SH2-containing inositol phosphatase (SHIP-1) transiently translocates to raft domains and modulates CD16-mediated cytotoxicity in human NK cells

Blood. 2002 Dec 15;100(13):4581-9. doi: 10.1182/blood-2002-04-1058. Epub 2002 Aug 8.


Membrane recruitment of the SH2-containing 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 zeta 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 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody-Dependent Cell Cytotoxicity*
  • Catalytic Domain
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Membrane Microdomains / metabolism*
  • Microscopy, Confocal
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / physiology*
  • Protein Structure, Tertiary
  • Protein Transport
  • Receptors, IgG / immunology*
  • Recombinant Fusion Proteins / physiology


  • Receptors, IgG
  • Recombinant Fusion Proteins
  • Phosphoric Monoester Hydrolases
  • INPPL1 protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases