Modulation of Tlr4 Signaling by a Novel Adaptor Protein Signal-transducing Adaptor Protein-2 in Macrophages.
From: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Journal of immunology (Baltimore, Md. : 1950)
- Publish Date: Jan 2006
- ISSN: 0022-1767
- Volume: 176
- Issue: 1
- Pages: 380-9
- Medium: Print
- Language: English
- Citation (JAMA): Sekine Yuichi, Yumioka Taro, Yamamoto Tetsuya, et al. Modulation of Tlr4 Signaling by a Novel Adaptor Protein Signal-transducing Adaptor Protein-2 in Macrophages.. J. Immunol. Jan 2006;176:380-9
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.
Mesh Headings (Keywords): Adaptor Proteins, Signal Transducing, Animals, Cell Line, Cytokines, Electrophoretic Mobility Shift Assay, I-kappa B Kinase, Immunoblotting, Immunoprecipitation, Interleukin-1 Receptor-Associated Kinases, Intracellular Signaling Peptides and Proteins, Lipopolysaccharides, Macrophages, Mice, Myeloid Differentiation Factor 88, NF-kappa B, Protein-Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Toll-Like Receptor 4, Transfection, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 16365431
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