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Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data

William W Chen1, Birgit Schoeberl, Paul J Jasper

  • 1Department of Systems Biology, Center for Cell Decision Processes, Harvard Medical School, Boston, MA 02115, USA.

Molecular Systems Biology
|January 22, 2009
PubMed

Insights

This study models ErbB signaling pathways, revealing how interactions between components, not just individual parts, drive cell responses like ERK and Akt activation. Understanding these complex dynamics is key to deciphering signaling mechanisms.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Systems biology

Background:

  • ErbB signaling pathways regulate critical cellular functions like survival and proliferation.
  • The precise mechanisms by which different ligands trigger distinct responses and how oncogenic mutations influence these pathways remain unclear.

Purpose of the Study:

  • To quantify signal flow through ErbB-activated pathways.
  • To investigate how ligand type and oncogenic mutations affect signaling outcomes.
  • To understand the context-dependent nature of ErbB signaling.

Main Methods:

  • Construction, training, and analysis of a mass action model for immediate-early signaling.
  • Inclusion of ErbB1-4 receptors (EGFR, HER2/Neu2, ErbB3, ErbB4) and downstream MAPK and PI3K/Akt cascades.
  • Examination of parameter sensitivity and context-dependent responses.

Main Results:

  • Parameter sensitivity is highly dependent on the specific signaling feature (e.g., ERK, Akt) and stimulation condition (e.g., EGF, heregulin).
  • Modeling predicts log-linear amplification, enabling significant pathway activation at sub-K(d) ligand concentrations.
  • Isolated MAPK and Akt modules show switch-like responses, contrasting with the system-wide behavior.

Conclusions:

  • Key system-wide features of ErbB signaling emerge from nonlinear interactions among signaling elements.
  • The properties of signaling components differ significantly when analyzed in isolation versus within the complete system context.
  • This context-dependent behavior provides insights into the mechanisms of signal propagation in ErbB pathways.

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