Dermokine-β impairs ERK signaling through direct binding to GRP78

Dermokine-β is abundant in stratified epithelia and in differentiating cultured keratinocytes. In this study, we investigated the role of dermokine-β in differentiation of keratinocytes. Treatment of keratinocytes or skin tumor cells with dermokine-β attenuated phosphorylation of extracellular-signal-regulated kinase (ERK). Exposure of cells to dermokine-β, as well as its carboxyl-terminus domain peptide, interrupted phosphorylation of ERK and stimulated dermokine gene expression. Inhibition of ERK signaling by its specific inhibitor also increased dermokine expression level. A combination of chemical cross-linking and immunoprecipitation, followed by proteomics analyses, identified glucose-regulated protein 78 (GRP78) as a dermokine-β-associated protein. Blockage of GRP78 expression by a specific siRNA abrogated actions of dermokine-β. These findings provide novel insights into the physiological significance of dermokine-β in the epidermis.