Press Releases
Mar. 14, 2012

Analysis of sensitivity control through signal transduction

— Mechanisms for controlling sensitivity of drug response —
Presenters
  • Yu Toyoshima (Department of Biophysics and Biochemistry, University of Tokyo)
  • Hiroaki Kakuda (Department of Computational Biology, University of Tokyo)
  • Shinya Kuroda (Department of Biophysics and Biochemistry, University of Tokyo)

Abstract

Sensitivity is one of the hallmarks of biological and pharmacological responses. However, the principle of controlling sensitivity remains unclear. Here we theoretically analyse a simple biochemical reaction and find that the signal transfer efficiency of the transient peak amplitude attenuates depending on the strength of negative regulation. We experimentally find that many signalling pathways in various cell lines, including the Akt and ERK pathways, can be approximated by simple biochemical reactions and that the same property of the attenuation of signal transfer efficiency was observed for such pathways. Because of this property, a downstream molecule should show higher sensitivity to an activator and lower sensitivity to an inhibitor than an upstream molecule. Indeed, we experimentally verify that S6, which lies downstream of Akt, shows lower sensitivity to an epidermal growth factor receptor inhibitor than Akt. Thus, cells can control downstream sensitivity through the attenuation of signal transfer efficiency by changing the expression level of negative regulators.

Paper information

Author:
Yu Toyoshima,1 Hiroaki Kakuda,2 Kazuhiro A. Fujita,2 Shinsuke Uda,1 and Shinya Kuroda1,2,3
Affiliations:
1Department of Biophysics and Biochemistry, Graduate School of Science, 2Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; and 3CREST, Japan Science and Technology Corporation, Bunkyo-ku, Tokyo 113-0033, Japan
Title:
Sensitivity control through attenuation of signal transfer efficiency by negative regulation of cellular signaling
Journal:
Nature Communications. 2012 Mar 13; 3:743. doi:10.1038/ncomms1745
Figure 1

Negative regulation controls the signal transfer efficiency and sensitivity to an activator or an inhibitor.

(a) Conceptual description of the activator and inhibitor model. The negative regulation of Z may correspond to the degradation or dephosphorylation of a signalling pathway. (b) Attenuation of the signal transfer efficiency by negative regulation. The weaker the negative regulation becomes, the stronger the attenuation of efficiency becomes. (c) Control of sensitivity to an activator by negative regulation. The weaker the negative regulation becomes, the more sensitive the downstream molecule becomes. (d) Control of sensitivity to an inhibitor by negative regulation. The weaker the negative regulation becomes, the less sensitive the downstream molecule becomes.