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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1058.
Submitted April 8, 2002
Accepted July 23, 2002
SH2-containing inostiol phosphatase SHIP-1 transiently translocates to raft domains and modulates CD16-mediated cytotoxicity in human NK cells
Ricciarda Galandrini*, Ilaria Tassi, Gianfranco Mattia, Luisa Lenti, Mario Piccoli, Luigi Frati, and Angela Santoni
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University 'La Sapienza', Rome, Italy
Department of Clinical Biochemistry, Istituto Superiore di Sanita', Rome, Italy
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University 'La Sapienza', Rome, Italy; Istituto Mediterraneo di Neuroscienze 'Neuromed', Pozzilli, Italy
* Corresponding author; email: ricciarda.galandrini{at}uniroma1.it.
Membrane recruitment of the SH2-containing 5' inositol phosphatase (SHIP) 1 is responsible for the inhibitory signals that modulate phosphatidylinositol 3-kinase-dependent (PI3-K) signaling pathways. Here we have investigated the molecular mechanisms underlying SHIP-1 activation and its role in CD16-mediated cytotoxicity. We initially demonstrated that a substantial fraction of SHIP-1-mediated 5' inositol phosphatase activity associates with CD16 zeta chain upon receptor cross-linking. Moreover, CD16 stimulation on human primary NK cells induces the rapid and transient translocation of SHIP-1 in the lipid-enriched plasma membrane microdomains termed rafts, where it associates with tyrosine-phosphorylated zeta chain and shc adaptor protein. As evaluated by confocal microscopy, CD16 engagement by reverse antibody-dependent cellular cytotoxicity (ADCC), rapidly induces SHIP-1 redistribution toward the area of NK cell contact with target cells and its co-distribution with aggregated rafts where CD16 receptor also co-localizes. The functional role of SHIP-1 in the modulation of CD16-induced cytotoxicity was explored in NK cells infected with recombinant vaccinia viruses encoding wild-type or catalytic domain deleted mutant SHIP-1. We found a significant SHIP-1-mediated decrease of CD16-induced cytotoxicity which is strictly dependent on its catalytic activity. These data demonstrate that CD16 engagement on NK cells induces membrane targeting and activation of SHIP-1 which acts as negative regulator of ADCC function.
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