title: SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fcgamma 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.
authors.affiliation: Molecular, Cellular, and Developmental Biology Program, Dorothy M. Davis Heart and Lung Institute, James Cancer Hospital, Ohio State University, Columbus 43210, USA.
authors.forename: Ruma A
authors.initials: RA
authors.lastname: Pengal
authors.forename: Latha P
authors.initials: LP
authors.lastname: Ganesan
authors.forename: Huiqing
authors.initials: H
authors.lastname: Fang
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
authors.forename: Clark L
authors.initials: CL
authors.lastname: Anderson
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016676:Macrophages, Alveolar / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000201:enzymology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D014158:Transcription, Genetic; D020298:U937 Cells
chemical_list: D016328:NF-kappa B; D017452:Receptors, IgG; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases