Dapper1 Is A Nucleocytoplasmic Shuttling Protein That Negatively Modulates Wnt Signaling In The Nucleus

Wnt signaling, via the activation of the canonicalβ-catenin and lymphoid enhancer factor/T-cell factor (LEF/TCF) pathway, plays an important role in embryogenesis and cancer development by regulating the expression of genes involved in cell proliferation, differentiation and survival. Dapper1 (Dpr1), as a Dishevelled interactor, has been suggested to modulate Wnt signaling by promoting Dishevelled degradation. Here, we provide evidence that Dpr1 shuttles between the cytoplasm and the nucleus. Although overexpressed Dpr1 was mainly found in the cytoplasm, endogenous Dpr1 were localized over the cell and Wnt1 induced its nuclear export. Treatment with leptomycin B induced nuclear accumulation of both endogenous and overexpressed Dpr1, suggesting that Dpr1 shuttles between the cytoplasma and the nucleus. We further identified the nuclear localization signal and the nuclear export signal within Dpr1. Using reporter assay and in vivo zebrafish embryo assay, we demonstrated that the forced nuclear localization of Dpr1 possessed the ability to antagonize Wnt signaling. Dpr1 interacted withβ-catenin and LEF1 and disrupted their complex formation. Furthermore, Dpr1 could associate with HDAC1 and enhance the LEF1-HDAC1 interaction. Together, our findings suggest that Dpr1 negatively modulates the basal activity of Wnt/β-catenin signaling in the nucleus by keeping LEF1 in the repressive state. Thus, Dpr1 controls Wnt/β-catenin signaling in both the cytoplasm and the nucleus.