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Mechanosensitive mTORC2 independently coordinates leading and trailing edge polarity programs during neutrophil
Suvrajit Saha1, Jason P Town1, Orion D Weiner1
1Cardiovascular Research Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
Molecular Biology of the Cell
|March 1, 2023
Summary
Physical forces regulate cell shape and movement by integrating cytoskeletal organization. This study reveals how mechanosensitive mTOR complex 2 (mTORC2) coordinates neutrophil polarity and migration through distinct kinase-dependent and -independent pathways.
Area of Science:
- Cell Biology
- Biophysics
- Mechanobiology
Background:
- Physical forces are crucial for integrating cell shape and movement, influencing cytoskeletal organization.
- Mechanosensitive signaling pathways, particularly mTOR complex 2 (mTORC2), play a conserved role in cellular responses to mechanical cues.
Purpose of the Study:
- To investigate the role of mechanosensitive mTOR complex 2 (mTORC2) in neutrophil polarity and motility.
- To elucidate how mTORC2 integrates physical forces and biochemical signals to control cell migration.
Main Methods:
- Utilized genetic, pharmacological, and optogenetic perturbations.
- Analyzed neutrophil polarity and migration under confined conditions.
- Investigated the kinase-dependent and -independent functions of mTORC2.
Main Results:
- Tension-based inhibition of leading-edge signals (Rac, F-actin) is regulated by mTORC2's kinase-independent role.
- Trailing-edge contractility (RhoA, myosin II) depends on mTORC2's kinase activity.
- Membrane stretch synergizes with phosphatidylinositol (3,4,5)-trisphosphate to enhance mTORC2 activation.
Conclusions:
- mTORC2 is essential for coordinating front and back polarity programs for persistent neutrophil migration, especially under confinement.
- Distinct signaling arms of mTORC2 regulate spatially and molecularly divergent cytoskeletal programs.
- This mechanosensory pathway provides efficient coordination of neutrophil shape and movement.
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