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Published online before print September 11, 2006
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Article |
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 |
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Fc gamma receptors (Fc
Rs) 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 (Fc
R) 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 Fc
R phagocytosis. Herein, we demonstrate that these kinases are not required for Fc
R endocytosis. Endocytosis of heat-aggregated IgG (HA-IgG) by COS-1 cells stably transfected with Fc
RIIA or chimeric Fc
RI-
-
(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 Fc
RIIA was cross-linked using HA-IgG or EA. However, inhibition of Fc
R phosphorylation prevented only Fc
R phagocytosis. Finally, biochemical analyses of PI3K(p85)-Syk binding indicated that direct interactions between native Syk and PI3K proteins are differentially regulated during Fc
R phagocytosis and endocytosis. Overall, our results indicate that Fc
R 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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