Abstract
Impaired adhesion and differentiation of keratinocytes is a hallmark of several skin diseases, but only some of the factors that regulate these processes have been identified. Here, we studied the role of isoform-rich dermokine — a wound- and tumor-regulated protein — in keratinocytes using a combination of multiomics and functional approaches. CRISPR/Cas9-induced knockout of dermokine isoforms in human keratinocytes inhibited differentiation of these cells in 3-dimensional organotypic skin cultures, which was confirmed by quantitative proteomics. In 2-dimensional monocultures, dermokine deficiency affected the proteome and phosphoproteome as revealed by mass spectrometry. We found reduced abundance of differentiation-specific proteins and increased phosphorylation of the cell adhesion protein p120 (catenin δ-1). The adhesive strength of dermokine-knockout keratinocytes was impaired, which was rescued by p120 knockdown or ROCK inhibition. Finally, we verified the correlation between decreased dermokine expression and increased p120 phosphorylation in human non-healing wounds. These results identify dermokine as a regulator of keratinocyte adhesion and differentiation, involving at least in part its effect on p120 phosphorylation and ROCK. Our data point to a function of dermokine in the pathogenesis of chronic wounds.
Authors
Vahap Canbay, Till Wüstemann, Weihua Tian, Tobias A. Beyer, Camilla Reiter Elbæk, Michael Stumpe, Gaetana Restivo, Chatpakorn Christiansen, Anabel Migenda Herranz, Susanne Mailand, Jürg Hafner, Rune Busk Damgaard, Steffen Goletz, Jörn Dengjel, Ulrich auf dem Keller, Chiara Francavilla
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