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

24 Citations (Scopus)

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

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Shc Signaling Adaptor Proteins
Natural Killer Cells
Antibodies
Inositol 1,4,5-Trisphosphate
Cell Communication
Protein-Tyrosine Kinases
Ligation
Tyrosine
Down-Regulation
Phosphorylation
Ligands
Calcium
Cell Line

Keywords

  • Cytotoxicity
  • NK cell
  • Signal transduction

ASJC Scopus subject areas

  • Immunology

Cite this

The adaptor protein shc is involved in the negative regulation of NK cell-mediated cytotoxicity. / Galandrini, Ricciarda; Tassi, Ilaria; Morrone, Stefania; Lanfrancone, Luisa; Pelicci, Piergiuseppe; Piccoli, Mario; Frati, Luigi; Santoni, Angela.

In: European Journal of Immunology, Vol. 31, No. 7, 2001, p. 2016-2025.

Research output: Contribution to journalArticle

Galandrini, Ricciarda ; Tassi, Ilaria ; Morrone, Stefania ; Lanfrancone, Luisa ; Pelicci, Piergiuseppe ; Piccoli, Mario ; Frati, Luigi ; Santoni, Angela. / The adaptor protein shc is involved in the negative regulation of NK cell-mediated cytotoxicity. In: European Journal of Immunology. 2001 ; Vol. 31, No. 7. pp. 2016-2025.
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