Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration
Yiyan Lin1,2, Dhiman Sankar Pal3, Parijat Banerjee4
1Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Nature Cell Biology
|July 1, 2024
Summary
Ras GTPases regulate cell migration, but their role is complex. Inhibiting Ras activity can paradoxically enhance cell polarization and speed, impacting chemotaxis and offering new drug design strategies.
Area of Science:
- Cell Biology
- Molecular Biology
- Biophysics
Background:
- Ras proteins are known regulators of cell proliferation.
- The role of Ras in cell migration and motility remains less understood.
- Ras GTPase-activating proteins (RasGAPs) modulate Ras activity.
Purpose of the Study:
- To investigate the direct effects of Ras activity on cell motility and polarity.
- To explore the function of RasGAPs in regulating cell migration dynamics.
- To understand the context-dependent consequences of Ras inhibition on cell movement.
Main Methods:
- Utilized Dictyostelium amoebae and HL-60 neutrophils/macrophages as model systems.
- Employed optogenetic recruitment of RasGAPs (C2GAPB, RASAL3) to specific cellular locations.
- Integrated experimental observations with computational simulations.
Main Results:
- Recruiting RasGAPs to the cell front inhibited protrusions and altered migration direction.
- Uniform RasGAP recruitment led to enhanced cell polarization and faster migration.
- RasGAP-mediated polarization was dependent on myosin II and mTORC2 signaling pathways.
- Computational models confirmed Ras levels control feedback loops influencing cell polarity.
Conclusions:
- Ras activity has counterintuitive effects on cell migration, with inhibition potentially promoting directed movement.
- RasGAP-mediated polarization involves rear contraction and front actin polymerization.
- Findings have significant implications for developing targeted therapies against oncogenic Ras.
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