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Ultrasensitization: switch-like regulation of cellular signaling by transcriptional induction

Stefan Legewie1, Nils Blüthgen, Reinhold Schäfer

  • 1Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de

Plos Computational Biology
|November 2, 2005
PubMed

Insights

Minor changes in protein levels can cause large shifts in cellular signals through ultrasensitization. This mechanism, observed in phosphorylation cycles, explains precise cell regulation and all-or-none cell fate decisions.

Area of Science:

  • Cellular and Molecular Biology
  • Systems Biology
  • Biophysics

Background:

  • Cellular signaling networks rely on complex regulatory mechanisms, including transcriptional and proteolytic control.
  • Altered protein expression, particularly phosphorylation, is implicated in cellular differentiation and diseases like cancer.
  • The quantitative relationship between moderate protein expression changes and significant signal transmission alterations, such as in haploinsufficiency, remains poorly understood.

Purpose of the Study:

  • To investigate how minor alterations in protein concentration affect signal transduction within fundamental cellular motifs.
  • To elucidate the mechanism of "ultrasensitization" in biological signaling pathways.
  • To explore the role of ultrasensitization in cellular decision-making, specificity, and network properties.

Main Methods:

  • Mathematical modeling of a core phosphorylation-dephosphorylation cycle.
  • Analysis of enzymatic rate constants and substrate sequestration effects.
  • Investigation of coordinated gene expression (synexpression) in protein kinase cascades.

Main Results:

  • Minor changes in substrate or phosphatase concentration can lead to highly ultrasensitive signal transmission.
  • Substrate sequestration significantly enhances ultrasensitization.
  • Coordinated transcription of multiple signaling proteins amplifies all-or-none signal transmission behavior.
  • Ultrasensitization explains specificity and modularity in cellular regulation.

Conclusions:

  • Ultrasensitization is a key mechanism for achieving switch-like signal processing in cellular networks.
  • This phenomenon can drive all-or-none cell-fate decisions and fine-tune cellular responses.
  • Ultrasensitization contributes to essential network properties like bistability, oscillations, noise reduction, and cellular heterogeneity.

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