Aires (IFIBA), CONICET, and Department of Physics, FCEN, UBA, C1428EGA Buenos Aires, Argentina; Fundación Instituto Leloir, C1405BWE Buenos Aires, Argentina;
authors.forename: Ariel
authors.initials: A
authors.lastname: Chernomoretz
authors.affiliation: Institute of Physiology, Molecular Biology, and Neuroscience (IFIBYNE), University of Buenos Aires (UBA)-National Scientific and Technical Research Council (CONICET), Department of Physiology, Molecular, and Cell Biology, School of Exact and Natural Sciences (FCEN), colman-lerner@fbmc.fcen.uba.ar.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Colman-Lerner
mesh_terms: D016764:Cell Polarity; D005110:Extracellular Space / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D008024:Ligands; D011956:Receptors, Cell Surface
keywords: binding kinetics; cellular signaling; dose–response