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

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 39; no. 11; pp. 556 - 569
• Main Authors: Ferrell, James E., Jr, Ha, Sang Hoon
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-11-2014
• Subjects: 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
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2014.09.003

•To understand the responses of complex signaling networks, one must first understand the responses of the individual monocycles that comprise the network.•Monocycles sometimes exhibit switch-like ultrasensitive responses.•In a previous installment in this series, we showed how enzyme saturation can generate switch-like responses through zero-order ultrasensitivity.•In this review, we discuss several other mechanisms – multisite phosphorylation, stoichiometric inhibitors, and positive feedback, and several variations thereof – that can also generate ultrasensitive responses.
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.