Abstract
Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies have demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, STAP-2 was found to positively regulate LPS/TLR4-mediated signals in macrophages. Disruption of STAP-2 resulted in impaired LPS/TLR4-induced cytokine production and NF-kappaB activation. Conversely, overexpression of STAP-2 enhanced these LPS/TLR4-induced biological activities. STAP-2, particularly its Src homology 2-like domain, bound to both MyD88 and IkappaB kinase (IKK)-alphabeta, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-alphabeta. These interactions augmented MyD88- and/or IKK-alphabeta-dependent signals, leading to enhancement of the NF-kappaB activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-kappaB activation instead of the TNFR-associated factor 6-IL-1R-associated kinase 1 pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / immunology*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cell Line
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Cytokines / biosynthesis
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Electrophoretic Mobility Shift Assay
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I-kappa B Kinase / immunology
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I-kappa B Kinase / metabolism
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Immunoblotting
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Immunoprecipitation
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Interleukin-1 Receptor-Associated Kinases
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Intracellular Signaling Peptides and Proteins / immunology
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Intracellular Signaling Peptides and Proteins / metabolism
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Lipopolysaccharides / immunology
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Macrophages / immunology*
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Macrophages / metabolism
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Mice
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Myeloid Differentiation Factor 88
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NF-kappa B / immunology
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NF-kappa B / metabolism
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology*
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Toll-Like Receptor 4 / immunology*
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Toll-Like Receptor 4 / metabolism
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Transfection
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / immunology
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cytokines
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
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Interleukin-1 Receptor-Associated Kinases
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Protein Serine-Threonine Kinases
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I-kappa B Kinase