Abstract
Effector functions mediated by NK cells involve cytotoxicity and transcription-dependent production and release of cytokines and chemokines. Although the JAK/STAT pathway mediates lymphokine-induced transcriptional regulation in NK cells, very little is known about transcriptional regulation induced during cell-cell contact. We demonstrate that the Wiskott-Aldrich syndrome protein (WASp) is an important component for integration of signals leading to nuclear translocation of NFAT2 and NF-kappaB (RelA) during cell-cell contact and NKp46-dependent signaling. This WASp function is independent of its known role in F-actin polymerization and cytoskeletal rearrangement. Absence of WASp results in decreased accumulation of calcineurin, WASp-interacting protein, and molecules upstream of calcium mobilization, i.e., activated ZAP70 and phospholipase C-gamma1, in the disorganized NK cell immune synapse. Production of GM-CSF, but not IFN-gamma, is decreased, while natural cytotoxicity of Wiskott-Aldrich syndrome-NK cells is maintained. Our results indicate that WASp independently regulates its dual functions, i.e., actin cytoskeletal remodeling and transcription in NK cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / metabolism*
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Active Transport, Cell Nucleus / genetics
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Cell Communication / genetics
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Cell Communication / immunology
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Cell Line, Transformed
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Cell Nucleus / metabolism*
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Clone Cells
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Cytoskeleton / metabolism*
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Cytotoxicity, Immunologic / genetics
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DNA-Binding Proteins / metabolism*
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Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
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Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
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Humans
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Interferon-gamma / biosynthesis
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Killer Cells, Natural / enzymology
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lymphocyte Activation / genetics
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Membrane Glycoproteins / physiology
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Membrane Microdomains / enzymology
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Membrane Microdomains / immunology
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Membrane Microdomains / metabolism
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NF-kappa B / metabolism*
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NFATC Transcription Factors
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Natural Cytotoxicity Triggering Receptor 1
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Nuclear Proteins / metabolism*
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Phospholipase C gamma
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Proteins / genetics
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Proteins / physiology*
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Receptors, Immunologic / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Transcription Factor RelA
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Transcription Factors / metabolism*
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Type C Phospholipases / antagonists & inhibitors
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Type C Phospholipases / metabolism
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Wiskott-Aldrich Syndrome / genetics
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Wiskott-Aldrich Syndrome / immunology*
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Wiskott-Aldrich Syndrome / metabolism*
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Wiskott-Aldrich Syndrome Protein
Substances
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Actins
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DNA-Binding Proteins
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Membrane Glycoproteins
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NCR1 protein, human
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NF-kappa B
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NFATC Transcription Factors
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Natural Cytotoxicity Triggering Receptor 1
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Nuclear Proteins
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Proteins
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Receptors, Immunologic
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Transcription Factor RelA
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Transcription Factors
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WAS protein, human
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Wiskott-Aldrich Syndrome Protein
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Interferon-gamma
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Granulocyte-Macrophage Colony-Stimulating Factor
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Type C Phospholipases
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Phospholipase C gamma