TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis.

TitleTGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis.
Publication TypeJournal Article
Year of Publication2021
AuthorsEsposito, M, Fang, C, Cook, KC, Park, N, Wei, Y, Spadazzi, C, Bracha, D, Gunaratna, RT, Laevsky, G, DeCoste, CJ, Slabodkin, H, Brangwynne, CP, Cristea, IM, Kang, Y
JournalNat Cell Biol
Date Published2021 Mar
KeywordsAdaptor Proteins, Signal Transducing, Animals, Bone Neoplasms, Breast Neoplasms, Casein Kinase II, Cell Line, Tumor, Cell Movement, Cell Proliferation, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Male, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoplasm Invasiveness, Nuclear Proteins, Prostatic Neoplasms, Transforming Growth Factor beta, Wnt Signaling Pathway, Wnt3A Protein

<p>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.</p>

Alternate JournalNat Cell Biol
PubMed ID33723425
PubMed Central IDPMC7970447
Grant ListR01 CA212410 / CA / NCI NIH HHS / United States
F31 CA192461 / CA / NCI NIH HHS / United States
F31 AI147637 / AI / NIAID NIH HHS / United States
R01 GM114141 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States