Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity

J Exp Med. 1997 Dec 15;186(12):1965-74. doi: 10.1084/jem.186.12.1965.

Abstract

Natural killer (NK) cells are named based on their natural cytotoxic activity against a variety of target cells. However, the mechanisms by which sensitive targets activate killing have been difficult to study due to the lack of a prototypic NK cell triggering receptor. Pharmacologic evidence has implicated protein tyrosine kinases (PTKs) in natural killing; however, Lck-deficient, Fyn-deficient, and ZAP-70-deficient mice do not exhibit defects in natural killing despite demonstrable defects in T cell function. This discrepancy implies the involvement of other tyrosine kinases. Here, using combined biochemical, pharmacologic, and genetic approaches, we demonstrate a central role for the PTK Syk in natural cytotoxicity. Biochemical analyses indicate that Syk is tyrosine phosphorylated after stimulation with a panel of NK-sensitive target cells. Pharmacologic exposure to piceatannol, a known Syk family kinase inhibitor, inhibits natural cytotoxicity. In addition, gene transfer of dominant-negative forms of Syk to NK cells inhibits natural cytotoxicity. Furthermore, sensitive targets that are rendered NK-resistant by major histocompatibility complex (MHC) class I transfection no longer activate Syk. These data suggest that Syk activation is an early and requisite signaling event in the development of natural cytotoxicity directed against a variety of cellular targets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibody-Dependent Cell Cytotoxicity*
  • Calcium / metabolism
  • Enzyme Precursors / metabolism*
  • Genes, MHC Class I
  • Inositol Phosphates / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Killer Cells, Natural / enzymology*
  • Killer Cells, Natural / immunology
  • Kinetics
  • Mice
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Syk Kinase
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Enzyme Precursors
  • Inositol Phosphates
  • Intracellular Signaling Peptides and Proteins
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • Calcium