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

Research output: Contribution to journalArticlepeer-review

119 Scopus citations


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
Issue number12
StatePublished - Dec 15 1997

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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