Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity.
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.
Brumbaugh
K M
KM
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Binstadt
B A
BA
Billadeau
D D
DD
Schoon
R A
RA
Dick
C J
CJ
Ten
R M
RM
Leibson
P J
PJ
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D002118:Calcium / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism*; D005805:Genes, MHC Class I; D007295:Inositol Phosphates / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology; D007700:Kinetics; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D014162:Transfection; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D007295:Inositol Phosphates; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D002118:Calcium