Identification of an S100A8 Receptor Neuroplastin-β and its Heterodimer Formation with EMMPRIN

Masakiyo Sakaguchi, Mami Yamamoto, Masashi Miyai, Tatsuo Maeda, Junichiro Hiruma, Hitoshi Murata, Rie Kinoshita, I. Made Winarsa Ruma, Endy Widya Putranto, Yusuke Inoue, Shin Morizane, Nam Ho Huh, Ryoji Tsuboi, Toshihiko Hibino

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


We previously reported a positive feedback loop between S100A8/A9 and proinflammatory cytokines mediated by extracellular matrix metalloproteinase inducer, an S100A9 receptor. Here, we identify neuroplastin-β as an unreported S100A8 receptor. Neuroplastin-β and extracellular matrix metalloproteinase inducer form homodimers and a heterodimer, and they are co-localized on the surface of cultured normal human keratinocytes. Knockdown of both receptors suppressed cell proliferation and proinflammatory cytokine induction. Upon stimulation with S100A8, neuroplastin-β recruited GRB2 and activated extracellular signal-regulated kinase, resulting in keratinocyte proliferation. Keratinocyte proliferation in response to inflammatory stimuli was accelerated in involucrin promoter-driven S100A8 transgenic mice. Further, S100A8 and S100A9 were strongly up-regulated and co-localized in lesional skin of atopic dermatitis patients. Our results indicate that neuroplastin-β and extracellular matrix metalloproteinase inducer form a functional heterodimeric receptor for S100A8/A9 heterodimer, followed by recruitment of specific adaptor molecules GRB2 and TRAF2, and this signaling pathway is involved in activation of both keratinocyte proliferation and skin inflammation in atopic skin. Suppression of this pathway might have potential for treatment of skin diseases associated with chronic inflammation such as atopic dermatitis.

Original languageEnglish
Pages (from-to)2240-2250
Number of pages11
JournalJournal of Investigative Dermatology
Issue number11
Publication statusPublished - Nov 1 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology


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