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-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.
| Original language | English |
|---|---|
| Pages (from-to) | 380-389 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 176 |
| Issue number | 1 |
| Publication status | Published - 2006 Jan 1 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages. / Sekine, Yuichi; Yumioka, Taro; Yamamoto, Tetsuya; Muromoto, Ryuta; Imoto, Seiyu; Sugiyma, Kenji; Oritani, Kenji; Shimoda, Kazuya; Minoguchi, Mayu; Akira, Shizuo; Yoshimura, Akihiko; Matsuda, Tadashi.
In: Journal of Immunology, Vol. 176, No. 1, 01.01.2006, p. 380-389.Research output: Contribution to journal › Article
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=29644441336&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=29644441336&partnerID=8YFLogxK
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 -