Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation
The Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis through the Gli family of transcription factors. Gli is thought to be activated at the tip of primary cilium, but the underlying mechanism has remained poorly understood. Here, we show that Unc-5...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-12-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/88637 |
| _version_ | 1797390939403059200 |
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| author | Mengmeng Zhou Yuhong Han Jin Jiang |
| author_facet | Mengmeng Zhou Yuhong Han Jin Jiang |
| author_sort | Mengmeng Zhou |
| collection | DOAJ |
| description | The Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis through the Gli family of transcription factors. Gli is thought to be activated at the tip of primary cilium, but the underlying mechanism has remained poorly understood. Here, we show that Unc-51-like kinase 4 (Ulk4), a pseudokinase and a member of the Ulk kinase family, acts in conjunction with another Ulk family member Stk36 to promote Gli2 phosphorylation and Hh pathway activation. Ulk4 interacts with Stk36 through its N-terminal region containing the pseudokinase domain and with Gli2 via its regulatory domain to bridge the kinase and substrate. Although dispensable for Hh-induced Stk36 kinase activation, Ulk4 is essential for Stk36 ciliary tip localization, Gli2 phosphorylation, and activation. In response to Hh, both Ulk4 and Stk36 colocalize with Gli2 at ciliary tip, and Ulk4 and Stk36 depend on each other for their ciliary tip accumulation. We further show that ciliary localization of Ulk4 depends on Stk36 kinase activity and phosphorylation of Ulk4 on Thr1023, and that ciliary tip accumulation of Ulk4 is essential for its function in the Hh pathway. Taken together, our results suggest that Ulk4 regulates Hh signaling by promoting Stk36-mediated Gli2 phosphorylation and activation at ciliary tip. |
| first_indexed | 2024-03-08T23:24:38Z |
| format | Article |
| id | doaj.art-3e88d51026194aef89a44b61da39ed62 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T23:24:38Z |
| publishDate | 2023-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3e88d51026194aef89a44b61da39ed622023-12-14T18:14:13ZengeLife Sciences Publications LtdeLife2050-084X2023-12-011210.7554/eLife.88637Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylationMengmeng Zhou0https://orcid.org/0000-0002-4945-8632Yuhong Han1Jin Jiang2https://orcid.org/0000-0002-5951-372XDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United StatesThe Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis through the Gli family of transcription factors. Gli is thought to be activated at the tip of primary cilium, but the underlying mechanism has remained poorly understood. Here, we show that Unc-51-like kinase 4 (Ulk4), a pseudokinase and a member of the Ulk kinase family, acts in conjunction with another Ulk family member Stk36 to promote Gli2 phosphorylation and Hh pathway activation. Ulk4 interacts with Stk36 through its N-terminal region containing the pseudokinase domain and with Gli2 via its regulatory domain to bridge the kinase and substrate. Although dispensable for Hh-induced Stk36 kinase activation, Ulk4 is essential for Stk36 ciliary tip localization, Gli2 phosphorylation, and activation. In response to Hh, both Ulk4 and Stk36 colocalize with Gli2 at ciliary tip, and Ulk4 and Stk36 depend on each other for their ciliary tip accumulation. We further show that ciliary localization of Ulk4 depends on Stk36 kinase activity and phosphorylation of Ulk4 on Thr1023, and that ciliary tip accumulation of Ulk4 is essential for its function in the Hh pathway. Taken together, our results suggest that Ulk4 regulates Hh signaling by promoting Stk36-mediated Gli2 phosphorylation and activation at ciliary tip.https://elifesciences.org/articles/88637HedgehogUlk4pseudokinaseGli2primary ciliumStk36 |
| spellingShingle | Mengmeng Zhou Yuhong Han Jin Jiang Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation eLife Hedgehog Ulk4 pseudokinase Gli2 primary cilium Stk36 |
| title | Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation |
| title_full | Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation |
| title_fullStr | Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation |
| title_full_unstemmed | Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation |
| title_short | Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation |
| title_sort | ulk4 promotes shh signaling by regulating stk36 ciliary localization and gli2 phosphorylation |
| topic | Hedgehog Ulk4 pseudokinase Gli2 primary cilium Stk36 |
| url | https://elifesciences.org/articles/88637 |
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