Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling Journal Article


Authors: Ceraudo, E.; Horioka, M.; Mattheisen, J. M.; Hitchman, T. D.; Moore, A. R.; Kazmi, M. A.; Chi, P.; Chen, Y.; Sakmar, T. P.; Huber, T.
Article 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. © 2021 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
Keywords: proteins; signaling; down-regulation; oncology; therapeutic targets; dermatology; gene encoding; signaling pathways; encoding (symbols); functional properties; malignant transformations; constitutively actives; g protein coupled receptors; operational model
Journal Title: Journal of Biological Chemistry
Volume: 296
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2021-01-01
Start Page: 100163
Language: English
DOI: 10.1074/jbc.RA120.015352
PUBMED: 33288675
PROVIDER: scopus
PMCID: PMC7948404
DOI/URL:
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
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MSK Authors
  1. Yu Chen
    96 Chen
  2. Ping Chi
    90 Chi
  3. Amanda Roxanne Moore
    8 Moore