Role for WNT16B in human epidermal keratinocyte proliferation and differentiation.
WNT signalling regulates a variety of cell functions including cell fate, polarity, and differentiation via the canonical or beta-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 beta-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 beta-catenin-independent non-canonical WNT transduction pathway.
Teh
Muy-Teck
MT
Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and London School of Medicine and Dentistry, Queen Mary, University of London, Blizard Building, 4 Newark Street, London, E1 2AT, UK. m.t.teh@qmul.ac.uk
Blaydon
Diana
D
Ghali
Lucy R
LR
Briggs
Victoria
V
Edmunds
Scott
S
Pantazi
Eleni
E
Barnes
Michael R
MR
Leigh
Irene M
IM
Kelsell
David P
DP
Philpott
Michael P
MP
D000255:Adenosine Triphosphate / Q000032:analysis; D000595:Amino Acid Sequence; D002280:Basal Cell Carcinoma; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D005091:Exons; D017930:Genes, Reporter; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000502:physiology*; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000166:cytology; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D006023:Glycoproteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C417262:WNT16 protein, human; D051153:Wnt Proteins; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases