Abstract
Although the best-defined function of type II major histocompatibility complex (MHC-II) is presentation of antigenic peptides to T lymphocytes, these molecules can also transduce signals leading alternatively to cell activation or apoptotic death. MHC-II is a heterodimer of two transmembrane proteins, each containing a short cytoplasmic tail that is dispensable for transduction of death signals. This suggests the function of an undefined MHC-II-associated transducer in signaling the death response. Here we describe a novel plasma membrane tetraspanner (MPYS) that is associated with MHC-II and mediates its transduction of death signals. MPYS is unusual among tetraspanners in containing an extended C-terminal cytoplasmic tail (approximately 140 amino acids) with multiple embedded signaling motifs. MPYS is tyrosine phosphorylated upon MHC-II aggregation and associates with inositol lipid and tyrosine phosphatases. Finally, MHC class II-mediated cell death signaling requires MPYS-dependent activation of the extracellular signal-regulated kinase signaling pathway.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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Antibodies, Monoclonal / pharmacology
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Apoptosis* / drug effects
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Calcium Signaling / drug effects
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Cell Line
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Chromatography, Liquid
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Enzyme Activation / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Histocompatibility Antigens Class II / metabolism*
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Lymphoma / enzymology
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Lymphoma / pathology
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Mass Spectrometry
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism*
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Mice
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Molecular Sequence Data
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Nanotechnology
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Phosphorylation / drug effects
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Phosphotyrosine / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrimidines / pharmacology
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Signal Transduction* / drug effects
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Time Factors
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p38 Mitogen-Activated Protein Kinases / metabolism
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src-Family Kinases / metabolism
Substances
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AG 1879
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Antibodies, Monoclonal
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Histocompatibility Antigens Class II
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Membrane Proteins
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Pyrimidines
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Sting1 protein, mouse
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Phosphotyrosine
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src-Family Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases