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

Vikrant K Bhosle1, Tapas Mukherjee2, Yi-Wei Huang1

  • 1Program in Cell Biology, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.

Nature Communications
|August 19, 2020
PubMed

Insights

Slit guidance ligand 2 (SLIT2) inhibits macropinocytosis, a process crucial for immune cells and cancer cell growth. This discovery reveals SLIT2 as a natural inhibitor, impacting inflammatory responses and cancer cell survival.

Area of Science:

  • Cell Biology
  • Immunology
  • Cancer Biology

Background:

  • Macropinocytosis is vital for myeloid cell surveillance and RAS-transformed cancer cell proliferation.
  • While inducers of macropinocytosis are known, endogenous inhibitors remain unidentified.
  • Slit guidance ligands binding Roundabout receptors typically inhibit cell migration.

Purpose of the Study:

  • To identify endogenous inhibitors of macropinocytosis.
  • To investigate the role of SLIT2 in regulating macropinocytosis in immune and cancer cells.

Main Methods:

  • In vitro and in vivo studies using macrophages and RAS-transformed cancer cells.
  • Analysis of cytoskeletal changes induced by SLIT2.
  • Assessment of muramyl dipeptide uptake and NOD2-dependent NF-κB activation.
  • Evaluation of CXCL1 chemokine secretion.
  • Investigation of cancer cell survival under nutrient-deficient conditions.

Main Results:

  • SLIT2 was identified as a physiological inhibitor of macropinocytosis in macrophages.
  • SLIT2 induces cytoskeletal changes that suppress macropinocytosis.
  • In vivo, SLIT2 attenuates muramyl dipeptide uptake, inhibiting NOD2-mediated NF-κB activation and CXCL1 secretion.
  • Blocking endogenous SLIT2 enhances CXCL1 secretion.
  • SLIT2 inhibits macropinocytosis in RAS-transformed cancer cells, reducing their survival in nutrient-poor environments.

Conclusions:

  • SLIT2 is a physiological inhibitor of macropinocytosis.
  • SLIT2 plays a role in regulating inflammatory responses by modulating macrophage function.
  • SLIT2 impacts the survival of RAS-transformed cancer cells in nutrient-deficient conditions.
  • The findings challenge the inverse relationship between macropinocytosis and cell migration signaling.

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