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
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / drug effects
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Actins / metabolism
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Amides / pharmacology
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Androstadienes / pharmacology
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Cell Membrane Permeability
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Cell Movement / drug effects*
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Cell Polarity / drug effects
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Cell Size / drug effects
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Esters
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Humans
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Intracellular Signaling Peptides and Proteins
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Neutrophils / cytology
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Neutrophils / drug effects*
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Neutrophils / metabolism
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Phosphatidylinositol Phosphates / chemistry
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Phosphatidylinositol Phosphates / pharmacology*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Pyridines / pharmacology
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Signal Transduction
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Wortmannin
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rho-Associated Kinases
Substances
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Actins
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Amides
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Androstadienes
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Enzyme Inhibitors
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Esters
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Intracellular Signaling Peptides and Proteins
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Phosphatidylinositol Phosphates
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Phosphoinositide-3 Kinase Inhibitors
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Pyridines
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phosphatidylinositol 3,4,5-triphosphate
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Y 27632
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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Wortmannin