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

K. M. Brumbaugh, B. A. Binstadt, Daniel D Billadeau, R. A. Schoon, C. J. Dick, R. M. Ten, P. J. Leibson

Research output: Contribution to journalArticle

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 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)
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998

Fingerprint

natural killer cells
Cytotoxicity
Natural Killer Cells
Protein-Tyrosine Kinases
tyrosine
cytotoxicity
phosphotransferases (kinases)
Natural Killer Cell Receptors
Dominant Genes
non-specific protein-tyrosine kinase
Gene transfer
Defects
protein-tyrosine kinases
Transfection
T-cells
Tyrosine
Molecular Biology
transfection
gene transfer
T-Lymphocytes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Brumbaugh, K. M., Binstadt, B. A., Billadeau, D. D., Schoon, R. A., Dick, C. J., Ten, R. M., & Leibson, P. J. (1998). Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. FASEB Journal, 12(5).

Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. / Brumbaugh, K. M.; Binstadt, B. A.; Billadeau, Daniel D; Schoon, R. A.; Dick, C. J.; Ten, R. M.; Leibson, P. J.

In: FASEB Journal, Vol. 12, No. 5, 20.03.1998.

Research output: Contribution to journalArticle

Brumbaugh, KM, Binstadt, BA, Billadeau, DD, Schoon, RA, Dick, CJ, Ten, RM & Leibson, PJ 1998, 'Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity', FASEB Journal, vol. 12, no. 5.
Brumbaugh KM, Binstadt BA, Billadeau DD, Schoon RA, Dick CJ, Ten RM et al. Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. FASEB Journal. 1998 Mar 20;12(5).
Brumbaugh, K. M. ; Binstadt, B. A. ; Billadeau, Daniel D ; Schoon, R. A. ; Dick, C. J. ; Ten, R. M. ; Leibson, P. J. / Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity. In: FASEB Journal. 1998 ; Vol. 12, No. 5.
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