Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis |
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Authors: | Philbert Lee Shangwen Jiang Yuanyuan Li Jiping Yue Xuewen Gou Shao‐Yu Chen Yingming Zhao Markus Schober Minjia Tan Xiaoyang Wu |
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Institution: | 1. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA;2. The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;3. Department of Pharmacology and Toxicology, University of Louisville Health Science Center, Louisville, KY, USA;4. The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA |
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Abstract: | 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 Pkp1 or Ripk4 impairs skin differentiation and enhances epidermal carcinogenesis in vivo. 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. |
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Keywords: | differentiation epidermal progenitor cell skin tumorigenesis |
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