Phosphorylation barcodes direct biased chemokine signaling at CXCR3

Eiger, Dylan S.; Smith, Jeffrey S.; Shi, Tujin; Stepniewski, Tomasz Maciej; Tsai, Chia-Feng; Honeycutt, Christopher; Boldizsar, Noelia; Gardner, Julia; Nicora, Carrie D.; Moghieb, Ahmed M.; Kawakami, Kouki; Choi, Issac; Hicks, Chloe; Zheng, Kevin; Warman, Anmol; Alagesan, Priya; Knape, Nicole M.; Huang, Ouwen; Silverman, Justin D.; Smith, Richard D.; Inoue, Asuka; Selent, Jana; Jacobs, Jon M.; Rajagopal, Sudarshan

doi:10.1016/j.chembiol.2023.03.006

Phosphorylation barcodes direct biased chemokine signaling at CXCR3

Journal Article · Thu Apr 06 20:00:00 EDT 2023 · Cell Chemical Biology

DOI:https://doi.org/10.1016/j.chembiol.2023.03.006· OSTI ID:3006969

^[1]; Smith, Jeffrey S. ^[2]; Shi, Tujin ^[3]; Stepniewski, Tomasz Maciej ^[4]; Tsai, Chia-Feng ^[1]; Honeycutt, Christopher ^[3]; Boldizsar, Noelia ^[1]; Gardner, Julia ^[1]; ^[3]; Moghieb, Ahmed M. ^[5]; Kawakami, Kouki ^[6]; Choi, Issac ^[1]; Hicks, Chloe ^[1]; Zheng, Kevin ^[7]; Warman, Anmol ^[1]; Alagesan, Priya ^[1]; ^[1]; Huang, Ouwen ^[1]; Silverman, Justin D. ^[8]; ^[3] more »

Duke Univ., Durham, NC (United States)
Massachusetts General Hospital, Boston, MA (United States); Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States); Beth Israel Deaconess Medical Center, Boston, MA (United States); Boston Children’s Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Pompeu Fabra Univ. (UPF), Barcelona (Spain)
GlaxoSmithKline, Collegeville, PA (United States)
Tohoku Univ., Sendai (Japan)
Harvard Medical School, Boston, MA (United States)
Pennsylvania State Univ., University Park, PA (United States)
Duke Univ., Durham, NC (United States); Tohoku Univ., Sendai (Japan)

Chemokine receptors, a group of G protein-coupled receptors (GPCRs), interact with transducers such as G proteins, ß-arrestins, and GPCR kinases (GRKs). In the chemokine system, many chemokine agonists act as “biased agonists” that preferentially activate distinct signaling effectors when binding to the same receptor, resulting in distinct physiological effects. Although one third of FDA-approved drugs target GPCRs, there has been limited success in targeting the chemokine system. Currently, there is little evidence that differential receptor phosphorylation, or “phosphorylation barcodes,” direct these biased responses at chemokine receptors. To address this knowledge gap, we used mass spectrometry to demonstrate that chemokines of CXCR3 promote different ensembles of phosphorylation barcodes that are associated with differential activation of G proteins, ß-arrestins and GRKs. Chemokine stimulation also resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of specific CXCR3 phosphosites altered ß-arrestin conformation and impacted ß-arrestin activation in molecular dynamics simulations. T-cells expressing phosphorylation-deficient CXCR3 mutants resulted in distinct agonist- and receptor-specific chemotactic and signaling profiles that were not completely explained by engagement of G proteins, ß-arrestins, and GRKs alone. In conclusion, our results directly link distinct GPCR phosphorylation patterns with non-redundant chemokine signaling (Figure 1).

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); American Heart Association (AHA)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 3006969

Report Number(s):: PNNL-SA--174068

Journal Information:: Cell Chemical Biology, Journal Name: Cell Chemical Biology Journal Issue: 4 Vol. 30; ISSN 2451-9456

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: English

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Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid μ-opioid receptor desensitization Miess, Elke; Gondin, Arisbel B.; Yousuf, Arsalan Science Signaling, Vol. 11, Issue 539 https://doi.org/10.1126/scisignal.aas9609	journal	July 2018
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Biased agonists of the chemokine receptor CXCR3 differentially signal through Gα _i :β-arrestin complexes Zheng, Kevin; Smith, Jeffrey S.; Eiger, Dylan S. Science Signaling, Vol. 15, Issue 726 https://doi.org/10.1126/scisignal.abg5203	journal	March 2022
CXCR3 Requires Tyrosine Sulfation for Ligand Binding and a Second Extracellular Loop Arginine Residue for Ligand-Induced Chemotaxis Colvin, Richard A.; Campanella, Gabriele S. V.; Manice, Lindsay A. Molecular and Cellular Biology, Vol. 26, Issue 15 https://doi.org/10.1128/MCB.00556-06	journal	August 2006
Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity Griffith, Jason W.; Sokol, Caroline L.; Luster, Andrew D. Annual Review of Immunology, Vol. 32, Issue 1 https://doi.org/10.1146/annurev-immunol-032713-120145	journal	March 2014
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Key phosphorylation sites in GPCR s orchestrate the contribution of β‐Arrestin 1 in ERK 1/2 activation Baidya, Mithu; Kumari, Punita; Dwivedi‐Agnihotri, Hemlata EMBO reports, Vol. 21, Issue 9 https://doi.org/10.15252/embr.201949886	journal	July 2020
Phosphorylation-Dependent Protein-Protein Interaction Modules As Potential Molecular Targets for Cancer Therapy Watanabe, Nobumoto; Osada, Hiroyuki Current Drug Targets, Vol. 13, Issue 13 https://doi.org/10.2174/138945012803530035	journal	October 2012
The Role of CXCR3 and Its Chemokine Ligands in Skin Disease and Cancer Kuo, Paula T.; Zeng, Zhen; Salim, Nazhifah Frontiers in Medicine, Vol. 5 https://doi.org/10.3389/fmed.2018.00271	journal	September 2018
GPCR Signaling Regulation: The Role of GRKs and Arrestins Gurevich, Vsevolod V.; Gurevich, Eugenia V. Frontiers in Pharmacology, Vol. 10 https://doi.org/10.3389/fphar.2019.00125	journal	February 2019

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Phosphorylation barcodes direct biased chemokine signaling at CXCR3

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