Leukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell Attachment

Dev Cell. 2019 Apr 22;49(2):206-219.e7. doi: 10.1016/j.devcel.2019.02.023. Epub 2019 Mar 28.


Cell polarization is important for various biological processes. However, its regulation, particularly initiation, is incompletely understood. Here, we investigated mechanisms by which neutrophils break their symmetry and initiate their cytoskeleton polarization from an apolar state in circulation for their extravasation during inflammation. We show here that a local increase in plasma membrane (PM) curvature resulting from cell contact to a surface triggers the initial breakage of the symmetry of an apolar neutrophil and is required for subsequent polarization events induced by chemical stimulation. This local increase in PM curvature recruits SRGAP2 via its F-BAR domain, which in turn activates PI4KA and results in PM PtdIns4P polarization. Polarized PM PtdIns4P is targeted by RPH3A, which directs PIP5K1C90 and subsequent phosphorylated myosin light chain polarization, and this polarization signaling axis regulates neutrophil firm attachment to endothelium. Thus, this study reveals a mechanism for the initiation of cell cytoskeleton polarization.

Keywords: BAR domain; SRGAP2; adhesion; cell polarization; neutrophil; phosphatidylinositol-4-phosphate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Cell Adhesion
  • Cell Membrane / metabolism
  • Cell Membrane / physiology
  • Cell Movement / physiology
  • Cell Polarity / physiology*
  • Cell-Matrix Junctions
  • Cytoskeleton / metabolism
  • Endothelium / metabolism
  • Female
  • GTPase-Activating Proteins / metabolism
  • GTPase-Activating Proteins / physiology
  • HEK293 Cells
  • Humans
  • Leukocytes / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens / metabolism
  • Myosin Light Chains / metabolism
  • Neutrophils / metabolism
  • Neutrophils / physiology*
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Signal Transduction


  • Actins
  • GTPase-Activating Proteins
  • Minor Histocompatibility Antigens
  • Myosin Light Chains
  • Phosphatidylinositol Phosphates
  • SRGAP2 protein, human
  • phosphatidylinositol 4-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol phosphate 4-kinase