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

20 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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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