TY - JOUR
T1 - Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages
AU - Sekine, Yuichi
AU - Yumioka, Taro
AU - Yamamoto, Tetsuya
AU - Muromoto, Ryuta
AU - Imoto, Seiyu
AU - Sugiyma, Kenji
AU - Oritani, Kenji
AU - Shimoda, Kazuya
AU - Minoguchi, Mayu
AU - Akira, Shizuo
AU - Yoshimura, Akihiko
AU - Matsuda, Tadashi
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2006/1/1
Y1 - 2006/1/1
N2 - 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-κB 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 IκB kinase (IKK)-αβ, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-αβ. These interactions augmented MyD88- and/or IKK-αβ-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 TNFR-associated factor 6-IL-1R-associated kinase 1 pathway.
AB - 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-κB 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 IκB kinase (IKK)-αβ, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-αβ. These interactions augmented MyD88- and/or IKK-αβ-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 TNFR-associated factor 6-IL-1R-associated kinase 1 pathway.
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U2 - 10.4049/jimmunol.176.1.380
DO - 10.4049/jimmunol.176.1.380
M3 - Article
C2 - 16365431
AN - SCOPUS:29644441336
VL - 176
SP - 380
EP - 389
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 1
ER -