Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback

Trends Biochem Sci. 2014 Nov;39(11):556-69. doi: 10.1016/j.tibs.2014.09.003. Epub 2014 Oct 23.


In this series of reviews, we are examining ultrasensitive responses, the switch-like input-output relationships that contribute to signal processing in a wide variety of signaling contexts. In the first part of this series, we explored one mechanism for generating ultrasensitivity, zero-order ultrasensitivity, where the saturation of two converting enzymes allows the output to switch from low to high over a tight range of input levels. In this second installment, we focus on three conceptually distinct mechanisms for ultrasensitivity: multisite phosphorylation, stoichiometric inhibitors, and positive feedback. We also examine several related mechanisms and concepts, including cooperativity, reciprocal regulation, coherent feed-forward regulation, and substrate competition, and provide several examples of signaling processes where these mechanisms are known or are suspected to be applicable.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Binding, Competitive
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Feedback, Physiological*
  • Humans
  • Kinetics
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*


  • Enzyme Inhibitors
  • Protein-Serine-Threonine Kinases
  • Phosphoprotein Phosphatases