Upregulation of N-acetylglucosaminyltransferase-V by heparin-binding EGF-like growth factor induces keratinocyte proliferation and epidermal hyperplasia

Akihiro Kimura, Mika Terao, Arisa Kato, Takaaki Hanafusa, Hiroyuki Murota, Ichiro Katayama, Eiji Miyoshi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Oligosaccharide modification by N-acetylglucosaminyltransferase-V (GnT-V), a glycosyltransferase encoded by the Mgat5 gene that catalyses the formation of β1,6 GlcNAc (N-acetylglucosamine) branches on N-glycans, is thought to be associated with cancer growth and metastasis. Overexpression of GnT-V in cancer cells enhances the signalling of growth factors such as epidermal growth factor (EGF) and transforming growth factor-β by increasing galectin-3 binding to polylactosamine structures on receptor N-glycans. We previously demonstrated that transgenic mice overexpressing GnT-V fail to develop spontaneous tumors in any organs, but phenotypes reminiscent of epithelial-to-mesenchymal transition were observed in their skin. However, the biological function of GnT-V in normal skin remained unknown. In this study, we examined the role of GnT-V in keratinocyte proliferation using GnT-V-deficient mice. Proliferation of human keratinocytes was suppressed by treatment with GnT-V siRNA. Mgat5-/- mouse keratinocytes also showed impaired cell proliferation through the reduction in EGF receptors on the cell surface. Although the skin of Mgat5-/- mice appeared normal, epidermal hyperplasia and proliferation of keratinocytes induced by the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) were downregulated in these mutants. Moreover, a dramatic increase in GnT-V expression was observed by treatment with TPA or heparin-binding EGF-like growth factor (HB-EGF) in normal human epidermal keratinocytes. This increase was inhibited by an EGF receptor inhibitor. These results indicate that a high expression of GnT-V in keratinocytes contributes to HB-EGF-mediated epidermal hyperproliferation by inhibiting endocytosis of EGF receptors bearing β1,6 GlcNAc on their N-glycans. Our findings demonstrate a novel role for GnT-V in epidermal homoeostasis, particularly in hyperproliferative conditions.

Original languageEnglish
Pages (from-to)515-519
Number of pages5
JournalExperimental Dermatology
Volume21
Issue number7
DOIs
Publication statusPublished - 2012 Jul

Keywords

  • Glycosylation
  • GnT-V
  • HB-EGF
  • Hyperproliferation
  • Keratinocytes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology

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