JaLCDOI 10.18926/AMO/55582
フルテキストURL 71_6_459.pdf
著者 Sakaguchi, Masakiyo| Kinoshita, Rie| Endy Widya Putranto| I Made Winarsa Ruma| I Wayan Sumardika| Youyi, Chen| Tomonobu, Naoko| Yamamoto, Ken-ichi| Murata, Hitoshi|
抄録 The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE’s cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE’s cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE’s signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.
キーワード receptor for advanced glycation end products RAGE adaptor protein signal transduction inflammatory pathogenesis
Amo Type Review
発行日 2017-12
出版物タイトル Acta Medica Okayama
出版者 Okayama University Medical School
開始ページ 459
終了ページ 465
ISSN 0386-300X
NCID AA00508441
資料タイプ 学術雑誌論文
言語 English
著作権者 CopyrightⒸ 2017 by Okayama University Medical School
論文のバージョン publisher
査読 有り
PubMed ID 29276218
フルテキストURL K0005298_other1.pdf
著者 Sakaguchi, Masakiyo| Murata, Hitoshi| Aoyama, Yumi| Hibino, Toshihiko| Widya Putranto, Endy| Winarsa Ruma, I. Made| Inoue, Yusuke| Sakaguchi, Yoshihiko| Yamamoto, Ken-ichi| Kinoshita, Rie| Futami, Junichiro| Kataoka, Ken| Iwatsuki, Keiji| Huh, Nam-ho|
抄録 The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many inflammatory, degenerative, and hyperproliferative diseases, including cancer. Previously, we revealed mechanisms of downstream signaling from ligand-activated RAGE, which recruits TIRAP/MyD88. Here, we showed that DNAX-activating protein 10 (DAP10), a transmembrane adaptor protein, also binds to RAGE. By artificial oligomerization of RAGE alone or RAGE-DAP10, we found that RAGE-DAP10 heterodimer formation resulted in a marked enhancement of Akt activation, whereas homomultimeric interaction of RAGE led to activation of caspase 8. Normal human epidermal keratinocytes exposed to S100A8/A9, a ligand for RAGE, at a nanomolar concentration mimicked the pro-survival response of RAGE-DAP10 interaction, although at a micromolar concentration, the cells mimicked the pro-apoptotic response of RAGE-RAGE. In transformed epithelial cell lines, A431 and HaCaT, in which endogenous DAP10 was overexpressed, and S100A8/A9, even at a micromolar concentration, led to cell growth and survival due to RAGE-DAP10 interaction. Functional blocking of DAP10 in the cell lines abrogated the Akt phosphorylation from S100A8/A9-activated RAGE, eventually leading to an increase in apoptosis. Finally, S100A8/A9, RAGE, and DAP10 were overexpressed in the psoriatic epidermis. Our findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes.
キーワード Cancer Cell Biology Keratinocyte Psoriasis Receptor for Advanced Glycation End Products (RAGE)
備考 学位審査副論文
発行日 2014-08
出版物タイトル Journal of Biological Chemistry
出版者 American Society for Biochemistry and Molecular
開始ページ 23389
終了ページ 23402
ISSN 0021-9258
NCID AA00251083
資料タイプ 学術雑誌論文
言語 English
OAI-PMH Set 岡山大学
著作権者 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.ja
論文のバージョン publisher
PubMed ID 25002577
DOI 10.1074/jbc.M114.573071
Web of Sience KeyUT 000341505000014
関連URL https://doi.org/10.1074/jbc.M114.573071 http://ousar.lib.okayama-u.ac.jp/54281