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

Proc Natl Acad Sci U S A. 2018 Aug 7;115(32):E7522-E7531. doi: 10.1073/pnas.1802422115. Epub 2018 Jul 23.


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.

Keywords: CK1; LRP6; TPA; Wnt/β-catenin signaling; two-stage skin chemical carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / metabolism
  • Carcinogenesis / chemically induced
  • Carcinogenesis / pathology
  • Carcinogens / toxicity*
  • Casein Kinase Idelta / antagonists & inhibitors
  • Casein Kinase Idelta / metabolism*
  • Casein Kinase Iepsilon / antagonists & inhibitors
  • Casein Kinase Iepsilon / metabolism*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Fibroblasts
  • HEK293 Cells
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
  • Mice
  • Phosphorylation
  • Protein Stability / drug effects
  • Purines / pharmacology
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / pathology*
  • Tetradecanoylphorbol Acetate / toxicity*
  • Transcription Factor 4
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / metabolism


  • AXIN1 protein, human
  • Axin Protein
  • CTNNB1 protein, human
  • Carcinogens
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Purines
  • SR-3029
  • TCF4 protein, human
  • Transcription Factor 4
  • Wnt Proteins
  • beta Catenin
  • Casein Kinase Idelta
  • Casein Kinase Iepsilon
  • Tetradecanoylphorbol Acetate