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Published on: October 4, 2024
Crosstalk and competition in signaling networks
Michael A Rowland1, Walter Fontana, Eric J Deeds
1Center for Bioinformatics, University of Kansas, Lawrence, KS, USA.
Biophysical Journal
|January 4, 2013
Summary
Cellular signaling networks exhibit ultrasensitive responses due to enzyme crosstalk. Mathematical models show that one substrate can cause all substrates to respond ultrasensitively, impacting kinase inhibitor development.
Area of Science:
- Cellular signaling and systems biology
- Biochemical network dynamics
Background:
- Cellular decisions (growth, differentiation, apoptosis) rely on signaling networks transducing information.
- Network crosstalk, where enzymes affect targets in other pathways, creates interconnected systems.
- The impact of interconnections on network signal response remains unclear.
Purpose of the Study:
- To mathematically model and characterize the influence of multiple substrates on each other within signaling networks.
- To understand the effects of enzyme crosstalk on network response dynamics.
Main Methods:
- Development of mathematical models based on kinase/phosphatase pairs acting on single substrates.
- Analysis of ultrasensitive, switch-like responses in these motifs.
- Investigation of substrate interactions and enzyme independence effects.
Main Results:
- Ultrasensitivity becomes transitive: saturation of enzymes by one substrate leads to ultrasensitive responses in all substrates, irrespective of their saturation.
- Phosphatases can induce crosstalk independently, even when kinases are not directly interacting.
- Demonstration of how enzyme-substrate dynamics dictate network behavior.
Conclusions:
- Crosstalk significantly alters network response dynamics, leading to emergent ultrasensitive behavior across multiple substrates.
- Findings necessitate a re-evaluation of how crosstalk is understood and classified in signaling pathways.
- Provides insights for the rational design of kinase inhibitors for therapeutic modulation of cellular networks.
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