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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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Official URL: https://doi.org/10.1016/j.redox.2020.101629

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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
Subjects: Q Science > QD Chemistry
Q Science > QP Physiology
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:
DateEvent
30 June 2020Available
29 June 2020Accepted
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:
Project/Grant IDRIOXX Funder NameFunder ID
31600949[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
31271243[NSFC] National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
ZR2018MC005Natural Science Foundation of Shandong Provincehttp://dx.doi.org/10.13039/501100007129
ZR2018PC011Natural Science Foundation of Shandong Provincehttp://dx.doi.org/10.13039/501100007129
2019QL013Shandong Universityhttp://dx.doi.org/10.13039/100009108
J16LE01Department of Science and Technology of Shandong Provincehttp://dx.doi.org/10.13039/100012905
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