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The Inositol 5'-Phosphatase SHIP-2 Negatively Regulates IgE-Induced Mast Cell Degranulation and Cytokine Production¹

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

Aggregation of the high-affinity IgE receptor (FcRI) on mast cells initiates signaling pathways leading to degranulation and cytokine release. It has been reported that SHIP-1 negatively regulates FcRI-triggered pathways but it is unknown whether its homologous protein SHIP-2 has the same function. We have used a lentiviral-based RNA interference technique to obtain SHIP-2 knockdown bone marrow-derived mast cells (BMMCs) and have found that elimination of SHIP-2 results in both increased mast cell degranulation and cytokine (IL-4 and IL-13) gene expression upon FcRI stimulation. Elimination of SHIP-2 from BMMCs has no effect on FcRI-triggered calcium flux, tyrosine phosphorylation of MAPKs or in actin depolymerization following activation. Rather, we observe that absence of SHIP-2 results in increased activation of the small GTPase Rac-1 and in enhanced microtubule polymerization upon FcRI engagement. Coimmunoprecipitation experiments in rat basophilic leukemia (RBL 2H3) cells show that SHIP-2 interacts with the FcRI -chain, Gab2 and Lyn and that unlike SHIP-1, it does not associate with SHC in mast cells. Our results report a negative regulatory role of SHIP-2 on mast cell activation that is calcium independent and distinct from the regulation by SHIP-1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Silvia Bolland, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, 12441 Parklawn Drive, Twinbrook 2, Room 217, Rockville, MD 20852. E-mail address: sbolland{at}nih.gov

³ Abbreviations used in this paper: PIP3, phosphatidylinositol 3,4,5-trisphosphate; BMMC, bone marrow-derived mast cell; KD, knockdown; RNAi, RNA interference; shRNA, short hairpin RNA; PLC, phospholipase; SCF, stem cell factor; TNP, trinitrophenyl.