Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases
- PMID: 29438012
- PMCID: PMC6404747
- DOI: 10.1126/scisignal.aan8660
Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases
Abstract
Hedgehog (Hh) induces signaling by promoting the reciprocal trafficking of its receptor Patched (Ptc) and the signal transducer Smoothened (Smo), which is inhibited by Ptc, at the cell surface. We identified Smurf family E3 ubiquitin ligases as essential for Smo ubiquitylation and cell surface clearance and demonstrated that Smurf family members mediate the reciprocal trafficking of Ptc and Smo in Drosophila melanogaster G protein-coupled receptor kinase 2 (Gprk2)-mediated phosphorylation of Smurf promoted Smo ubiquitylation by increasing the recruitment of Smurf to Smo, whereas protein kinase A (PKA)-mediated phosphorylation of Smo caused Smurf to dissociate from Smo, thereby inhibiting Smo ubiquitylation. Smo and Ptc competed for the same pool of Smurf family E3 ubiquitin ligases, and Hh promoted Ptc ubiquitylation and degradation by disrupting the association of Smurf family E3 ubiquitin ligases with Smo and stimulating their binding to Ptc. Our study identifies the E3 ubiquitin ligases that target Smo and provides insight into how Hh regulates the reciprocal trafficking of its receptor and signal transducer.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Conflict of interest statement
Figures
![Fig 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0001.gif)
![Fig 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0002.gif)
![Fig 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0003.gif)
![Fig 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0004.gif)
![Fig 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0005.gif)
![Fig 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0006.gif)
![Fig 7](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0007.gif)
![Fig. 8](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/6404747/bin/nihms-1015458-f0008.gif)
Comment in
-
Grking the Smoothened signal.Sci Signal. 2018 Feb 6;11(516):eaar6377. doi: 10.1126/scisignal.aar6377. Sci Signal. 2018. PMID: 29438011 Review.
Similar articles
-
Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover.PLoS Biol. 2013 Nov;11(11):e1001721. doi: 10.1371/journal.pbio.1001721. Epub 2013 Nov 26. PLoS Biol. 2013. PMID: 24302888 Free PMC article.
-
Control of the dynamics and homeostasis of the Drosophila Hedgehog receptor Patched by two C2-WW-HECT-E3 Ubiquitin ligases.Open Biol. 2015 Oct;5(10):150112. doi: 10.1098/rsob.150112. Open Biol. 2015. PMID: 26446620 Free PMC article.
-
Regulation of Smoothened ubiquitylation and cell surface expression through a Cul4-DDB1-Gβ E3 ubiquitin ligase complex.J Cell Sci. 2018 Aug 1;131(15):jcs218016. doi: 10.1242/jcs.218016. J Cell Sci. 2018. PMID: 29930086 Free PMC article.
-
Regulation of Hedgehog Signal Transduction by Ubiquitination and Deubiquitination.Int J Mol Sci. 2021 Dec 11;22(24):13338. doi: 10.3390/ijms222413338. Int J Mol Sci. 2021. PMID: 34948134 Free PMC article. Review.
-
Mechanisms of Smoothened Regulation in Hedgehog Signaling.Cells. 2021 Aug 20;10(8):2138. doi: 10.3390/cells10082138. Cells. 2021. PMID: 34440907 Free PMC article. Review.
Cited by
-
Phosphatidic acid binding to Patched contributes to the inhibition of Smoothened and Hedgehog signaling in Drosophila wing development.Sci Signal. 2023 Oct 17;16(807):eadd6834. doi: 10.1126/scisignal.add6834. Epub 2023 Oct 17. Sci Signal. 2023. PMID: 37847757 Free PMC article.
-
Smurf1 and Smurf2 mediated polyubiquitination and degradation of RNF220 suppresses Shh-group medulloblastoma.Cell Death Dis. 2023 Aug 3;14(8):494. doi: 10.1038/s41419-023-06025-2. Cell Death Dis. 2023. PMID: 37537194 Free PMC article.
-
GRAMD1/ASTER-mediated cholesterol transport promotes Smoothened cholesterylation at the endoplasmic reticulum.EMBO J. 2023 Feb 1;42(3):e111513. doi: 10.15252/embj.2022111513. Epub 2022 Dec 16. EMBO J. 2023. PMID: 36524353 Free PMC article.
-
High hedgehog signaling is transduced by a multikinase-dependent switch controlling the apico-basal distribution of the GPCR smoothened.Elife. 2022 Sep 9;11:e79843. doi: 10.7554/eLife.79843. Elife. 2022. PMID: 36083801 Free PMC article.
-
Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review.Cell Mol Life Sci. 2022 Apr 29;79(5):266. doi: 10.1007/s00018-022-04233-1. Cell Mol Life Sci. 2022. PMID: 35486193 Free PMC article. Review.
References
-
- Briscoe J, Therond PP, The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14, 418–431 (2013). - PubMed
-
- Ingham PW, McMahon AP, Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15, 3059–3087. (2001). - PubMed
-
- Taipale J, Beachy PA, The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001). - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous