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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 im...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
1997
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199178/ https://www.ncbi.nlm.nih.gov/pubmed/9396765 |
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author | Brumbaugh, Kathryn M. Binstadt, Bryce A. Billadeau, Daniel D. Schoon, Renee A. Dick, Christopher J. Ten, Rosa M. Leibson, Paul J. |
author_facet | Brumbaugh, Kathryn M. Binstadt, Bryce A. Billadeau, Daniel D. Schoon, Renee A. Dick, Christopher J. Ten, Rosa M. Leibson, Paul J. |
author_sort | Brumbaugh, Kathryn M. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2199178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1997 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21991782008-04-16 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. J Exp Med Article 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. The Rockefeller University Press 1997-12-15 /pmc/articles/PMC2199178/ /pubmed/9396765 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article 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 |
title | Functional Role for Syk Tyrosine Kinase in Natural Killer Cell–mediated Natural Cytotoxicity |
title_full | Functional Role for Syk Tyrosine Kinase in Natural Killer Cell–mediated Natural Cytotoxicity |
title_fullStr | Functional Role for Syk Tyrosine Kinase in Natural Killer Cell–mediated Natural Cytotoxicity |
title_full_unstemmed | Functional Role for Syk Tyrosine Kinase in Natural Killer Cell–mediated Natural Cytotoxicity |
title_short | Functional Role for Syk Tyrosine Kinase in Natural Killer Cell–mediated Natural Cytotoxicity |
title_sort | functional role for syk tyrosine kinase in natural killer cell–mediated natural cytotoxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199178/ https://www.ncbi.nlm.nih.gov/pubmed/9396765 |
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