ArticlePLoS genetics2015
Functional Divergence in the Role of N-Linked Glycosylation in Smoothened Signaling.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 50 citations in OpenAlex.
- Receptor allostery promotes context-specific Sonic Hedgehog signaling during embryonic development.Nature communications · 2026Article
- Domain-specific N-glycosylation of the adhesion G-protein-coupled receptor ADGRG6 N-terminal fragment regulates trafficking, proteolytic processing, and signaling.Molecular biology of the cell · 2025Article
- Functional Divergence for N-Linked Glycosylation Sites in Equine Lutropin/Choriogonadotropin Receptors.Current issues in molecular biology · 2025Article
- The N-Linked Glycosylation Site N201 in eel Lutropin/Choriogonadotropin Receptor Is Uniquely Indispensable for cAMP Responsiveness and Receptor Surface Loss, but Not pERK1/2 Activity.Current issues in molecular biology · 2025Article
- N-Glycosylation Modification of Fzd4 Is Essential for the Fzd4-Wnt-β-Catenin Signalling Axis.Journal of cellular and molecular medicine · 2025Article
- Multiomic profiling of medulloblastoma reveals subtype-specific targetable alterations at the proteome and N-glycan level.Nature communications · 2024Article
- Article
- Fully activated structure of the sterol-bound Smoothened GPCR-Gi protein complex.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- GRAMD1/ASTER-mediated cholesterol transport promotes Smoothened cholesterylation at the endoplasmic reticulum.The EMBO journal · 2023Article
- Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer.Journal of personalized medicine · 2022Review
- The cation-π interaction in cysteine-rich domain of Smoothened is critical for its cholesterylation and function.Acta biochimica et biophysica Sinica · 2022Article
- TMED2 binding restricts SMO to the ER and Golgi compartments.PLoS biology · 2022Article
- E3 ubiquitin ligase Wwp1 regulates ciliary dynamics of the Hedgehog receptor Smoothened.The Journal of cell biology · 2021Article
- Post-Translational Modifications of G Protein-Coupled Receptors Control Cellular Signaling Dynamics in Space and Time.Pharmacological reviews · 2021Review
- Role of N-Linked Glycosylation in PKR2 Trafficking and Signaling.Frontiers in neuroscience · 2021Article
- Expression and Characterization of Relaxin Family Peptide Receptor 1 Variants.Frontiers in pharmacology · 2021Article
- Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.Nature chemical biology · 2020Article
- Mechanistic Insights into the Generation and Transduction of Hedgehog Signaling.Trends in biochemical sciences · 2020Review
- G Protein-Coupled Receptors in the Sweet Spot: Glycosylation and other Post-translational Modifications.ACS pharmacology & translational science · 2020Review
- Functional analysis of glycosylation using Drosophila melanogaster.Glycoconjugate journal · 2020Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice.
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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.