title: Speed, sensitivity, and bistability in auto-activating signaling circuits.
abstract: Cells employ a myriad of signaling circuits to detect environmental signals and drive specific gene expression responses. A common motif in these circuits is inducible auto-activation: a transcription factor that activates its own transcription upon activation by a ligand or by post-transcriptional modification. Examples range from the two-component signaling systems in bacteria and plants to the genetic circuits of animal viruses such as HIV. We here present a theoretical study of such circuits, based on analytical calculations, numerical computations, and simulation. Our results reveal several surprising characteristics. They show that auto-activation can drastically enhance the sensitivity of the circuit's response to input signals: even without molecular cooperativity, an ultra-sensitive threshold response can be obtained. However, the increased sensitivity comes at a cost: auto-activation tends to severely slow down the speed of induction, a stochastic effect that was strongly underestimated by earlier deterministic models. This slow-induction effect again requires no molecular cooperativity and is intimately related to the bimodality recently observed in non-cooperative auto-activation circuits. These phenomena pose strong constraints on the use of auto-activation in signaling networks. To achieve both a high sensitivity and a rapid induction, an inducible auto-activation circuit is predicted to acquire low cooperativity and low fold-induction. Examples from Escherichia coli's two-component signaling systems support these predictions.
authors: Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California, USA. hermsen@ctbp.ucsd.edu
authors: Rutger
authors: R
authors: Hermsen
authors: David W
authors: DW
authors: Erickson
authors: Terence
authors: T
authors: Hwa
mesh_terms: D019295:Computational Biology; D004926:Escherichia coli / Q000502:physiology; D029968:Escherichia coli Proteins; D005786:Gene Expression Regulation / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D029968:Escherichia coli Proteins; D014157:Transcription Factors