PMID- 16921024 OWN - NLM STAT- MEDLINE DCOM- 20070118 LR - 20191210 IS - 0741-5400 (Print) IS - 0741-5400 (Linking) VI - 80 IP - 6 DP - 2006 Dec TI - Differential kinase requirements in human and mouse Fc-gamma receptor phagocytosis and endocytosis. PG - 1553-62 AB - Fc gamma receptors (FcgammaRs) contribute to the internalization of large and small immune complexes through phagocytosis and endocytosis, respectively. The molecular processes underlying these internalization mechanisms differ dramatically and have distinct outcomes in immune clearance and modulation of cell function. However, it is unclear how the same receptors (FcgammaR) binding to identical ligands (IgG) can elicit such distinct responses. We and others have shown that Syk kinase, Src-related tyrosine kinases (SRTKs) and phosphatidyl inositol 3-kinases (PI3K) play important roles in FcgammaR phagocytosis. Herein, we demonstrate that these kinases are not required for FcgammaR endocytosis. Endocytosis of heat-aggregated IgG (HA-IgG) by COS-1 cells stably transfected with FcgammaRIIA or chimeric FcgammaRI-gamma-gamma (EC-TM-CYT) was not significantly altered by PP2, piceatannol, or wortmannin. In contrast, phagocytosis of large opsonized particles (IgG-sensitized sheep erythrocytes, EA) was markedly reduced by these inhibitors. These results were confirmed in primary mouse bone marrow-derived macrophages and freshly isolated human monocytes. Levels of receptor phosphorylation were similar when FcgammaRIIA was cross-linked using HA-IgG or EA. However, inhibition of FcgammaR phosphorylation prevented only FcgammaR phagocytosis. Finally, biochemical analyses of PI3K(p85)-Syk binding indicated that direct interactions between native Syk and PI3K proteins are differentially regulated during FcgammaR phagocytosis and endocytosis. Overall, our results indicate that FcgammaR endocytosis and phagocytosis differ dramatically in their requirement for Syk, SRTKs, and PI3K, pointing to striking differences in their signal transduction mechanisms. We propose a competitive inhibition-based model in which PI3K and c-Cbl play contrasting roles in the induction of phagocytosis or endocytosis signaling cascades. FAU - Huang, Zhen-Yu AU - Huang ZY AD - University of Pennsylvania School of Medicine, Hematology and Oncology Division, 421 Curie Blvd., Philadelphia, PA 19104, USA. FAU - Barreda, Daniel R AU - Barreda DR FAU - Worth, Randall G AU - Worth RG FAU - Indik, Zena K AU - Indik ZK FAU - Kim, Moo-Kyung AU - Kim MK FAU - Chien, Paul AU - Chien P FAU - Schreiber, Alan D AU - Schreiber AD LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20060911 PL - England TA - J Leukoc Biol JT - Journal of leukocyte biology JID - 8405628 RN - 0 (Immunoglobulin G) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Receptors, IgG) RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (SYK protein, human) RN - EC 2.7.10.2 (Syk Kinase) RN - EC 2.7.10.2 (Syk protein, mouse) RN - EC 6.3.2.- (CBL protein, human) RN - EC 6.3.2.- (Cbl protein, mouse) SB - IM MH - Animals MH - Bone Marrow Cells/immunology MH - COS Cells MH - Chlorocebus aethiops MH - Erythrocytes/immunology MH - Humans MH - Immunoglobulin G/immunology MH - Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/genetics/*immunology MH - Macrophages/*immunology MH - Mice MH - Models, Immunological MH - Phagocytosis/genetics/*immunology MH - Phosphatidylinositol 3-Kinases/genetics/*immunology MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/pharmacology MH - Protein Processing, Post-Translational/drug effects/genetics/immunology MH - Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/*immunology MH - Proto-Oncogene Proteins c-cbl/immunology MH - Receptors, IgG/genetics/*immunology MH - Sheep MH - Signal Transduction/drug effects/genetics/*immunology MH - Syk Kinase EDAT- 2006/08/22 09:00 MHDA- 2007/01/19 09:00 CRDT- 2006/08/22 09:00 PHST- 2006/08/22 09:00 [pubmed] PHST- 2007/01/19 09:00 [medline] PHST- 2006/08/22 09:00 [entrez] AID - jlb.0106019 [pii] AID - 10.1189/jlb.0106019 [doi] PST - ppublish SO - J Leukoc Biol. 2006 Dec;80(6):1553-62. doi: 10.1189/jlb.0106019. Epub 2006 Sep 11.