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Individual phosphorylation sites at the C-terminus of the apelin receptor play different roles in signal transduction
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Chen, Jing, Chen, Xiaoyu, Li, Sheng, Jiang, Yunlu, Mao, Huiling, Zhang, Rumin, Ji, Bingyuan, Yan, Maocai, Cai, Xin and Wang, Chunmei (2020) Individual phosphorylation sites at the C-terminus of the apelin receptor play different roles in signal transduction. Redox Biology . 101629. doi:10.1016/j.redox.2020.101629 (In Press)
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WRAP-Individual-phosphorylation-apelin-receptor-roles-signal-Chen-2020.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (3557Kb) | Preview |
Official URL: https://doi.org/10.1016/j.redox.2020.101629
Abstract
The apelin and Elabela proteins constitute a spatiotemporal double-ligand system that controls apelin receptor (APJ) signal transduction. Phosphorylation of multiple sites within the C-terminus of APJ is essential for the recruitment of β-arrestins. We sought to determine the precise mechanisms by which apelin and Elabela promote APJ phosphorylation, and to elucidate the influence of β-arrestin phosphorylation on G-protein-coupled receptor (GPCR)/β-arrestin-dependent signaling. We used techniques including mass spectrometry (MS), mutation analysis, and bioluminescence resonance energy transfer (BRET) to evaluate the role of phosphorylation sites in APJ-mediated G-protein-dependent and β-dependent signaling. Phosphorylation of APJ occurred at five serine residues in the C-terminal region (Ser335, Ser339, Ser345, Ser348 and Ser369). We also identified two phosphorylation sites in β-arrestin1 and three in β-arrestin2, including three previously identified residues (Ser412, Ser361, and Thr383) and two new sites, Tyr47 in β-arrestin1 and Tyr48 in β-arrestin2. APJ mutations did not affect the phosphorylation of β-arrestins, but it affects the β-arrestin signaling pathway, specifically Ser335 and Ser339. Mutation of Ser335 decreased the ability of the receptor to interact with β-arrestin1/2 and AP2, indicating that APJ affects the β-arrestin signaling pathway by stimulating Elabela. Mutation of Ser339 abolished the capability of the receptor to interact with GRK2 and β-arrestin1/2 upon stimulation with apelin-36, and disrupted receptor internalization and β-arrestin-dependent ERK1/2 activation. Five peptides act on distinct phosphorylation sites at the APJ C-terminus, differentially regulating APJ signal transduction and causing different biological effects. These findings may facilitate screening for drugs to treat cardiovascular and metabolic diseases.
| Item Type: | Journal Article | |||||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Divisions: | Faculty of Medicine > Warwick Medical School | |||||||||||||||||||||
| SWORD Depositor: | Library Publications Router | |||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Phosphorylation, Mass spectrometry, Cellular signal transduction, Bioluminescence, Energy transfer, G proteins | |||||||||||||||||||||
| Journal or Publication Title: | Redox Biology | |||||||||||||||||||||
| Publisher: | Elsevier | |||||||||||||||||||||
| ISSN: | 2213-2317 | |||||||||||||||||||||
| Official Date: | 30 June 2020 | |||||||||||||||||||||
| Dates: |
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| Date of first compliant deposit: | 3 July 2020 | |||||||||||||||||||||
| Article Number: | 101629 | |||||||||||||||||||||
| DOI: | 10.1016/j.redox.2020.101629 | |||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||
| Publication Status: | In Press | |||||||||||||||||||||
| Access rights to Published version: | Open Access | |||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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