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Upregulation of N ‐acetylglucosaminyltransferase‐V by heparin‐binding EGF‐like growth factor induces keratinocyte proliferation and epidermal hyperplasia
Author(s) -
Kimura Akihiro,
Terao Mika,
Kato Arisa,
Hanafusa Takaaki,
Murota Hiroyuki,
Katayama Ichiro,
Miyoshi Eiji
Publication year - 2012
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.1600-0625.2012.01515.x
Subject(s) - downregulation and upregulation , keratinocyte , heparin binding egf like growth factor , epidermal growth factor , keratinocyte growth factor , cell growth , hyperplasia , cancer research , microbiology and biotechnology , chemistry , growth factor , biology , endocrinology , biochemistry , receptor , in vitro , gene
Oligosaccharide modification by N ‐acetylglucosaminyltransferase‐V (GnT‐V), a glycosyltransferase encoded by the Mgat5 gene that catalyses the formation of β1,6 Glc NA c ( 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 si RNA . 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 Glc NA c on their N ‐glycans. Our findings demonstrate a novel role for GnT‐V in epidermal homoeostasis, particularly in hyperproliferative conditions.