TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis
- 9 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 23 (3), 257-267
- https://doi.org/10.1038/s41556-021-00641-w
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.Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (F31CA192461, F31AI147637, T32GM007388, R01GM114141)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA212410)
- U.S. Department of Defense (BC123187)
This publication has 64 references indexed in Scilit:
- The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroupsNature, 2012
- Cancer to bone: a fatal attractionNature Reviews Cancer, 2011
- Protein Kinase A-mediated 14-3-3 Association Impedes Human Dapper1 to Promote Dishevelled DegradationOnline Journal of Public Health Informatics, 2011
- Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone CellsCancer Cell, 2011
- Genes that mediate breast cancer metastasis to the brainNature, 2009
- Chromatin Immunoprecipitation on Microarray Analysis of Smad2/3 Binding Sites Reveals Roles of ETS1 and TFAP2A in Transforming Growth Factor β SignalingMolecular and Cellular Biology, 2009
- Imaging individual mRNA molecules using multiple singly labeled probesNature Methods, 2008
- Optical imaging of cell mass and growth dynamicsAmerican Journal of Physiology-Cell Physiology, 2008
- TGF‐β1 and WISP‐1/CCN‐4 can regulate each other's activity to cooperatively control osteoblast functionJournal of Cellular Biochemistry, 2008
- TGFβ Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-like 4Cell, 2008