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

Kathryn M. Brumbaugh, Bryce A. Binstadt, Daniel D Billadeau, Renee A. Schoon, Christopher J. Dick, Rosa M. Ten, Paul J. Leibson

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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.

Original languageEnglish (US)
Pages (from-to)1965-1974
Number of pages10
JournalJournal of Experimental Medicine
Volume186
Issue number12
DOIs
StatePublished - Dec 15 1997

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Natural Killer Cells
Protein-Tyrosine Kinases
Natural Killer Cell Receptors
Dominant Genes
Major Histocompatibility Complex
Transfection
Tyrosine
Molecular Biology
T-Lymphocytes
Syk Kinase
3,3',4,5'-tetrahydroxystilbene

ASJC Scopus subject areas

  • Immunology

Cite this

Brumbaugh, K. M., Binstadt, B. A., Billadeau, D. D., Schoon, R. A., Dick, C. J., Ten, R. M., & Leibson, P. J. (1997). Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. Journal of Experimental Medicine, 186(12), 1965-1974. https://doi.org/10.1084/jem.186.12.1965

Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. / Brumbaugh, Kathryn M.; Binstadt, Bryce A.; Billadeau, Daniel D; Schoon, Renee A.; Dick, Christopher J.; Ten, Rosa M.; Leibson, Paul J.

In: Journal of Experimental Medicine, Vol. 186, No. 12, 15.12.1997, p. 1965-1974.

Research output: Contribution to journalArticle

Brumbaugh, Kathryn M. ; Binstadt, Bryce A. ; Billadeau, Daniel D ; Schoon, Renee A. ; Dick, Christopher J. ; Ten, Rosa M. ; Leibson, Paul J. / Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. In: Journal of Experimental Medicine. 1997 ; Vol. 186, No. 12. pp. 1965-1974.
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