Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages.

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 Terms:
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
J. Immunol.
Date: Jan. 01, 2006
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