Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:296 |
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| Enthalten in: |
The Journal of biological chemistry - 296(2021) vom: 07. Jan., Seite 100163 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ceraudo, Emilie [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.08.2021 Date Revised 29.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.RA120.015352 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM318543567 |
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| 100 | 1 | |a Ceraudo, Emilie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 24.08.2021 | ||
| 500 | |a Date Revised 29.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CysLTR2 | |
| 650 | 4 | |a G protein | |
| 650 | 4 | |a G protein–coupled receptor | |
| 650 | 4 | |a biased signaling | |
| 650 | 4 | |a constitutive activity | |
| 650 | 4 | |a signaling | |
| 650 | 4 | |a uveal melanoma | |
| 650 | 4 | |a β-arrestins | |
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| 650 | 7 | |a Green Fluorescent Proteins |2 NLM | |
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| 650 | 7 | |a cysteinyl leukotriene receptor 2 |2 NLM | |
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| 700 | 1 | |a Horioka, Mizuho |e verfasserin |4 aut | |
| 700 | 1 | |a Mattheisen, Jordan M |e verfasserin |4 aut | |
| 700 | 1 | |a Hitchman, Tyler D |e verfasserin |4 aut | |
| 700 | 1 | |a Moore, Amanda R |e verfasserin |4 aut | |
| 700 | 1 | |a Kazmi, Manija A |e verfasserin |4 aut | |
| 700 | 1 | |a Chi, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Sakmar, Thomas P |e verfasserin |4 aut | |
| 700 | 1 | |a Huber, Thomas |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1074/jbc.RA120.015352 |3 Volltext |
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