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J Biol Chem, Vol. 274, Issue 3, 1240-1247, January 15, 1999
From the Departments of Medicine and Pharmacology, Columbia
University College of Physicians and Surgeons,
New York, New York 10032
Phagocytosis requires actin assembly and
pseudopod extension, two cellular events that coincide spatially and
temporally. The signal transduction events underlying both processes
may be distinct. We tested whether phagocytic signaling resembles that of growth factor receptors, which induce actin polymerization via
activation of phosphatidylinositol 3-kinase (PI 3-kinase). Fc
receptor-mediated phagocytosis was accompanied by a rapid increase in
the accumulation of phosphatidylinositol 3,4,5-trisphosphate in vivo, and addition of wortmannin (WM) or LY294002, two
inhibitors of PI 3-kinase(s), inhibited phagocytosis but not Fc
receptor-directed actin polymerization. However, both compounds
prevented maximal pseudopod extension, suggesting that PI 3-kinase
inhibition produced a limitation in membrane required for pseudopod
extension. Availability of plasma membrane was not limiting for
phagocytosis, because blockade of ingestion in the presence of WM was
not overcome by reducing the number of particles adhering to
macrophages. However, decreasing bead size, and hence the magnitude of
pseudopod extension required for particle engulfment, relieved the
inhibition of phagocytosis in the presence of WM or LY294002 by up to
80%. The block in phagocytosis of large particles occurred before
phagosomal closure, because both compounds inhibited spreading of
macrophages on substrate-bound IgG. Macrophage spreading on IgG was
accompanied by exocytic insertion of membrane from an intracellular
source, as measured by the dye FM1-43. These results indicate that one
or more isoforms of PI 3 kinase are required for maximal pseudopod
extension but not phagocytosis per se. We suggest that PI 3-kinase is
required for coordinating exocytic membrane insertion and pseudopod extension.
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