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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 15, 2007 Accepted July 23, 2007 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. Horan, Ken-ichi Watanabe, Anne M. Kong, Charles G. Bailey, John E.J. Rasko, Takehiko Sasaki, and Christina A. Mitchell* Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia Department of Pathology and Immunology, Akita University School of Medicine, Akita, Japan Gene and Stem Cell Therapy Program, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Sydney, Australia Cell and Molecular Therapies, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, Australia Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Australia * Corresponding author; email: christina.mitchell{at}med.monash.edu.au. Macrophages phagocytose particles to resolve infections and remove apoptotic cells. Phosphoinositide 3-kinase generates phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) which is restricted to the phagocytic cup, promoting phagocytosis. The PtdIns(3,4,5)P3 5-phosphatase (5-ptase) SHIP1 inhibits phagocytosis. We report here another PtdIns(3,4,5)P3-5-ptase, the 72 kDa-5-phosphatase (72-5ptase), inhibits FcR but not complement-receptor 3 (CR3)-mediated phagocytosis, affecting pseudopod extension and phagosome closure. siRNA knock-down of the 72-5ptase increased FcR but not CR3-stimulated phagocytosis. 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 the cup in response to complement. To determine if 5-ptases focally degrade PtdIns(3,4,5)P3 at the phagocytic cup following specific stimuli, time-lapse imaging of specific biosensors was performed. Transfection of dominant-negative 72-5ptase, or 72-5ptase siRNA resulted in amplified and prolonged PtdIns(3,4,5)P3 at the phagocytic cup, in response to FcR but not CR3 activation. 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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