{"doi":"10.1074/jbc.ra120.015352","title":"Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling","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. 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. The superfamily of G protein–coupled receptors (GPCRs) is the largest gene family encoding cell-signaling transmembrane proteins, and approximately one-quarter of ∼400 nonolfactory GPCRs are therapeutic drug targets. Large-scale genomic analysis has revealed that one in five individuals carries a missense variant (MV) in a clinically relevant GPCR gene. The rate of de novo germline MVs in a GPCR gene is one in every 300 newborns, and one in 7 MVs is observed at a potential functionally relevant site (1Hauser A.S. Chavali S. Masuho I. Jahn L.J. Martemyanov K.A. Gloriam D.E. Babu M.M. Pharmacogenomics of GPCR drug targets.Cell. 2018; 172: 41-54.e19Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). In addition, GPCR genes are commonly mutated in cancer. Somatic mutations are found in 20% of tumor samples, but the lack of specific “hotspot” variants makes it difficult to identify and validate individual receptors as driver oncogenes (2Moore A.R. Ceraudo E. Sher J.J. Guan Y. Shoushtari A.N. Chang M.T. Zhang J.Q. Walczak E.G. Kazmi M.A. Taylor B.S. Huber T. Chi P. Sakmar T.P. Chen Y. Recurrent activating mutations of G-protein-coupled receptor","journal":"Journal of Biological Chemistry","year":2020,"id":66727,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":353500,"name":"Mizuho Horioka","orcid":"0000-0003-0947-2744","position":1,"is_corresponding":false},{"id":353501,"name":"Jordan M. Mattheisen","orcid":"0000-0002-9334-9521","position":2,"is_corresponding":false},{"id":353502,"name":"Tyler D. Hitchman","orcid":"0000-0002-3228-412X","position":3,"is_corresponding":false},{"id":353503,"name":"Amanda R. Moore","orcid":"0000-0003-3864-6387","position":4,"is_corresponding":false},{"id":353504,"name":"Manija A. Kazmi","orcid":"0000-0003-0855-0827","position":5,"is_corresponding":false},{"id":245664,"name":"Ping Chi","orcid":"0000-0002-0159-5531","position":6,"is_corresponding":false},{"id":259330,"name":"Yu Chen","orcid":"0000-0002-0171-3884","position":7,"is_corresponding":false},{"id":353505,"name":"Thomas P. Sakmar","orcid":"0000-0002-2836-8953","position":8,"is_corresponding":false},{"id":353506,"name":"Thomas Huber","orcid":"0000-0002-1844-262X","position":9,"is_corresponding":false},{"id":353499,"name":"Emilie Ceraudo","orcid":"0000-0001-6563-9751","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-18T21:14:50.590588Z","pmid":"33288675","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}