TGF-β-induced DACT1 Biomolecular Condensates Repress Wnt Signaling To Promote Bone Metastasis

The complexity of intracellular signaling requires both a diversity of molecular players and the sequestration of activity to unique compartments within the cell. Recent findings on the role of liquid-liquid phase separation provide a distinct mechanism for spatial segregation of proteins to regulate signaling pathway crosstalk. Here we discover that DACT1 is induced by TGF-β and forms protein condensates in the cytoplasm to repress Wnt signaling. These condensates do not localize to any known organelles but rather exist as phase-separated proteinaceous cytoplasmic bodies. Deletion of intrinsically disordered domains within the DACT1 protein eliminates its ability to both form protein condensates and suppress Wnt signaling. Isolation and mass spectrometry analysis of these particles revealed a complex of protein machinery that sequesters Casein Kinase 2, a Wnt pathway activator. We further demonstrate that DACT1 condensates are maintained in vivo and that DACT1 is critical to breast and prostate cancer bone metastasis.