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Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate

Silvia D M Santos1, Peter J Verveer, Philippe I H Bastiaens

  • 1European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.

Nature Cell Biology
|February 21, 2007
PubMed

Insights

Cell signaling specificity is determined by the structure of the mitogen-activated protein kinase (MAPK) network. Rewiring feedback loops reversed cell responses to growth factors, revealing context-dependent network dynamics.

Area of Science:

  • Cellular signaling and systems biology
  • Molecular and developmental biology

Background:

  • The mitogen-activated protein kinase (MAPK) network is crucial for cell fate regulation, processing growth factor signals.
  • Understanding how the MAPK network achieves signal specificity from diverse inputs remains a challenge.

Purpose of the Study:

  • To investigate the mechanisms of MAPK network signal specificity in PC-12 cells, a model for neuronal differentiation.
  • To determine how network topology and feedback mechanisms influence cell fate decisions.

Main Methods:

  • Employed reverse engineering and modular-response analysis to uncover MAPK network topology.
  • Investigated network responses to epidermal growth factor (EGF) and nerve growth factor (NGF) stimulation.
  • Experimentally rewired regulatory feedback loops to assess their impact on cell responses.

Main Results:

  • Identified distinct MAPK network topologies for EGF (negative feedback only) and NGF (positive and negative feedback) stimulation.
  • Observed bi-stable Erk activation dynamics specific to NGF stimulation, driven by positive feedback.
  • Demonstrated that rewiring feedback loops could reverse cell fate responses to EGF and NGF.

Conclusions:

  • Growth factor context dictates the topology and regulatory feedback of the MAPK signaling network.
  • The emergent network dynamics, governed by its topology, are critical determinants of cell fate.
  • This study provides insights into the fundamental principles of signal processing in biological systems.

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