Dishevelled localization and function are differentially regulated by structurally distinct sterols
Summary: The Dishevelled (DVL) protein family forms supramolecular protein and lipid complexes at the cytoplasmic interface of the plasma membrane to regulate tissue patterning, proliferation, cell polarity, and DVL-dependent signaling, such as Wnt/β-catenin. While DVL binding to cholesterol is requ...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225009654 |
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| author | Sonali Sengupta Jazmine D.W. Yaeger Maycie M. Schultz Danielle G. May Kyle J. Roux Kevin R. Francis |
| author_facet | Sonali Sengupta Jazmine D.W. Yaeger Maycie M. Schultz Danielle G. May Kyle J. Roux Kevin R. Francis |
| author_sort | Sonali Sengupta |
| collection | DOAJ |
| description | Summary: The Dishevelled (DVL) protein family forms supramolecular protein and lipid complexes at the cytoplasmic interface of the plasma membrane to regulate tissue patterning, proliferation, cell polarity, and DVL-dependent signaling, such as Wnt/β-catenin. While DVL binding to cholesterol is required for its membrane association, the specific structural requirements and cellular impacts of DVL-sterol association are unclear. We report that sterols found within both natural and pathological conditions cause aberrant DVL activity. In silico and molecular analyses suggested orientation of the β- and α-sterol face within the DVL-PDZ domain regulates DVL-sterol binding. Aberrant sterols impaired DVL2 plasma membrane association, inducing DVL2 nuclear localization via FoxK2. Altered sterol homeostasis also selectively impaired DVL2 protein-protein interactions with impacts on multiple signaling pathways. This work identifies sterol specificity as a regulator of DVL signaling, demonstrates intracellular sterols impact DVL localization and activity, and supports a role for aberrant DVL activity within disorders of sterol metabolism. |
| format | Article |
| id | doaj-art-a43d993065dc401495e48e6450cabcbd |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-a43d993065dc401495e48e6450cabcbd2025-08-20T03:26:35ZengElsevieriScience2589-00422025-06-0128611270410.1016/j.isci.2025.112704Dishevelled localization and function are differentially regulated by structurally distinct sterolsSonali Sengupta0Jazmine D.W. Yaeger1Maycie M. Schultz2Danielle G. May3Kyle J. Roux4Kevin R. Francis5Cellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD 57104, USACellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD 57104, USACellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD 57104, USAEnabling Technologies Group, Sanford Research, Sioux Falls, SD 57104, USAEnabling Technologies Group, Sanford Research, Sioux Falls, SD 57104, USA; Department of Pediatrics, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USACellular Therapies and Stem Cell Biology Group, Sanford Research, Sioux Falls, SD 57104, USA; Department of Pediatrics, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA; Corresponding authorSummary: The Dishevelled (DVL) protein family forms supramolecular protein and lipid complexes at the cytoplasmic interface of the plasma membrane to regulate tissue patterning, proliferation, cell polarity, and DVL-dependent signaling, such as Wnt/β-catenin. While DVL binding to cholesterol is required for its membrane association, the specific structural requirements and cellular impacts of DVL-sterol association are unclear. We report that sterols found within both natural and pathological conditions cause aberrant DVL activity. In silico and molecular analyses suggested orientation of the β- and α-sterol face within the DVL-PDZ domain regulates DVL-sterol binding. Aberrant sterols impaired DVL2 plasma membrane association, inducing DVL2 nuclear localization via FoxK2. Altered sterol homeostasis also selectively impaired DVL2 protein-protein interactions with impacts on multiple signaling pathways. This work identifies sterol specificity as a regulator of DVL signaling, demonstrates intracellular sterols impact DVL localization and activity, and supports a role for aberrant DVL activity within disorders of sterol metabolism.http://www.sciencedirect.com/science/article/pii/S2589004225009654Natural sciencesBiological sciencesBiochemistry |
| spellingShingle | Sonali Sengupta Jazmine D.W. Yaeger Maycie M. Schultz Danielle G. May Kyle J. Roux Kevin R. Francis Dishevelled localization and function are differentially regulated by structurally distinct sterols iScience Natural sciences Biological sciences Biochemistry |
| title | Dishevelled localization and function are differentially regulated by structurally distinct sterols |
| title_full | Dishevelled localization and function are differentially regulated by structurally distinct sterols |
| title_fullStr | Dishevelled localization and function are differentially regulated by structurally distinct sterols |
| title_full_unstemmed | Dishevelled localization and function are differentially regulated by structurally distinct sterols |
| title_short | Dishevelled localization and function are differentially regulated by structurally distinct sterols |
| title_sort | dishevelled localization and function are differentially regulated by structurally distinct sterols |
| topic | Natural sciences Biological sciences Biochemistry |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225009654 |
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