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

Ricciarda Galandrini, Ilaria Tassi, Stefania Morrone, Luisa Lanfrancone, Piergiuseppe Pelicci, Mario Piccoli, Luigi Frati, Angela Santoni

Research output: Contribution to journalArticle

Abstract

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 antibody-dependent 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 ζ 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.

Original languageEnglish
Pages (from-to)2016-2025
Number of pages10
JournalEuropean Journal of Immunology
Volume31
Issue number7
DOIs
Publication statusPublished - 2001

Keywords

  • Cytotoxicity
  • NK cell
  • Signal transduction

ASJC Scopus subject areas

  • Immunology

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