Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis

Science. 2009 Apr 17;324(5925):384-7. doi: 10.1126/science.1170179. Epub 2009 Mar 26.

Abstract

During chemotaxis, activation of the small guanosine triphosphatase Rac is spatially regulated to organize the extension of membrane protrusions in the direction of migration. In neutrophils, Rac activation is primarily mediated by DOCK2, an atypical guanine nucleotide exchange factor. Upon stimulation, we found that DOCK2 rapidly translocated to the plasma membrane in a phosphatidylinositol 3,4,5-trisphosphate-dependent manner. However, subsequent accumulation of DOCK2 at the leading edge required phospholipase D-mediated synthesis of phosphatidic acid, which stabilized DOCK2 there by means of interaction with a polybasic amino acid cluster, resulting in increased local actin polymerization. When this interaction was blocked, neutrophils failed to form leading edges properly and exhibited defects in chemotaxis. Thus, intracellular DOCK2 dynamics are sequentially regulated by distinct phospholipids to localize Rac activation during neutrophil chemotaxis.

Publication types

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

MeSH terms

  • 1-Butanol / pharmacology
  • Actins / metabolism
  • Animals
  • Cell Line
  • Cell Membrane / metabolism*
  • Cell Polarity
  • Chemotaxis, Leukocyte*
  • Enzyme Inhibitors / pharmacology
  • GTPase-Activating Proteins / chemistry
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Mice
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / physiology*
  • Phosphatidic Acids / metabolism*
  • Phosphatidic Acids / pharmacology
  • Phosphatidylinositol Phosphates / metabolism*
  • Phospholipase D / genetics
  • Phospholipase D / metabolism
  • Protein Binding
  • Pseudopodia / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • rac GTP-Binding Proteins / metabolism

Substances

  • Actins
  • DOCK2 protein, mouse
  • Enzyme Inhibitors
  • GTPase-Activating Proteins
  • Phosphatidic Acids
  • Phosphatidylinositol Phosphates
  • Recombinant Fusion Proteins
  • phosphatidylinositol 3,4,5-triphosphate
  • 1-Butanol
  • phospholipase D2
  • Phospholipase D
  • rac GTP-Binding Proteins