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

• Published in: The Journal of experimental medicine Vol. 186; no. 12; pp. 1965 - 1974
• Main Authors: Brumbaugh, K M, Binstadt, B A, Billadeau, D D, Schoon, R A, Dick, C J, Ten, R M, Leibson, P J
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 15.12.1997
• Subjects: 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
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.186.12.1965

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.