Emilie Ceraudo, Mizuho Horioka, Jordan M Mattheisen, Tyler D Hitchman, Amanda R Moore, Manija A Kazmi, Ping Chi, Yu Chen, Thomas P Sakmar, Thomas Huber
The Journal of biological chemistry 2021 Jan-JunUveal 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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Emilie Ceraudo, Mizuho Horioka, Jordan M Mattheisen, Tyler D Hitchman, Amanda R Moore, Manija A Kazmi, Ping Chi, Yu Chen, Thomas P Sakmar, Thomas Huber. Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling. The Journal of biological chemistry. 2021 Jan-Jun;296:100163
PMID: 33288675
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