TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis
Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel la protéine cytoplasmique DACT1 induite par le facteur TGFbêta, en réprimant la signalisation des glycoprotéines Wnt via la formation de condensats biomoléculaires, favorise le développement de métastases osseuses
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.
Nature Cell Biology 2021