ArticlePLoS biology2012
USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization.
Article in PLoS biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers.
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Who cites it
88 citing papers in PubMed, 127 citations in OpenAlex.
- The Sonic Hedgehog Pathway is Activated in Cushing's Disease with USP8 Mutations.Biochemical genetics · 2026Article
- Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.Neuroscience bulletin · 2026Review
- Deubiquitinase USP8 regulates the spindle assembly checkpoint in oocytes.Science advances · 2026Article
- Smoothened turnover regulated by Hedgehog signaling in Drosophila.bioRxiv : the preprint server for biology · 2026Article
- Adipose tissue-secreted Spz5 promotes distal tumor progression via Toll-6-mediated Hh pathway activation in Drosophila.The EMBO journal · 2025Article
- Proximity based proteomics reveals Git1 as a regulator of Smoothened signaling.bioRxiv : the preprint server for biology · 2025Article
- Mendelian randomization analysis to identify potential drug targets for osteoarthritis.PloS one · 2025Article
- Article
- Review
- Phosphatidic acid binding to Patched contributes to the inhibition of Smoothened and Hedgehog signaling inScience signaling · 2023Article
- Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators.Translational research : the journal of laboratory and clinical medicine · 2023Article
- The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis.Frontiers in endocrinology · 2023Review
- Hedgehog signaling mechanism and role in cancer.Seminars in cancer biology · 2022Review
- Aberrant Cholesterol Metabolism and Wnt/β-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Evolutionary changes in gene expression profiles associated with the coevolution of male and female genital parts among closely related ground beetle species.BMC genomics · 2022Article
- Genetic Basis of ACTH-Secreting Adenomas.International journal of molecular sciences · 2022Review
- Usp8 promotes tumor cell migration through activating the JNK pathway.Cell death & disease · 2022Article
- Cell-Based Assays for Smoothened Ubiquitination and Sumoylation.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Regulation of Smoothened Trafficking and Abundance in Hedgehog Signaling.Frontiers in cell and developmental biology · 2022Review
- Regulation of Hedgehog Signal Transduction by Ubiquitination and Deubiquitination.International journal of molecular sciences · 2021Review
28 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The seven transmembrane protein Smoothened (Smo) is a critical component of the Hedgehog (Hh) signaling pathway and is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hh stimulation. However, it is not clear how Hh regulates Smo accumulation on the cell surface or how Hh regulates the intracellular trafficking of Smo. In addition, little is known about whether ubiquitination is involved in Smo regulation. In this study, we demonstrate that Smo is multi-monoubiquitinated and that Smo ubiquitination is inhibited by Hh and by phosphorylation. Using an in vivo RNAi screen, we identified ubiquitin-specific protease 8 (USP8) as a deubiquitinase that down-regulates Smo ubiquitination. Inactivation of USP8 increases Smo ubiquitination and attenuates Hh-induced Smo accumulation, leading to decreased Hh signaling activity. Moreover, overexpression of USP8 prevents Smo ubiquitination and elevates Smo accumulation, leading to increased Hh signaling activity. Mechanistically, we show that Hh promotes the interaction of USP8 with Smo aa625-753, which covers the three PKA and CK1 phosphorylation clusters. Finally, USP8 promotes the accumulation of Smo at the cell surface and prevents localization to the early endosomes, presumably by deubiquitinating Smo. Our studies identify USP8 as a positive regulator in Hh signaling by down-regulating Smo ubiquitination and thereby mediating Smo intracellular trafficking.
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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.