SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fc gamma receptor-mediated signaling
ABSTRACT SHIP-2, a recently identified inositol 5'-phosphatase, shares high level homology with SHIP-1. Although the role of SHIP-1 has been extensively studied, the role of SHIP-2 in myeloid cell functions is not known. Here, we have analyzed the expression patterns, molecular mechanism of activation, and function of SHIP-2 in human myeloid cell Fcgamma receptor (FcgammaR) signaling. We report that SHIP-2 is expressed in transformed myeloid cells and in primary macrophages, but not in peripheral blood monocytes. Treatment of peripheral blood monocytes with bacterial lipopolysaccharide induced expression of SHIP-2 in a dose-dependent manner. FcgammaRIIa clustering in THP-1 cells induced SHIP-2 tyrosine phosphorylation, suggesting a role for SHIP-2 in modulating FcgammaR-mediated function. Consistent with this notion, overexpression of wild-type SHIP-2 (but not catalytically deficient SHIP-2) in THP-1 cells almost completely abrogated NFkappaB-mediated gene transcription in response to FcgammaRIIa clustering. Furthermore, FcgammaRIIa-induced Akt activation was blocked by wild-type SHIP-2, but not by a catalytically deficient mutant of SHIP-2. Additional experiments analyzing the molecular mechanism of SHIP-2 induction by FcgammaRIIa revealed that SHIP-2 associated with the phosphorylated FcgammaRIIa immunoreceptor tyrosine-based activation motif via the SHIP-2 SH2 domain. Thus, an SH2 domain mutant of SHIP-2 failed to associate with FcgammaRIIa or to become tyrosine-phosphorylated upon FcgammaRIIa clustering. Finally, we also demonstrate that SHIP-2 phosphorylation was induced by FcgammaRI clustering in THP-1 cells. These findings unravel a novel level of regulation of FcgammaR-mediated activation of human myeloid cells by the expression and function of the inositol phosphatase SHIP-2.
- SourceAvailable from: Mengyong Yan[Show abstract] [Hide abstract]
ABSTRACT: As human papillomavirus-like particles (HPV-VLP) represent a promising vaccine delivery vehicle, delineation of the interaction of VLP with professional APC should improve vaccine development. Differences in the capacity of VLP to signal dendritic cells (DC) and Langerhans cells (LC) have been demonstrated, and evidence has been presented for both clathrin-coated pits and proteoglycans (PG) in the uptake pathway of VLP into epithelial cells. Therefore, we compared HPV-VLP uptake mechanisms in human monocyte-derived DC and LC, and their ability to cross-present HPV VLP-associated antigen in the MHC class I pathway. DC and LC each took up virus-like particles (VLP). DC uptake of and signalling by VLP was inhibited by amiloride or cytochalasin D (CCD), but not by filipin treatment, and was blocked by several sulfated and non-sulfated polysaccharides and anti-CD16. In contrast, LC uptake was inhibited only by filipin, and VLP in LC were associated with caveolin, langerin, and CD1a. These data suggest fundamentally different routes of VLP uptake by DC and LC. Despite these differences, VLP taken up by DC and LC were each able to prime naive CD8(+) T cells and induce cytolytic effector T cells in vitro.Virology 08/2004; 324(2):297-310. DOI:10.1016/j.virol.2004.03.045 · 3.28 Impact Factor