Abstract
Natural killer (NK) cells and NKT cells play critical early roles in host defense. Here we show that MIST, an adaptor protein belonging to the SLP-76 family, functions negatively in NK cells but positively in CD4(+)NKT cells. NK-cell receptor-mediated IFN-gamma production was enhanced in NK cells, whereas TCR- or NK-cell receptor-mediated cytokine production was reduced in CD4(+)NKT cells from MIST-deficient mice. These opposite effects of MIST paralleled the exclusive expression of the Src family kinase, Fgr, in NK cells between the 2 cell populations. We further demonstrated that interaction of MIST with Fgr, mediated by the C-terminal proline-rich region of MIST and the SH3 domain of Fgr, was required for the suppression of NK-cell receptor-induced IFN-gamma production. This functional interdependence of signaling molecules demonstrates a new mechanism by which adaptor proteins can act as molecular switches to control diverse responses in different cell populations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Base Sequence
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism*
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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DNA, Complementary / genetics
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Female
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Interferon-gamma / biosynthesis*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism*
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasm Metastasis / physiopathology
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Phenotype
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Phospholipase C gamma / metabolism
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Signal Transduction
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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src Homology Domains
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src-Family Kinases / chemistry
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src-Family Kinases / genetics
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src-Family Kinases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Clnk protein, mouse
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DNA, Complementary
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Proto-Oncogene Proteins
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Interferon-gamma
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proto-oncogene proteins c-fgr
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src-Family Kinases
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Phospholipase C gamma