Multi-omics analysis of keratinocytes reveals dermokine-dependent regulation of cell-cell adhesion via p120

Loss of keratinocyte differentiation is a leading cause in several skin diseases and needs to be controlled in adult homeostasis by for instance growth factors and proteases. Among them, we studied the role of isoform-rich dermokine - a wound- and tumour-related matrix metalloproteinase 10 substrate - via functional multi-omics. We generated dermokine isoform-dependent keratinocyte knockouts and three dimensional (3D) organotypic skin cultures and analyzed changes in their proteome and phosphoproteome by quantitative mass spectrometry. Through functional in vitro assays, we demonstrate that in the absence of dermokine-isoforms, p120 phosphorylation increases while cell-cell adhesion decreases in keratinocytes. Furthermore, we validate the link between decreased dermokine expression and phosphorylated p120-mediated adhesion in non-healing wounds samples derived from patients. Our data reveal a novel dermokine-p120-dependent cell-cell adhesion phenotype in keratinocytes and improve our understanding of wound-edge keratinocytes, expanding the hypothesis that dysregulated wounds resemble cancer.