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Peer-reviewedCC BYNature Cell Biology

Long-range mutual activation establishes Rho and Rac polarity during cell migration

  • Henry De Belly1,2,3,4
  • Andreu F. Gallen5,6
  • Evelyn Strickland7,8,9,4
  • Dorothy C. Estrada7,8,4
  • David Sanchez Godinez7,8,4
  • Eric Neiva5,10
  • Patrick J. Zager7,8,11,12
  • Tamas L Nagy13,7,8,11,6
  • Janis K. Burkhardt14,4
  • Hervé Turlier15,16
  • Orion David Weiner17,18
18 affiliations
  1. 1Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. [email protected]
  2. 2Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected]
  3. 3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. [email protected]
  4. 4UC San Francisco - University of California [San Francisco] (505 Parnassus Ave, San Francisco, CA 94143 - United States)
  5. 5Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, Université PSL, Paris, France
  6. 6CIRB - Centre interdisciplinaire de recherche en biologie (11 place Marcellin Berthelot 75005 Paris - France)
  7. 7Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
  8. 8Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
  9. 9Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  10. 10Department of Fluid Mechanics, Universitat Politècnica de Catalunya - Barcelona Tech (UPC), Barcelona, Spain
  11. 11CHOP - Children’s Hospital of Philadelphia (3401 Civic Center Blvd, Philadelphia, PA 19104 - United States)
  12. 12University of Pennsylvania (3451 Walnut Street, Philadelphia, PA 19104 | 215-898-5000 - United States)
  13. 13Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA
  14. 14Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  15. 15Center for Integrative Biology (CBI), University of Toulouse, CNRS, Toulouse, France. [email protected]
  16. 16Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, Université PSL, Paris, France. [email protected]
  17. 17Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. [email protected]
  18. 18Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. [email protected]
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Abstract

In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back. How these GTPases are appropriately positioned at the opposite poles of migrating cells is unknown. Here we leverage optogenetics, manipulation of cell mechanics, and mathematical modeling to reveal a surprising mechanochemical long-range mutual activation of the front and back polarity programs that complements their well-known local mutual inhibition. Rac-based protrusion stimulates Rho activation at the opposite side of the cell via membrane tension-based activation of mTORC2. Conversely, Rho-based contraction induces cortical-flow-based regulation of phosphoinositide signaling to trigger Rac activation at the opposite side of the cell. We develop a minimal unifying mechanochemical model of the cell to explain how this long-range facilitation complements local inhibition to enable robust Rho and Rac partitioning. We show that this long-range mutual activation of Rac and Rho is conserved in epithelial cells and is also essential for efficient polarity and migration of primary human T cells, indicating the generality of this circuit. Our findings demonstrate that the actin cortex and plasma membrane function as an integrated mechanochemical system for long-range partitioning of Rac and Rho during cell migration and likely other cellular contexts.

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Cite

BibTeXRIS
BibTeX
@article{belly2026longrange,
  title = {{Long-range mutual activation establishes Rho and Rac polarity during cell migration}},
  author = {Henry De Belly and Andreu F. Gallen and Evelyn Strickland and Dorothy C. Estrada and David Sanchez Godinez and Eric Neiva and Patrick J. Zager and Tamas L Nagy and Janis K. Burkhardt and Hervé Turlier and Orion David Weiner},
  journal = {Nature Cell Biology},
  year = {2026},
  month = jun,
  doi = {10.1038/s41556-026-01965-1},
  url = {https://doi.org/10.1038/s41556-026-01965-1},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Long-range mutual activation establishes Rho and Rac polarity during cell migration
AU  - Henry De Belly
AU  - Andreu F. Gallen
AU  - Evelyn Strickland
AU  - Dorothy C. Estrada
AU  - David Sanchez Godinez
AU  - Eric Neiva
AU  - Patrick J. Zager
AU  - Tamas L Nagy
AU  - Janis K. Burkhardt
AU  - Hervé Turlier
AU  - Orion David Weiner
PY  - 2026
DA  - 2026/06/01
JO  - Nature Cell Biology
DO  - 10.1038/s41556-026-01965-1
UR  - https://doi.org/10.1038/s41556-026-01965-1
AB  - In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back. How these GTPases are appropriately positioned at the opposite poles of migrating cells is unknown. Here we leverage optogenetics, manipulation of cell mechanics, and mathematical modeling to reveal a surprising mechanochemical long-range mutual activation of the front and back polarity programs that complements their well-known local mutual inhibition. Rac-based protrusion stimulates Rho activation at the opposite side of the cell via membrane tension-based activation of mTORC2. Conversely, Rho-based contraction induces cortical-flow-based regulation of phosphoinositide signaling to trigger Rac activation at the opposite side of the cell. We develop a minimal unifying mechanochemical model of the cell to explain how this long-range facilitation complements local inhibition to enable robust Rho and Rac partitioning. We show that this long-range mutual activation of Rac and Rho is conserved in epithelial cells and is also essential for efficient polarity and migration of primary human T cells, indicating the generality of this circuit. Our findings demonstrate that the actin cortex and plasma membrane function as an integrated mechanochemical system for long-range partitioning of Rac and Rho during cell migration and likely other cellular contexts.
SN  - 1465-7392
SN  - 1476-4679
ER  -