TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis. Author Mark Esposito, Cao Fang, Katelyn Cook, Nana Park, Yong Wei, Chiara Spadazzi, Dan Bracha, Ramesh Gunaratna, Gary Laevsky, Christina DeCoste, Hannah Slabodkin, Clifford Brangwynne, Ileana Cristea, Yibin Kang Publication Year 2021 Type Journal Article Abstract The complexity of intracellular signalling 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 the spatial segregation of proteins to regulate signalling pathway crosstalk. Here, we discover that DACT1 is induced by TGFβ and forms protein condensates in the cytoplasm to repress Wnt signalling. These condensates do not localize to any known organelles but, rather, exist as phase-separated proteinaceous cytoplasmic bodies. The deletion of intrinsically disordered domains within the DACT1 protein eliminates its ability to both form protein condensates and suppress Wnt signalling. 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. Keywords Animals, Nuclear Proteins, Humans, Cell Proliferation, Female, Male, HEK293 Cells, Cell Line, Tumor, Cell Movement, Bone Neoplasms, Breast Neoplasms, Gene Expression Regulation, Neoplastic, Mice, Inbred NOD, Transforming Growth Factor beta, Wnt Signaling Pathway, Adaptor Proteins, Signal Transducing, Mice, Nude, Neoplasm Invasiveness, Prostatic Neoplasms, Mice, SCID, Wnt3A Protein, Casein Kinase II Journal Nat Cell Biol Volume 23 Issue 3 Pages 257-267 Date Published 2021 Mar ISSN Number 1476-4679 DOI 10.1038/s41556-021-00641-w Alternate Journal Nat Cell Biol PMCID PMC7970447 PMID 33723425 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML