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First published online 2 January 2007
doi: 10.1242/jcs.03329

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Role for WNT16B in human epidermal keratinocyte proliferation and differentiation

¹ Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Blizard Building, 4 Newark Street, London, E1 2AT, UK
² Centre for Clinical and Diagnostic Oral Sciences, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Blizard Building, 4 Newark Street, London, E1 2AT, UK
³ Bioinformatics Discovery and Analysis, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North) Third Avenue, Harlow, CM19 5AW, UK

^* Author for correspondence (e-mail: m.t.teh{at}qmul.ac.uk)

Accepted 7 November 2006

WNT signalling regulates a variety of cell functions including cell fate, polarity, and differentiation via the canonical or -catenin stabilisation pathway and/or the planar cell polarity or non-canonical pathway. We have previously demonstrated that two isoforms (A and B) from the WNT16 locus have differential expression in various adult human tissues. In this study we show that WNT16B but not WNT16A isoform was upregulated in basal cell carcinomas compared with normal skin. We further investigated the cellular and molecular functions of WNT16B in primary human epidermal keratinocytes and a keratinocyte cell line. Cellular expression of WNT16B neither stabilised -catenin nor activated the lymphoid enhancer factor or T-cell factor transcriptional reporter in primary keratinocytes. WNT16B activated the Jun-N-terminal kinase cascade suggesting the activation of a non-canonical WNT signalling pathway. Constitutive expression of WNT16B significantly enhanced the rate of cell proliferation and prolonged clonogenicity in primary keratinocytes. Silencing WNT16B by RNA interference reduced keratinocyte proliferation. Furthermore, overexpression of WNT16B induced a hyperproliferation phenotype in an organotypical culture system. This work presents the first evidence that WNT16B activates human keratinocyte proliferation possibly via a -catenin-independent non-canonical WNT transduction pathway.

Key words: WNT16 isoforms, Keratinocyte differentiation, -catenin, JNK, TOPFLASH, Basal cell carcinoma

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