Utilization of extracellular information before ligand-receptor binding reaches equilibrium expands and shifts the input dynamic range

VENTURA AC; ALAN BUSH; GUSTAVO VASEN; MATIAS GOLDIN; BRIANNE BURKINSHAW; NIRVEEK BHATTACHARJEE; ALBERT FOLCH; ROGER BRENT; ARIEL CHERNOMORETZ; ALEJANDRO COLMAN-LERNER

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2014 vol. 111 p. 3860 - 3869

0027-8424

Cell signaling systems sense and respond to ligands that bind cellsurface receptors. These systems often respond to changes in theconcentration of extracellular ligand more rapidly than the ligandequilibrates with its receptor. We demonstrate, by modeling andexperiment, a general ?systems level? mechanism cells use to takeadvantage of the information present in the early signal, beforereceptor binding reaches a new steady state. This mechanism, preequilibriumsensing and signaling (PRESS), operates in signaling systemsinwhich the kinetics of ligand-receptor binding are slower thanthe downstream signaling steps, and it typically involves transientactivation of a downstream step. In the systems where it operates,PRESS expands and shifts the input dynamic range, allowing cells tomake different responses to ligand concentrations so high as to beotherwise indistinguishable. Specifically,we showthat PRESS appliesto the yeast directional polarization in response to pheromone gradients.Consideration of preexisting kinetic data for ligand-receptorinteractions suggests that PRESS operates in many cell signaling systemsthroughout biology. The same mechanism may also operate atother levels in signaling systems inwhich a slowactivation step couplesto a faster downstream step.