ArticlePloS one2013
Hrs promotes ubiquitination and mediates endosomal trafficking of smoothened in Drosophila hedgehog signaling.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 22 citations in OpenAlex.
- Phenotypic analyses, protein localization, and bacteriostatic activity of Drosophila melanogaster transferrin-1.Insect biochemistry and molecular biology · 2022Article
- Regulation of Smoothened Trafficking and Abundance in Hedgehog Signaling.Frontiers in cell and developmental biology · 2022Review
- Review
- Hepatocyte growth factor-regulated tyrosine kinase substrate is essential for endothelial cell polarity and cerebrovascular stability.Cardiovascular research · 2021Article
- Dual functions of Rack1 in regulating Hedgehog pathway.Cell death and differentiation · 2020Article
- DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer.Cancers · 2020Review
- E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.Journal of molecular cell biology · 2019Article
- Genetic and Cell Biology Methods to Study ESCRTs in Drosophila melanogaster.Methods in molecular biology (Clifton, N.J.) · 2019Article
- An intracellular activation of Smoothened that is independent of Hedgehog stimulation inJournal of cell science · 2018Article
- Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway.Cancer research · 2017Article
- Control of Hedgehog Signalling by the Cilia-Regulated Proteasome.Journal of developmental biology · 2016Review
- Smoothened Regulation: A Tale of Two Signals.Trends in pharmacological sciences · 2016Review
- Smoothened regulation in response to Hedgehog stimulation.Frontiers in biology · 2015Article
- The Myopic-Ubpy-Hrs nexus enables endosomal recycling of Frizzled.Molecular biology of the cell · 2015Article
- Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling.Developmental cell · 2015Article
- Regulation of Hedgehog signaling by ubiquitination.Frontiers in biology · 2015Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
In Hedgehog (Hh) signaling, the seven-transmembrane protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation, ubiquitination, and cell surface accumulation. However, it is not clear how Smo cell surface accumulation and intracellular trafficking are regulated. Here, we demonstrate that inactivation of Hrs by deletion or RNAi accumulates Smo in the late endosome that is marked by late endosome markers. Inactivation of Hrs enhances the wing defects caused by dominant-negative Smo. We show that Hrs promotes Smo ubiquitination, deleting the ubiquitin-interacting-motif (UIM) in Hrs abolishes the ability of Hrs to regulate Smo ubiquitination. However, the UIM domain neither recognizes the ubiquitinated Smo nor directly interacts with Smo. Hrs lacking UIM domain still downregulates Smo activity even though to a less extent. We have characterized that the N-terminus of Hrs directly interacts with the PKA/CK1 phosphorylation clusters to prevent Smo phosphorylation and activation, indicating an ubiquitin-independent regulation of Smo by Hrs. Finally, we found that knockdown of Tsg101 accumulates Smo that is co-localized with Hrs and other late endosome markers. Taken together, our data indicate that Hrs mediates Smo trafficking in the late endosome by not only promoting Smo ubiquitination but also blocking Smo phosphorylation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.