2. Academic Validation
  3. TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis

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

  • Nat Cell Biol. 2021 Mar;23(3):257-267. doi: 10.1038/s41556-021-00641-w.
Mark Esposito 1,  Cao Fang  # 1,  Katelyn C Cook  # 1,  Nana Park 1,  Yong Wei 1,  Chiara Spadazzi 2,  Dan Bracha 3,  Ramesh T Gunaratna 1,  Gary Laevsky 1,  Christina J DeCoste 1,  Hannah Slabodkin 1,  Clifford P Brangwynne 3 4,  Ileana M Cristea 1,  Yibin Kang 5 6 7
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 2 Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
  • 3 Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
  • 4 Howard Hughes Medical Institute, Princeton University, Princeton, NJ, USA.
  • 5 Department of Molecular Biology, Princeton University, Princeton, NJ, USA. [email protected].
  • 6 Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA. [email protected].
  • 7 Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. [email protected].
  • # Contributed equally.
PMID: 33723425 DOI: 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.

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