ArticleThe Journal of biological chemistry
Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 50 citations in OpenAlex.
- Does the ERBB/EGF Signaling Network Serve as a Nexus for Oncogenic Signals in Uveal Melanoma?Biomolecules · 2026Review
- Computational design of constitutively active mutants of Dopamine D2 receptor inspired by ligand-independent activation mechanisms.BMC biology · 2026Article
- Mast cell-specific CysLT2 receptor signaling inhibits cysteinyl leukotriene-dependent mast cell activation and type 2 allergic lung inflammation.Cell reports · 2026Article
- Montelukast as a novel therapeutic approach in metastatic uveal melanoma harboring a CYSLTR2 mutation: a translational case report.ESMO open · 2026Article
- Clinical Molecular Pathology and Treatment Developments in Advanced Uveal Melanoma: State of the Art.Oncology research · 2026Review
- Multi-context modeling of driver pathways reveals common and specific mechanisms across 23 cancer types.PLoS computational biology · 2025Article
- Cysteinyl Leukotrienes in Allergic Inflammation.Annual review of pathology · 2025Review
- Hidden water's influence on rhodopsin activation.Biophysical journal · 2024Review
- Biased activation of the vasopressin V2 receptor probed by molecular dynamics simulations, NMR and pharmacological studies.Computational and structural biotechnology journal · 2024Article
- The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence.Science signaling · 2024Review
- Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins.Science advances · 2024Article
- Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation.NPJ systems biology and applications · 2024Article
- The role of circulating tumor DNA in melanomas of the uveal tract.Frontiers in immunology · 2024Review
- Large extraocular extension of a choroidal melanoma with orbital inflammation.American journal of ophthalmology case reports · 2023Article
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- Genetics and RNA Regulation of Uveal Melanoma.Cancers · 2023Review
- Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity.Science signaling · 2022Review
- Review
- Uveal melanoma-associated mutations in PLCβ4 are constitutively activating and promote melanocyte proliferation and tumorigenesis.Science signaling · 2021Article
- Targeting Oncogenic GαCancers · 2021Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Uveal melanoma is the most common eye cancer in adults and is clinically and genetically distinct from skin cutaneous melanoma. In a subset of cases, the oncogenic driver is an activating mutation in CYSLTR2, the gene encoding the G protein-coupled receptor cysteinyl-leukotriene receptor 2 (CysLTR2). The mutant CYSLTR2 encodes for the CysLTR2-L129Q receptor, with the substitution of Leu to Gln at position 129 (3.43). The ability of CysLTR2-L129Q to cause malignant transformation has been hypothesized to result from constitutive activity, but how the receptor could escape desensitization is unknown. Here, we characterize the functional properties of CysLTR2-L129Q. We show that CysLTR2-L129Q is a constitutively active mutant that strongly drives Gq/11 signaling pathways. However, CysLTR2-L129Q only poorly recruits β-arrestin. Using a modified Slack-Hall operational model, we quantified the constitutive activity for both pathways and conclude that CysLTR2-L129Q displays profound signaling bias for Gq/11 signaling pathways while escaping β-arrestin-mediated downregulation. CYSLTR2 is the first known example of a G protein-coupled receptor driver oncogene that encodes a highly biased constitutively active mutant receptor. These results provide new insights into the mechanism of CysLTR2-L129Q oncoprotein signaling and suggest CYSLTR2 as a promising potential therapeutic target in uveal melanoma.
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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.