Abstract
EAT-2 is an adaptor expressed in innate immune cells, including natural killer (NK) cells. It is closely related to the adaptor SAP, which regulates signaling lymphocyte activation molecule (SLAM)-related receptors by recruiting the kinase FynT to the receptors. Here we have studied the function of EAT-2 in NK cells by creating mice lacking or overexpressing EAT-2. Like SAP, EAT-2 was associated with the SLAM-related receptor 2B4 in NK cells. However, unlike SAP, EAT-2 was an inhibitor of NK cell function. EAT-2 repressed natural cytotoxicity and interferon-gamma secretion by a mechanism involving tyrosine phosphorylation of its C terminus. We have demonstrated a similar function for the adaptor ERT, a newly identified SAP family member expressed in mouse NK cells. These data identify a previously unknown mechanism of NK cell inhibition. Moreover, they indicate that EAT-2 and SAP have distinct and at times opposing functions in natural immunity.
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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Amino Acid Sequence
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Animals
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Animals, Genetically Modified
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Antigens, CD / genetics
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Antigens, CD / physiology
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CHO Cells
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Cell Line
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Cricetinae
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Cytotoxicity, Immunologic
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Down-Regulation
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Interferon-gamma / metabolism
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / physiology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Molecular Sequence Data
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Phosphorylation
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology
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Sequence Alignment
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tyrosine
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src Homology Domains / genetics
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src Homology Domains / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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Cd244a protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Receptors, Immunologic
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Sh2d1a protein, mouse
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Sh2d1b1 protein, mouse
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family
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Transcription Factors
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Tyrosine
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Interferon-gamma