Investigating local negative feedback of Rac activity by mathematical models and cell-motility simulations.

Area of Science:

• Cell biology
• Biophysics
• Mathematical modeling

Background:

• Cellular polarization is crucial for directed cell migration.
• Neutrophil-like HL-60 cells exhibit complex polarization dynamics.
• Optogenetic studies highlight the role of Rac signaling in cell motility.

Purpose of the Study:

• To investigate the minimal molecular circuit governing cell polarization and directed motion.
• To model the interactions between Rac, its inhibitor, and PIP3.
• To explain experimental data from optogenetic manipulation of cell polarity.

Main Methods:

• Adaptation of a previous mathematical model for cell polarity.
• Development of a partial differential equation (PDE) model.
• Parameter fitting to temporal and spatial experimental data.
• 2D simulations of cell shape, motility, and stimulus response.

Main Results:

• The Rac-inhibitor-PIP3 circuit accurately explains optogenetic experimental data, including unusual cell trajectories.
• This circuit is identified as the minimal system required for observed cell behaviors.
• The model demonstrates improved gradient sensing capabilities under noisy and dynamic conditions.

Conclusions:

• A minimal Rac-inhibitor-PIP3 feedback circuit is essential for robust and flexible cell polarization.
• This circuit enables rapid adaptation to changing directional cues.
• The findings provide insights into the fundamental mechanisms of cell migration and gradient sensing.