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Phosphorylation of Pkp1 by RIPK 4 regulates epidermal differentiation and skin tumorigenesis
Author(s) -
Lee Philbert,
Jiang Shangwen,
Li Yuanyuan,
Yue Jiping,
Gou Xuewen,
Chen ShaoYu,
Zhao Yingming,
Schober Markus,
Tan Minjia,
Wu Xiaoyang
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695679
Subject(s) - biology , microbiology and biotechnology , phosphorylation , kinome , cellular differentiation , phosphoproteomics , stem cell , carcinogenesis , protein phosphorylation , protein kinase a , genetics , gene , cancer
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, PKP 1 (plakophilin‐1) by RIPK 4 (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 PKP 1's N‐terminal domain by RIPK 4 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 ‐ PKP 1 signaling as novel axis involved in skin stratification and tumorigenesis.