{ "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.", "abstract_shown": true, "affiliations": [ "Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Henry.DeBelly@UTSouthwestern.edu", "Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. Henry.DeBelly@UTSouthwestern.edu", "Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. Henry.DeBelly@UTSouthwestern.edu", "UC San Francisco - University of California [San Francisco] (505 Parnassus Ave, San Francisco, CA 94143 - United States)", "Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, Université PSL, Paris, France", "CIRB - Centre interdisciplinaire de recherche en biologie (11 place Marcellin Berthelot 75005 Paris - France)", "Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA", "Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA", "Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA", "Department of Fluid Mechanics, Universitat Politècnica de Catalunya - Barcelona Tech (UPC), Barcelona, Spain", "CHOP - Children’s Hospital of Philadelphia (3401 Civic Center Blvd, Philadelphia, PA 19104 - United States)", "University of Pennsylvania (3451 Walnut Street, Philadelphia, PA 19104 | 215-898-5000 - United States)", "Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA", "Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", "Center for Integrative Biology (CBI), University of Toulouse, CNRS, Toulouse, France. herve.turlier@cnrs.fr", "Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, Université PSL, Paris, France. herve.turlier@cnrs.fr", "Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. Orion.Weiner@ucsf.edu", "Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. Orion.Weiner@ucsf.edu" ], "article_type": null, "arxiv": null, "author_total": 11, "authors": [ { "affs": [ 0, 1, 2, 3 ], "name": "Henry De Belly", "orcid": "0000-0003-2452-4450" }, { "affs": [ 4, 5 ], "name": "Andreu F. Gallen", "orcid": "0000-0002-4555-7238" }, { "affs": [ 6, 7, 8, 3 ], "name": "Evelyn Strickland", "orcid": "0000-0001-5131-5174" }, { "affs": [ 6, 7, 3 ], "name": "Dorothy C. Estrada" }, { "affs": [ 6, 7, 3 ], "name": "David Sanchez Godinez" }, { "affs": [ 4, 9 ], "name": "Eric Neiva" }, { "affs": [ 6, 7, 10, 11 ], "name": "Patrick J. Zager", "orcid": "0000-0002-3993-9686" }, { "affs": [ 12, 6, 7, 10, 5 ], "name": "Tamas L Nagy", "orcid": "0000-0001-6080-9782" }, { "affs": [ 13, 3 ], "name": "Janis K. Burkhardt", "orcid": "0000-0002-8176-1375" }, { "affs": [ 14, 15 ], "name": "Hervé Turlier", "orcid": "0000-0002-9332-9125" }, { "affs": [ 16, 17 ], "name": "Orion David Weiner", "orcid": "0000-0002-1778-6543" } ], "bibtex": "https://research.draconitic.com/paper/6xzss43n1c03e.bib", "cited_by": 18, "doi": "10.1038/s41556-026-01965-1", "fulltext_url": null, "id": "6xzss43n1c03e", "issns": [ "1465-7392", "1476-4679" ], "landing_url": "https://doi.org/10.1038/s41556-026-01965-1", "language": "en", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Protein Kinase Regulation and GTPase Signaling" ] ], "openalex": "W4403067808", "pdf_url": "https://www.nature.com/articles/s41556-026-01965-1.pdf", "pmcid": "PMC11996577", "pmid": "40236007", "published": "2026-06-01", "publisher": "Nature Portfolio", "ris": "https://research.draconitic.com/paper/6xzss43n1c03e.ris", "sources": [ { "first_seen": "2026-10-30T13:26:46Z", "native_id": "W4403067808", "source": "openalex", "url": "https://doi.org/10.1038/s41556-026-01965-1" } ], "subjects": [ { "field": "biochemistry", "origin": "openalex:1312|Protein Kinase Regulation and GTPase Signaling", "subfield": "molecular-biology" } ], "title": "Long-range mutual activation establishes Rho and Rac polarity during cell migration", "title_text": "Long-range mutual activation establishes Rho and Rac polarity during cell migration", "type": "peer-reviewed", "updated_at": "2026-11-08T13:20:41Z", "url": "https://research.draconitic.com/paper/6xzss43n1c03e", "venue": "Nature Cell Biology", "versions": [] }