Published online before print September 11, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0106019

Received for publication January 11, 2006.
Revised June 21, 2006.
Accepted for publication July 14, 2006.

Article

Differential kinase requirements in human and mouse Fc-gamma receptor phagocytosis and endocytosis

University of Pennsylvania School of Medicine, Hematology and Oncology Division, Philadelphia

^@ To whom correspondence should be addressed. E-mail: schreibr{at}mail.med.upenn.edu.

Abstract

Fc gamma receptors (FcRs) 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 (FcR) 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 FcR phagocytosis. Herein, we demonstrate that these kinases are not required for FcR endocytosis. Endocytosis of heat-aggregated IgG (HA-IgG) by COS-1 cells stably transfected with FcRIIA or chimeric FcRI-- (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 FcRIIA was cross-linked using HA-IgG or EA. However, inhibition of FcR phosphorylation prevented only FcR phagocytosis. Finally, biochemical analyses of PI3K(p85)-Syk binding indicated that direct interactions between native Syk and PI3K proteins are differentially regulated during FcR phagocytosis and endocytosis. Overall, our results indicate that FcR 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.

Key Words: Syk kinase • Src-related tyrosine kinases • phosphatidyl inositol 3 kinase

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