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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4480-4491. Prepublished online as a Blood First Edition Paper on August 6, 2007; DOI 10.1182/blood-2007-02-073874. This Article Full Text Full Text (PDF) Supplemental Videos All Versions of this Article: blood-2007-02-073874v1 110/13/4480    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Horan, K. A. Articles by Mitchell, C. A. Search for Related Content PubMed PubMed Citation Articles by Horan, K. A. Articles by Mitchell, C. A. Related Collections Cytoskeleton Signal Transduction Immunobiology Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES Regulation of FcR-stimulated phagocytosis by the 72-kDa inositol polyphosphate 5-phosphatase: SHIP1, but not the 72-kDa 5-phosphatase, regulates complement receptor 3–mediated phagocytosis by differential recruitment of these 5-phosphatases to the phagocytic cup Kristy A. Horan1, Ken-ichi Watanabe2, Anne M. Kong1, Charles G. Bailey3, John E. J. Rasko3,4, Takehiko Sasaki2,5, and Christina A. Mitchell1 1 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia; 2 Department of Pathology and Immunology, Akita University School of Medicine, Hondo, Japan; 3 Gene and Stem Cell Therapy Program, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Newtown, Australia; 4 Cell and Molecular Therapies, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, Australia; and 5 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan Macrophages phagocytose particles to resolve infections and remove apoptotic cells. Phosphoinositide 3-kinase generates phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] is restricted to the phagocytic cup, promoting phagocytosis. The PtdIns(3,4,5)P3 5-phosphatase (5-ptase) Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) inhibits phagocytosis. We report here that another PtdIns(3,4,5)P3-5-ptase, the 72-kDa-5-phosphatase (72-5ptase), inhibits Fc receptor (FcR)– but not complement receptor 3 (CR3)–mediated phagocytosis, affecting pseudopod extension and phagosome closure. In contrast, SHIP1 inhibited FcR and CR3 phagocytosis with greater effects on CR3-stimulated phagocytosis. The 72-5ptase and SHIP1 were both dynamically recruited to FcR-stimulated phagocytic cups, but only SHIP1 was recruited to CR3-stimulated phagocytic cups. To determine whether 5-ptases focally degrade PtdIns(3,4,5)P3 at the phagocytic cup after specific stimuli, time-lapse imaging of specific biosensors was performed. Transfection of dominant-negative 72-5ptase or 72-5ptase small interfering RNA (siRNA) resulted in amplified and prolonged PtdIns(3,4,5)P3 at the phagocytic cup in response to FcR- but not CR3-stimulation. In contrast, macrophages from Ship1–/–/AktPH-GFP transgenic mice exhibited increased and sustained PtdIns(3,4,5)P3 at the cup in response to CR3 activation, with minimal changes to FcR activation. Therefore, 72-5ptase and SHIP1 exhibit specificity in regulating FcR- versus CR3-stimulated phagocytosis by controlling the amplitude and duration of PtdIns(3,4,5)P3 at the phagocytic cup. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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