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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