© The Rockefeller University Press, 0022-1007/1997/12/1965/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 12, December 15, 1997 1965-1974
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
, and
Paul J. Leibson*
From the * Department of Immunology, and the
Division of Allergy, Mayo Clinic and Foundation, Rochester, Minnesota 55905
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.
Address correspondence to Dr. Paul J. Leibson, Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905. Phone: 507-284-4563; FAX: 507-284-1637; E-mail: leibson.paul{at}mayo.edu
This research was supported by the Mayo Foundation and by grant CA-47752 from the National Institutes of Health.
1 Abbreviations used in this paper: ADCC, antibody-dependent cell-mediated cytotoxicity; ITAM, immunoreceptor tyrosine-based activation motif; KAR, killer cell activating receptor; KARAP, KAR-associated protein; KIR, killer cell inhibitory receptor; PTK, protein tyrosine kinase.
Kathryn M. Brumbaugh and Bryce A. Binstadt contributed equally to this work.

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