The adaptor protein shc is involved in the negative regulation of NK cell-mediated cytotoxicity

✍ Scribed by Ricciarda Galandrini; Ilaria Tassi; Stefania Morrone; Luisa Lanfrancone; Piergiuseppe Pelicci; Mario Piccoli; Luigi Frati; Angela Santoni

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 151 KB
• Volume: 31
• Category: Article
• ISSN: 0014-2980
• DOI: 10.1002/1521-4141(200107)31:7<2016::aid-immu2016>3.0.co;2-w

✦ Synopsis

The activation of protein tyrosine kinase(s) (PTK) is a critical event required for the development of NK cell-mediated cytotoxicity. Here we demonstrate that the adaptor protein shc undergoes tyrosine phosphorylation during the generation of antibody-dependent cellular cytotoxicity (ADCC) and natural killing. In addition, we report that, upon direct or antibodydependent target cell interaction, shc coprecipitates with the Src homology 2 (SH2)containing inositol phosphatase, SHIP. To gain information on the functional role of shc in NK cytotoxicity, we overexpressed wild-type or dominant negative shc constructs in the human NKL cell line. Our findings show a consistent shc-mediated down-regulation of ADCC and natural killing. Such functional effect correlates with a perturbation of the phoshoinositide (PI) metabolism by means of a shc-mediated negative regulation of inositol 1, 4, 5 triphosphate (IP3) generation and intracellular calcium flux upon CD16 ligation. Furthermore, our data show that dominant-negative shc-mediated perturbation of shc/SHIP interaction leads to inhibition of ligand-dependent SHIP recruitment to CD16 ´chain. We suggest that shc plays a role of negative adaptor by modulating SHIP recruitment to activation receptors involved in the generation of NK cytotoxic function.