@article{183726, keywords = {Animals, Humans, Cell Proliferation, Female, Male, Nuclear Proteins, Cell Line, Tumor, Cell Movement, Breast Neoplasms, Gene Expression Regulation, Neoplastic, Neoplasm Invasiveness, Transforming Growth Factor beta, Adaptor Proteins, Signal Transducing, HEK293 Cells, Mice, SCID, Mice, Inbred NOD, Mice, Nude, Wnt Signaling Pathway, Casein Kinase II, Bone Neoplasms, Prostatic Neoplasms, Wnt3A Protein}, author = {Mark Esposito and Cao Fang and Katelyn Cook and Nana Park and Yong Wei and Chiara Spadazzi and Dan Bracha and Ramesh Gunaratna and Gary Laevsky and Christina DeCoste and Hannah Slabodkin and Clifford Brangwynne and Ileana Cristea and Yibin Kang}, title = {TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis}, 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.

}, year = {2021}, journal = {Nat Cell Biol}, volume = {23}, pages = {257-267}, month = {03/2021}, issn = {1476-4679}, doi = {10.1038/s41556-021-00641-w}, language = {eng}, }