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Modulation of Toll‐like receptor 4 signaling by a novel adaptor protein STAP‐2 in macrophages
Author(s) -
Sekine Yuichi,
Tsuji Satoshi,
Ikeda Osamu,
Sugiyama Kenji,
Akira Shizuo,
Yoshimiura Akihiko,
Matsuda Tadashi
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a114-c
Subject(s) - signal transducing adaptor protein , pleckstrin homology domain , tlr4 , microbiology and biotechnology , toll like receptor , sh2 domain , signal transduction , trif , chemistry , proto oncogene tyrosine protein kinase src , receptor , biology , biochemistry , innate immune system
Signal transducing adaptor protein‐2 (STAP‐2) is a recently identified adaptor protein, that contains pleckstrin and Src homology 2 (SH2)‐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‐κB activation. Conversely, overexpression of STAP‐2 enhanced these LPS/TLR4‐induced biological activities. STAP‐2, particularly its SH2‐like domain, bound to both MyD88 and IKK‐α/β, but not TRAF6 or IRAK1, and formed a functional complex composed of MyD88‐STAP‐2‐IKK‐α/β. These interactions augmented MyD88‐ and/or IKK‐α/β‐dependent signals, leading to enhancement of the NF‐κB activity. These results demonstrate that STAP‐2 may constitute an alternative LPS/TLR4 pathway for NF‐κB activation instead of the TRAF6‐IRAK1pathway.