ArticleThe Journal of biological chemistry2020
Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 21 citations in OpenAlex.
- Renoprotective effects of tubular glucagon receptor activation mediated by V-ATPase.Science advances · 2026Article
- Article
- Insights into the structure and activation mechanism of some class B1 GPCR family members.Molecular biology reports · 2024Review
- Ras-related Protein in Brain 4A (Rab4A) is Downregulated by miR-496 to inhibit the Progression of Gastric Cancer.Combinatorial chemistry & high throughput screening · 2024Article
- Glucagon and Its Receptors in the Mammalian Heart.International journal of molecular sciences · 2023Review
- Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice.Science advances · 2023Article
- The Nature of Functional Features of Different Classes of G-Protein-Coupled Receptors.Biology · 2022Article
- Review
- Double life: How GRK2 and β-arrestin signaling participate in diseases.Cellular signalling · 2022Review
- Glucagon transiently stimulates mTORC1 by activation of an EPAC/Rap1 signaling axis.Cellular signalling · 2021Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein-coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule-binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR.
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