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Deciphering signaling outcomes from a system of complex networks
Robert C Hsueh1, Madhusudan Natarajan, Iain Fraser
1University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
Science Signaling
|May 21, 2009
Summary
Cellular signal transduction complexity was studied using combinations of immune cell stimuli. Researchers found that while simple combinations show synergy, complex combinations do not lead to exponentially more cellular behaviors.
Area of Science:
- Immunology
- Cell Biology
- Systems Biology
Background:
- Cellular signal transduction integrates diverse inputs to control specific cell behaviors.
- Understanding interaction complexity is crucial for predicting cellular responses to multiple stimuli.
Purpose of the Study:
- To investigate if cellular signal transduction machinery exhibits iterative complexity.
- To determine if increasing numbers of inputs lead to exponential increases in discrete cellular behaviors.
Main Methods:
- Examined modulated secretion of six cytokines from macrophages.
- Utilized up to five-way combinations of stimuli: Toll-like receptor 4 agonist, three cytokines, and cyclic adenosine monophosphate pathway activators.
Main Results:
- Synergy was observed in paired ligand combinations.
- Few nonadditive outputs were detected in higher-order (three or more) ligand combinations.
- Most potential interactions among stimuli are not realized in cellular responses.
Conclusions:
- Cellular responses to complex stimuli combinations are not exponentially increasing.
- Unique cellular responses are limited to specific subsets of ligands and pathways.
- Signal transduction complexity is constrained, leading to discrete functional enhancements rather than broad combinatorial outputs.
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