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Significance The phorbol ester 12-O-tetra-decanoylphorbol-13-acetate (TPA) is a well-known tumor promoter in two-stage mouse skin carcinogenesis, but the exact mechanism by which TPA promotes tumorigenesis remains elusive. This study discovered that TPA could stabilize CK1ε, enhance its kinase activity, and induce phosphorylation of LRP6, resulting in the formation of CK1ε–LRP6–axin1 complex, which may bypass the requirement of Wnt–Fzd–Dvl complex. TPA also increased the interaction between β-catenin and TCF4E in a CK1ε/δ-dependent way, and finally led to activation of the Wnt/β-catenin pathway. Our findings reveal a pathway by which TPA activates the Wnt/β-catenin signaling cascade. This pathway may represent a common mechanism for the tumor-promoting activity of some carcinogenic agents., 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.