Spontaneous signal generation by an excitable system for cell migration

Area of Science:

• Cell Biology
• Systems Biology
• Biophysics

Background:

• Eukaryotic cells exhibit random migration, crucial for processes like chemotaxis.
• Spontaneous generation of internal signals dictates cell polarity during migration.
• Excitable systems are identified as key mechanisms for this spontaneous signal generation.

Purpose of the Study:

• To explore the role of the Ras excitable system in regulating intracellular signaling networks for cell migration.
• To understand how this system generates spontaneous cell polarity in the absence of external cues.
• To analyze the integration of intrinsic and extrinsic signals by the Ras system for robust cell migration.

Main Methods:

• Mathematical modeling using reaction-diffusion equations to explain spatiotemporal dynamics.
• Analysis of downstream phosphoinositide metabolic networks (PI3K, PTEN, PI(3,4,5)P3, PI(4,5)P2).
• Investigation of upstream local excitation/global inhibition networks and parallel cGMP signaling pathways.

Main Results:

• The Ras excitable system creates an active Ras domain on the cell membrane, serving as the anterior signal.
• Reaction-diffusion models quantitatively explain the spatiotemporal characteristics of Ras activity.
• Downstream networks exhibit bistability, and upstream networks bias Ras excitability for chemotaxis.
• Coupling with intercellular cAMP signaling facilitates collective cell migration.

Conclusions:

• The Ras excitable system is central to spontaneous cell polarization and migration in eukaryotic cells.
• It integrates multiple signals, ensuring robust cellular activity and adaptable responses in complex environments.
• This system provides a platform for understanding fundamental cell motility mechanisms.