A membrane-permeant ester of phosphatidylinositol 3,4, 5-trisphosphate (PIP(3)) is an activator of human neutrophil migration.
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.
Niggli
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Department of Pathology, University of Bern, Murtenstr. 31, P.O. Box 62, CH-3010, Bern, Switzerland. niggli@patho.unibe.ch
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002465:Cell Movement / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004952:Esters; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D000077191:Wortmannin; D054460:rho-Associated Kinases
D000199:Actins; D000577:Amides; D000730:Androstadienes; D004791:Enzyme Inhibitors; D004952:Esters; D047908:Intracellular Signaling Peptides and Proteins; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; C060974:phosphatidylinositol 3,4,5-triphosphate; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000077191:Wortmannin