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.
Abstract:
Ras has been extensively studied as a promoter of cell proliferation, whereas few studies have explored its role in migration. To investigate the direct and immediate effects of Ras activity on cell motility or polarity, we focused on RasGAPs, C2GAPB in Dictyostelium amoebae and RASAL3 in HL-60 neutrophils and macrophages. In both cellular systems, optically recruiting the respective RasGAP to the cell front extinguished pre-existing protrusions and changed migration direction. However, when these respective RasGAPs were recruited uniformly to the membrane, cells polarized and moved more rapidly, whereas targeting to the back exaggerated these effects. These unexpected outcomes of attenuating Ras activity naturally had strong, context-dependent consequences for chemotaxis. The RasGAP-mediated polarization depended critically on myosin II activity and commenced with contraction at the cell rear, followed by sustained mTORC2-dependent actin polymerization at the front. These experimental results were captured by computational simulations in which Ras levels control front- and back-promoting feedback loops. The discovery that inhibiting Ras activity can produce counterintuitive effects on cell migration has important implications for future drug-design strategies targeting oncogenic Ras.
Insights
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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