a b s t r a c tDermokine-b is abundant in stratified epithelia and in differentiating cultured keratinocytes. In this study, we investigated the role of dermokine-b in differentiation of keratinocytes. Treatment of keratinocytes or skin tumor cells with dermokine-b attenuated phosphorylation of extracellularsignal-regulated kinase (ERK). Exposure of cells to dermokine-b, 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-b-associated protein. Blockage of GRP78 expression by a specific siRNA abrogated actions of dermokine-b. These findings provide novel insights into the physiological significance of dermokine-b in the epidermis.