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Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner.

  • Author(s): Su, Zijie;
  • Song, Jiaxing;
  • Wang, Zhongyuan;
  • Zhou, Liang;
  • Xia, Yuqing;
  • Yu, Shubin;
  • Sun, Qi;
  • Liu, Shan-Shan;
  • Zhao, Liang;
  • Li, Shiyue;
  • Wei, Lei;
  • Carson, Dennis A;
  • Lu, Desheng
  • et al.
Abstract

The tumor promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA) has been defined by its ability to promote tumorigenesis on carcinogen-initiated mouse skin. Activation of Wnt/β-catenin signaling has a decisive role in mouse skin carcinogenesis, but it remains unclear how TPA activates Wnt/β-catenin signaling in mouse skin carcinogenesis. Here, we found that TPA could enhance Wnt/β-catenin signaling in a casein kinase 1 (CK1) ε/δ-dependent manner. TPA stabilized CK1ε and enhanced its kinase activity. TPA further induced the phosphorylation of LRP6 at Thr1479 and Ser1490 and the formation of a CK1ε-LRP6-axin1 complex, leading to an increase in cytosolic β-catenin. Moreover, TPA increased the association of β-catenin with TCF4E in a CK1ε/δ-dependent way, resulting in the activation of Wnt target genes. Consistently, treatment with a selective CK1ε/δ inhibitor SR3029 suppressed TPA-induced skin tumor formation in vivo, probably through blocking Wnt/β-catenin signaling. Taken together, our study has identified a pathway by which TPA activates Wnt/β-catenin signaling.

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