SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling

  • Nat Commun. 2020 Aug 17;11(1):4112. doi: 10.1038/s41467-020-17651-1.
Vikrant K Bhosle  1 ,  Tapas Mukherjee  2 ,  Yi-Wei Huang  1 ,  Sajedabanu Patel  1 ,  Bo Wen Frank Pang  1  3  4 ,  Guang-Ying Liu  1 ,  Michael Glogauer  5  6  7 ,  Jane Y Wu  8  9  10 ,  Dana J Philpott  2 ,  Sergio Grinstein  1  11  12 ,  Lisa A Robinson  13  14  15  16
Affiliations
  • 1. Program in Cell Biology, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
  • 2. Department of Immunology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
  • 3. Institute of Medical Science, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
  • 4. BenchSci, Suite 201, 559 College Street, Toronto, ON, M6G 1A9, Canada.
  • 5. Faculty of Dentistry, University of Toronto, 101 Elm Street, Toronto, ON, M5G 2L3, Canada.
  • 6. Department of Dental Oncology and Maxillofacial Prosthetics, University Health Network, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2C1, Canada.
  • 7. Centre for Advanced Dental Research and Care, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
  • 8. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 9. Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 10. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 11. Department of Biochemistry, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
  • 12. Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, 290 Victoria Street, Toronto, ON, M5C 1N8, Canada.
  • 13. Program in Cell Biology, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON, M5G 0A4, Canada. [email protected].
  • 14. Institute of Medical Science, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. [email protected].
  • 15. Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. [email protected].
  • 16. Department of Paediatrics, Faculty of Medicine, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. [email protected].
PMID: 32807784 DOI: 10.1038/s41467-020-17651-1
Abstract

Macropinocytosis is essential for myeloid cells to survey their environment and for growth of RAS-transformed Cancer cells. Several growth factors and inflammatory stimuli are known to induce macropinocytosis, but its endogenous inhibitors have remained elusive. Stimulation of Roundabout receptors by Slit ligands inhibits directional migration of many cell types, including immune cells and Cancer cells. We report that SLIT2 inhibits macropinocytosis in vitro and in vivo by inducing cytoskeletal changes in macrophages. In mice, SLIT2 attenuates the uptake of muramyl dipeptide, thereby preventing NOD2-dependent activation of NF-κB and consequent secretion of pro-inflammatory chemokine, CXCL1. Conversely, blocking the action of endogenous SLIT2 enhances CXCL1 secretion. SLIT2 also inhibits macropinocytosis in RAS-transformed Cancer cells, thereby decreasing their survival in nutrient-deficient conditions which resemble tumor microenvironment. Our results identify SLIT2 as a physiological inhibitor of macropinocytosis and challenge the conventional notion that signals that enhance macropinocytosis negatively regulate cell migration, and vice versa.