Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission
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- Ryan S. Lach
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
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- Chongxu Qiu
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
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- Erfan Zeyaei Kajbaf
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
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- Naomi Baxter
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
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- Dasol Han
- Neuroscience Research Institute, University of California, Santa Barbara, CA 93106
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- Alex Wang
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
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- Hannah Lock
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
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- Orlando Chirikian
- Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106
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- Beth Pruitt
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
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- Maxwell Z. Wilson
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106
抄録
<jats:p>Wnt signal transduction is controlled by the destruction complex (DC), a condensate comprising scaffold proteins and kinases that regulate β-catenin stability. Overexpressed DC scaffolds undergo liquid–liquid phase separation (LLPS), but DC mesoscale organization at endogenous expression levels and its role in β-catenin processing were previously unknown. Here, we find that DC LLPS is nucleated by the centrosome. Through a combination of CRISPR-engineered custom fluorescent tags, finite element simulations, and optogenetic tools that allow for manipulation of DC concentration and multivalency, we find that centrosomal nucleation drives processing of β-catenin by colocalizing DC components to a single reaction crucible. Enriching GSK3β partitioning on the centrosome controls β-catenin processing and prevents Wnt-driven embryonic stem cell differentiation to mesoderm. Our findings demonstrate the role of nucleators in controlling biomolecular condensates and suggest tight integration between Wnt signal transduction and the cell cycle.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 119 (36), e2204688119-, 2022-08-29
Proceedings of the National Academy of Sciences