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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1058.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4581-4589
IMMUNOBIOLOGY
SH2-containing inositol 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
From the Department of Experimental Medicine and
Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University
"La Sapienza," and Department of Clinical Biochemistry, Istituto
Superiore di Sanita', Rome, Italy; and Istituto Mediterraneo di
Neuroscienze "Neuromed," Pozzilli, Italy.
Membrane recruitment of the SH2containing 5' inositol
phosphatase 1 (SHIP-1) is responsible for the inhibitory signals that modulate phosphatidylinositol 3-kinase (PI3K)-dependent 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  chain after
receptor cross-linking. Moreover, CD16 stimulation on human primary
natural killer (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 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
codistribution with aggregated rafts where CD16 receptor also
colocalizes. 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 that 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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