DNAX-Activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes

Masakiyo Sakaguchi, Hitoshi Murata, Yumi Aoyama, Toshihiko Hibino, Endy Widya Putranto, I. Made Winarsa Ruma, Yusuke Inoue, Yoshihiko Sakaguchi, Ken-ichi Yamamoto, Rie Kinoshita, Junichiro Futami, Ken Kataoka, Keiji Iwatsuki, Nam Ho Huh

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)23389-23402
Number of pages14
JournalJournal of Biological Chemistry
Volume289
Issue number34
DOIs
Publication statusPublished - 2014

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Keratinocytes
Membrane Proteins
Membranes
Proteins
Advanced Glycosylation End Product-Specific Receptor
Chemical activation
Artificial Receptors
Ligands
Oligomerization
Transformed Cell Line
Phosphorylation
Survival
Caspase 8
Cell growth
Epidermis
Cell Survival
Epithelial Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

DNAX-Activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes. / Sakaguchi, Masakiyo; Murata, Hitoshi; Aoyama, Yumi; Hibino, Toshihiko; Putranto, Endy Widya; Ruma, I. Made Winarsa; Inoue, Yusuke; Sakaguchi, Yoshihiko; Yamamoto, Ken-ichi; Kinoshita, Rie; Futami, Junichiro; Kataoka, Ken; Iwatsuki, Keiji; Huh, Nam Ho.

In: Journal of Biological Chemistry, Vol. 289, No. 34, 2014, p. 23389-23402.

Research output: Contribution to journalArticle

Sakaguchi, Masakiyo ; Murata, Hitoshi ; Aoyama, Yumi ; Hibino, Toshihiko ; Putranto, Endy Widya ; Ruma, I. Made Winarsa ; Inoue, Yusuke ; Sakaguchi, Yoshihiko ; Yamamoto, Ken-ichi ; Kinoshita, Rie ; Futami, Junichiro ; Kataoka, Ken ; Iwatsuki, Keiji ; Huh, Nam Ho. / DNAX-Activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 34. pp. 23389-23402.
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abstract = "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.",
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AU - Murata, Hitoshi

AU - Aoyama, Yumi

AU - Hibino, Toshihiko

AU - Putranto, Endy Widya

AU - Ruma, I. Made Winarsa

AU - Inoue, Yusuke

AU - Sakaguchi, Yoshihiko

AU - Yamamoto, Ken-ichi

AU - Kinoshita, Rie

AU - Futami, Junichiro

AU - Kataoka, Ken

AU - Iwatsuki, Keiji

AU - Huh, Nam Ho

PY - 2014

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