title: Push-Pull and Feedback Mechanisms Can Align Signaling System Outputs with Inputs.
abstract: Many cell signaling systems, including the yeast pheromone response system, exhibit "dose-response alignment" (DoRA), in which output of one or more downstream steps closely matches the fraction of occupied receptors. DoRA can improve the fidelity of transmitted dose information. Here, we searched systematically for biochemical network topologies that produced DoRA. Most networks, including many containing feedback and feedforward loops, could not produce DoRA. However, networks including "push-pull" mechanisms, in which the active form of a signaling species stimulates downstream activity and the nominally inactive form reduces downstream activity, enabled perfect DoRA. Networks containing feedbacks enabled DoRA, but only if they also compared feedback to input and adjusted output to match. Our results establish push-pull as a non-feedback mechanism to align output with variable input and maximize information transfer in signaling systems. They also suggest genetic approaches to determine whether particular signaling systems use feedback or push-pull control.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA; The Molecular Sciences Institute, Berkeley, CA 94704, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Andrews
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Peria
authors.affiliation: The Molecular Sciences Institute, Berkeley, CA 94704, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Yu
authors.affiliation: Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET) and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Colman-Lerner
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA; The Molecular Sciences Institute, Berkeley, CA 94704, USA. Electronic address: rbrent@fhcrc.org.
authors.forename: Roger
authors.initials: R
authors.lastname: Brent
mesh_terms: D003198:Computer Simulation; D025461:Feedback, Physiological; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction
keywords: Saccharomyces cervisiae; cell signaling; dose response alignment; paradoxical signaling; pheromone response system; push-pull; yeast