Stefan Bonné

Defining desmosomal plakophilin-3 interactions

Plakophilin 3 (PKP3) is a recently described armadillo protein of the desmosomal plaque, which is synthesized in simple and stratified epithelia. We investigated the localization pattern of endogenous and exogenous PKP3 and fragments thereof. The desmosomal binding properties of PKP3 were determined using yeast two-hybrid, coimmunoprecipitation and colocalization experiments. To this end, novel mouse anti-PKP3 mAbs were generated. We found that PKP3 binds all three desmogleins, desmocollin (Dsc) 3a and -3b, and possibly also Dsc1a and -2a. As such, this is the first protein interaction ever observed with a Dsc-b isoform. Moreover, we determined that PKP3 interacts with plakoglobin, desmoplakin (DP) and the epithelial keratin 18. Evidence was found for the presence of at least two DP–PKP3 interaction sites. This finding might explain how lateral DP–PKP interactions are established in the upper layers of stratified epithelia, increasing the size of the desmosome and the number of anchoring points available for keratins. Together, these results show that PKP3, whose epithelial and epidermal desmosomal expression pattern and protein interaction repertoire are broader than those of PKP1 and -2, is a unique multiprotein binding element in the basic architecture of a vast majority of epithelial desmosomes.

The transcription factor ZEB1 (δEF1) represses Plakophilin 3 during human cancer progression

Plakophilin 3 (PKP3) belongs to the p120ctn family of armadillo‐related proteins predominantly functioning in desmosome formation. Here we report that PKP3 is transcriptionally repressed by the E‐cadherin repressor ZEB1 in metastatic cancer cells. ZEB1 physically associates with two conserved E‐box elements in the PKP3 promoter and partially represses the activity of corresponding human and mouse PKP3 promoter fragments in reporter gene assays. In human tumours ZEB1 is upregulated in invasive cancer cells at the tumour–host interface, which is accompanied by downregulation of PKP3 expression levels. Hence, the transcriptional repression of PKP3 by ZEB1 contributes to ZEB1‐mediated disintegration of intercellular adhesion and epithelial to mesenchymal transition.

Serum plakophilin-3 autoreactivity in paraneoplastic pemphigus.

Summary Background  Paraneoplastic pemphigus (PNP) is a malignancy‐associated autoimmune disease in which circulating autoantibodies recognize various polypeptides that constitute the desmosomes and hemidesmosomes of epithelial structures.

Assignment1 of the plakophilin-2 gene (PKP2) and a plakophilin-2 pseudogene (PKP2P1) to human chromosome bands 12p11 and 12p13, respectively, by in situ hybridization

Supported by the Geconcerteerde Onderzoeksactie, the Fund for Scientific Research– Flanders, and the ASLK Verzekeringen, Belgium. S.B. was supported by the Vlaams Instituut voor de bevordering van het Wetenschappelijk-Technologisch Onderzoek in de Industrie. J.v.H. is a postdoctoral fellow with the Fund for Scientific Research-Flanders, and F.v.R. is Research Director with the Fund for Scientific Research-Flanders.