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PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk
Chun-Chao Wang1, Murat Cirit, Jason M Haugh
1Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA.
Molecular Systems Biology
|February 20, 2009
Summary
This study quantifies pathway crosstalk in the platelet-derived growth factor (PDGF) receptor signaling network. It reveals how phosphoinositide 3-kinase (PI3K) signaling enhances extracellular signal-regulated kinase (Erk) activation, despite PI3K pathway insulation.
Area of Science:
- Cellular signaling
- Systems biology
- Molecular network analysis
Background:
- Canonical signal-transduction pathways are key regulatory modes within larger interaction networks.
- Quantifying pathway crosstalk within these complex networks remains a significant challenge.
Purpose of the Study:
- To elucidate cross-talk mechanisms within the platelet-derived growth factor (PDGF) receptor signaling network.
- To quantitatively assess the interplay between phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways.
Main Methods:
- Systematic quantitative measurements across diverse stimulation and molecular perturbation conditions.
- Computational modeling and kinetic analysis of the signaling network.
- Elucidation of cross-talk mechanisms and pathway interactions.
Main Results:
- Phosphoinositide 3-kinase (PI3K) signaling is insulated from crosstalk.
- PI3K enhances extracellular signal-regulated kinase (Erk) activation both upstream and downstream of Ras.
- The magnitude of PI3K's enhancement of Erk activation is dependent on stimulation conditions, saturation effects, and feedback loops.
Conclusions:
- A quantitative kinetic model precisely delineated PI3K-dependent and -independent modes of Ras/Erk activation.
- Understanding pathway crosstalk is crucial for deciphering complex cellular signaling dynamics.
- This study provides a quantitative framework for analyzing signal-transduction network interactions.
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