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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4165-4172. Prepublished online as a Blood First Edition Paper on December 11, 2007; DOI 10.1182/blood-2007-08-108886. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-08-108886v1 111/8/4165    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Micucci, F. Articles by Galandrini, R. Search for Related Content PubMed PubMed Citation Articles by Micucci, F. Articles by Galandrini, R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 22, 2007 Accepted December 4, 2007 PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway Federica Micucci, Cristina Capuano, Enzo Marchetti, Mario Piccoli, Luigi Frati, Angela Santoni, and Ricciarda Galandrini* Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci-Bolognettie, Rome, Italy Department of Genetic and Molecular Biology, Sapienza University, Rome, Italy Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy * Corresponding author; email: ricciarda.galandrini{at}uniroma1.it. Although membrane phospholipid phosphatidylinositol-4,5bisphosphate (PIP2) plays a key role as signaling intermediate and coordinator of actin dynamics and vesicle trafficking, it remains completely unknown its involvement in the activation of cytolytic machinery. By live confocal imaging of primary human NK cells expressing the chimeric protein GFP-PH we observed, during effector-target cell interaction, the consumption of a pre-existing PIP2 pool which is critically required for the activation of cytolytic machinery. We identified type I phosphatidylinositol4phosphate-5kinase (PI5KI) and isoforms as the enzymes responsible for PIP2 synthesis in NK cells. By means of shRNA-driven gene silencing we observed that both enzymes are required for the proper activation of NK cytotoxicity and for inositol-1,4,5trisphosphosphate (IP3) generation upon receptor stimulation. In an attempt to elucidate the specific step controlled by PI5KIs we found that lytic granule secretion but not polarization resulted impaired in PI5KI- and -silenced cells. Our findings delineate a novel mechanism implicating PI5KI and isoforms in the synthesis of PIP2 pools critically required for IP3-dependent Ca2+ response and lytic granule release. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Below the NK-cell surface: PIP2 Marco Colonna Blood 2008 111: 3916. [Full Text] [PDF] This article has been cited by other articles: Y. S. Mao, M. Yamaga, X. Zhu, Y. Wei, H.-Q. Sun, J. Wang, M. Yun, Y. Wang, G. Di Paolo, M. Bennett, et al. Essential and unique roles of PIP5K-{gamma} and -{alpha} in Fc{gamma} receptor-mediated phagocytosis J. Cell Biol., January 26, 2009; 184(2): 281 - 296. [Abstract] [Full Text] [PDF]

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