biostudies-literatureLee PUniversity of ChicagoNational Institute of Arthritis and Musculoskeletal and Skin DiseasesScience and Technology Commission of Shanghai MunicipalityAmerican Cancer SocietyNIAAA NIH HHSNCI NIH HHSNational Institutes of HealthNIAMS NIH HHSV Foundation for Cancer ResearchNIH HHSNIGMS NIH HHS1963-1980https://www.ebi.ac.uk/biostudies/studies/S-EPMC5494465biostudies-literatureUnknown36(13)Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Post-translational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen. This approach identified a key signaling event, phosphorylation of a desmosome component, PKP1 (plakophilin-1) by RIPK4 (receptor-interacting serine-threonine kinase 4) during epidermal differentiation. With genome-editing and mouse genetics approach, we show that loss of function of either <i>Pkp1</i> or <i>Ripk4</i> impairs skin differentiation and enhances epidermal carcinogenesis <i>in vivo</i> Phosphorylation of PKP1's N-terminal domain by RIPK4 is essential for their role in epidermal differentiation. Taken together, our study presents a global view of phosphoproteomic changes that occur during epidermal differentiation, and identifies RIPK-PKP1 signaling as novel axis involved in skin stratification and tumorigenesis.The EMBO journalPhosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis.PMC5494465GM007183R01 OD023700AA020265124933‐RSG‐13‐198‐01‐DDCRAR063630AAA021434R01 AR06363015410723100T32 GM007183P30 CA016087R01 AA021434R01 AA020265R01‐AR063630Lee PLi YChen SYTan MGou XJiang SZhao YYue JSchober MWu XfalsePhosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis.Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Post-translational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen. This approach identified a key signaling event, phosphorylation of a desmosome component, PKP1 (plakophilin-1) by RIPK4 (receptor-interacting serine-threonine kinase 4) during epidermal differentiation. With genome-editing and mouse genetics approach, we show that loss of function of either <i>Pkp1</i> or <i>Ripk4</i> impairs skin differentiation and enhances epidermal carcinogenesis <i>in vivo</i> Phosphorylation of PKP1's N-terminal domain by RIPK4 is essential for their role in epidermal differentiation. Taken together, our study presents a global view of phosphoproteomic changes that occur during epidermal differentiation, and identifies RIPK-PKP1 signaling as novel axis involved in skin stratification and tumorigenesis.2017-01-01T00:00:00Z2017 Jul2026-05-05T09:45:06.047Z2019-03-26T23:44:01ZS-EPMC54944652850722510.15252/embj.201695679