Biased Constitutive Activity in the Uveal Melanoma Oncogene CYSLTR2 is Unique in CYSLTR2 Germline and Pan-Cancer Human Variome
type: CreativeWork
description: 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 (GPCR) cysteinylleukotriene receptor 2. The mutant CYSLTR2 encodes for 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. In this work, we characterized the functional properties of CysLTR2-L129Q. CysLTR2 signals through the Gq/11/PLC-β pathways, so using a homogenous time resolved fluorescence (HTRF) IP1 accumulation assay, 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 as shown by a bioluminescence resonance energy transfer 2 (BRET2) based β-arrestin recruitment assay. 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 GPCR 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. Furthermore, we learned that CysLTR2 is a significantly mutated GPCR in several other cancers as well. We identified >100 CYSLTR2 missense variants of unknown significance (VUS) in human cancer genomes from available cancer databases, as well as another >100 CYSLTR2 single-nucleotide polymorphisms (SNPs) from exome sequence data. Here, we introduce a proof-of-concept, experi…
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 (GPCR) cysteinylleukotriene receptor 2. The mutant CYSLTR2 encodes for 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. In this work, we characterized the functional properties of CysLTR2-L129Q. CysLTR2 signals through the Gq/11/PLC-β pathways, so using a homogenous time resolved fluorescence (HTRF) IP1 accumulation assay, 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 as shown by a bioluminescence resonance energy transfer 2 (BRET2) based β-arrestin recruitment assay. 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 GPCR 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. Furthermore, we learned that CysLTR2 is a significantly mutated GPCR in several other cancers as well. We identified >100 CYSLTR2 missense variants of unknown significance (VUS) in human cancer genomes from available cancer databases, as well as another >100 CYSLTR2 single-nucleotide polymorphisms (SNPs) from exome sequence data. Here, we introduce a proof-of-concept, experi…
author: Horioka-Duplix, Mizuho
keywords: CysLTR2, G protein-coupled receptors (GPCRs), constitutive activity, beta-arrestin recruitment, activity-based profiling, loss-of-function variants, Life Sciences
date published: 2022-01-01T08:00:00Z
date modified: 2026-07-24T04:11:28Z
provider: Rockefeller
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Rockefeller