A Membrane-Permeant Ester of Phosphatidylinositol 3,4, 5-trisphosphate (PIP(3)) Is an Activator of Human Neutrophil Migration

FEBS Lett. 2000 May 12;473(2):217-21. doi: 10.1016/s0014-5793(00)01534-9.

Abstract

Activity of phosphatidylinositol (PI) 3-kinase is required for optimal migration of human neutrophils [Niggli and Keller (1999) Eur. J. Pharmacol. 335, 43-52]. We have tested the direct effect of a product of PI 3-kinase, phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), on neutrophil migration. To this end, a membrane-permeant ester of PIP(3), dilauroyl phosphatidylinositol 3,4, 5-trisphosphate-heptakis-(acetooxymethyl)ester (PIP(3)/AM) was used. PIP(3)/AM (ED(50): 10-17 microM) induced development of polarity and accumulation of F-actin in the leading lamellae in up to 70% of the cells. These cells exhibited stimulated random migration, comparable to that observed in uniform concentrations of chemotactic peptide. Evidence is provided for a role of Rho-kinase and for activation of PI 3-kinase in a positive feedback loop in PIP(3)/AM-induced motility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / drug effects
  • Actins / metabolism
  • Amides / pharmacology
  • Androstadienes / pharmacology
  • Cell Membrane Permeability
  • Cell Movement / drug effects*
  • Cell Polarity / drug effects
  • Cell Size / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Esters
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Neutrophils / cytology
  • Neutrophils / drug effects*
  • Neutrophils / metabolism
  • Phosphatidylinositol Phosphates / chemistry
  • Phosphatidylinositol Phosphates / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Pyridines / pharmacology
  • Signal Transduction
  • Wortmannin
  • rho-Associated Kinases

Substances

  • Actins
  • Amides
  • Androstadienes
  • Enzyme Inhibitors
  • Esters
  • Intracellular Signaling Peptides and Proteins
  • Phosphatidylinositol Phosphates
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • phosphatidylinositol 3,4,5-triphosphate
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Wortmannin