DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis

J Cell Biol. 2006 Aug 28;174(5):647-52. doi: 10.1083/jcb.200602142.

Abstract

Neutrophils are highly motile leukocytes, and they play important roles in the innate immune response to invading pathogens. Neutrophil chemotaxis requires Rac activation, yet the Rac activators functioning downstream of chemoattractant receptors remain to be determined. We show that DOCK2, which is a mammalian homologue of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, regulates motility and polarity during neutrophil chemotaxis. Although DOCK2-deficient neutrophils moved toward the chemoattractant source, they exhibited abnormal migratory behavior with a marked reduction in translocation speed. In DOCK2-deficient neutrophils, chemoattractant-induced activation of both Rac1 and Rac2 were severely impaired, resulting in the loss of polarized accumulation of F-actin and phosphatidylinositol 3,4,5-triphosphate (PIP3) at the leading edge. On the other hand, we found that DOCK2 associates with PIP3 and translocates to the leading edge of chemotaxing neutrophils in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. These results indicate that during neutrophil chemotaxis DOCK2 regulates leading edge formation through PIP3-dependent membrane translocation and Rac activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Movement
  • Cell Polarity
  • Chemotaxis, Leukocyte*
  • GTPase-Activating Proteins / deficiency
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Formylmethionine Leucyl-Phenylalanine
  • Neuropeptides / metabolism*
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Neutrophils / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • rac GTP-Binding Proteins / metabolism*
  • rac1 GTP-Binding Protein

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • DOCK2 protein, mouse
  • ELMO1 protein, mouse
  • GTPase-Activating Proteins
  • Neuropeptides
  • Phosphatidylinositol Phosphates
  • Rac1 protein, mouse
  • Recombinant Fusion Proteins
  • phosphatidylinositol 3,4,5-triphosphate
  • N-Formylmethionine Leucyl-Phenylalanine
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein