INVOLVEMENT OF PHOSPHATIDYLINOSITOL 3-KINASE IN FC-GAMMA RECEPTOR SIGNALING

Wortmannin, a potent and selective inhibitor of phosphatidylinositol ( PI) 3-kinase (Okada, T., Sakuma, L., Fukui, Y., Hazeki, 0., and Ui, M. (1994) J. Biol. Chem. 269, 3563-3567), prevented Fc receptor for IgG (Fc gamma R)-dependent phagocytosis of the human monocytic cell line U 937 or guinea pig neutrophils. Cross-linking of Fc gamma R on the surf ace of U937 cells increased PI 3-kinase activity that was immunoprecip itated with antibody against phosphotyrosine or antibody against the 8 5-kDa regulatory subunit of PI 3-kinase. Specific cross-linking of Fc gamma R subclass Fc gamma RI or Fc gamma RII, using monoclonal antibod ies against each receptor subclass and the F(ab')(2) fragment of goat antibody against mouse IgG, increased anti-phosphotyrosine-precipitabl e PI 3-kinase activity. Treatment of cells with anti-Fc gamma RIII ant ibody plus the same F(ab')(2) did not affect the activity, reflecting the lack of Fc gamma RIII in U937 cells. Fc gamma R stimulation trigge red prominent tyrosine phosphorylation of several proteins, among whic h the 115-kDa peptide showed strong association with PI 3-kinase. Thus , Fc gamma R appears to be coupled functionally, via a tyrosine kinase , to PI 3-kinase, which may regulate the phagocytotic activity of the cells.