Systems approach reveals distinct and shared signaling networks of the four PGE2 receptors in T cells

Anna M Lone; Piero Giansanti; Marthe Jøntvedt Jørgensen; Enio Gjerga; Aurelien Dugourd; Arjen Scholten; Julio Saez-Rodriguez; Albert J R Heck; Kjetil Taskén

doi:10.1126/scisignal.abc8579

Systems approach reveals distinct and shared signaling networks of the four PGE2 receptors in T cells

Anna M Lone, Piero Giansanti, Marthe Jøntvedt Jørgensen, Enio Gjerga, Aurelien Dugourd, Arjen Scholten, Julio Saez-Rodriguez, Albert J R Heck, Kjetil Taskén

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Prostaglandin E₂ (PGE₂) promotes an immunosuppressive microenvironment in cancer, partly by signaling through four receptors (EP₁, EP₂, EP₃, and EP₄) on T cells. Here, we comprehensively characterized PGE₂ signaling networks in helper, cytotoxic, and regulatory T cells using a phosphoproteomics and phosphoflow cytometry approach. We identified ~1500 PGE₂-regulated phosphosites and several important EP_1–4 signaling nodes, including PKC, CK2, PKA, PI3K, and Src. T cell subtypes exhibited distinct signaling pathways, with the strongest signaling in EP₂-stimulated CD8⁺ cells. EP₂ and EP₄, both of which signal through G_αs, induced similar signaling outputs, but with distinct kinetics and intensity. Functional predictions from the observed phosphosite changes revealed PGE₂ regulation of key cellular and immunological processes. Last, network modeling suggested signal integration between the receptors and a substantial contribution from G protein–independent signaling. This study offers a comprehensive view of the different PGE₂-regulated phosphoproteomes in T cell subsets, providing a valuable resource for further research on this physiologically and pathophysiologically important signaling system.

Original language	English
Article number	eabc8579
Pages (from-to)	1-20
Journal	Science Signaling
Volume	14
Issue number	703
DOIs	https://doi.org/10.1126/scisignal.abc8579
Publication status	Published - 5 Oct 2021

Bibliographical note

Funding Information:
We thank J. Solheim and J. Landskron for practical assistance with and advice on the methylation studies. We further thank T. Maruyama at ONO Pharmaceutical Co. Ltd. for providing EP receptor agonists and antagonists. The work was supported by grants from the Norwegian Cancer Society (grant no. 182794 and 215850), The Regional Health Authority for South-Eastern Norway (grant no. 2017119), the Research Council of Norway (grant no. 187615 and 294916), Stiftelsen Kristian Gerhard Jebsen (grant no. SKGJ-MED-09 and SKGJ-MED-19), and the European Union Horizon 2020 program INFRAIA project Epic-XS (project 823839). E. Gjerga and A. Dugourd were supported by the European Union?s Horizon 2020 research and innovation programme (675585 Marie-Curie ITN ?SymBioSys?) and the JRC for Computational Biomedicine, which was partially funded by Bayer.

Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved

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scisignal.abc8579Final published version, 2.19 MBLicence: Taverne

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title = "Systems approach reveals distinct and shared signaling networks of the four PGE2 receptors in T cells",

abstract = "Prostaglandin E2 (PGE2) promotes an immunosuppressive microenvironment in cancer, partly by signaling through four receptors (EP1, EP2, EP3, and EP4) on T cells. Here, we comprehensively characterized PGE2 signaling networks in helper, cytotoxic, and regulatory T cells using a phosphoproteomics and phosphoflow cytometry approach. We identified ~1500 PGE2-regulated phosphosites and several important EP1–4 signaling nodes, including PKC, CK2, PKA, PI3K, and Src. T cell subtypes exhibited distinct signaling pathways, with the strongest signaling in EP2-stimulated CD8+ cells. EP2 and EP4, both of which signal through Gαs, induced similar signaling outputs, but with distinct kinetics and intensity. Functional predictions from the observed phosphosite changes revealed PGE2 regulation of key cellular and immunological processes. Last, network modeling suggested signal integration between the receptors and a substantial contribution from G protein–independent signaling. This study offers a comprehensive view of the different PGE2-regulated phosphoproteomes in T cell subsets, providing a valuable resource for further research on this physiologically and pathophysiologically important signaling system.",

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note = "Funding Information: We thank J. Solheim and J. Landskron for practical assistance with and advice on the methylation studies. We further thank T. Maruyama at ONO Pharmaceutical Co. Ltd. for providing EP receptor agonists and antagonists. The work was supported by grants from the Norwegian Cancer Society (grant no. 182794 and 215850), The Regional Health Authority for South-Eastern Norway (grant no. 2017119), the Research Council of Norway (grant no. 187615 and 294916), Stiftelsen Kristian Gerhard Jebsen (grant no. SKGJ-MED-09 and SKGJ-MED-19), and the European Union Horizon 2020 program INFRAIA project Epic-XS (project 823839). E. Gjerga and A. Dugourd were supported by the European Union?s Horizon 2020 research and innovation programme (675585 Marie-Curie ITN ?SymBioSys?) and the JRC for Computational Biomedicine, which was partially funded by Bayer. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved",

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doi = "10.1126/scisignal.abc8579",

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AU - Dugourd, Aurelien

AU - Scholten, Arjen

AU - Saez-Rodriguez, Julio

AU - Heck, Albert J R

AU - Taskén, Kjetil

N1 - Funding Information: We thank J. Solheim and J. Landskron for practical assistance with and advice on the methylation studies. We further thank T. Maruyama at ONO Pharmaceutical Co. Ltd. for providing EP receptor agonists and antagonists. The work was supported by grants from the Norwegian Cancer Society (grant no. 182794 and 215850), The Regional Health Authority for South-Eastern Norway (grant no. 2017119), the Research Council of Norway (grant no. 187615 and 294916), Stiftelsen Kristian Gerhard Jebsen (grant no. SKGJ-MED-09 and SKGJ-MED-19), and the European Union Horizon 2020 program INFRAIA project Epic-XS (project 823839). E. Gjerga and A. Dugourd were supported by the European Union?s Horizon 2020 research and innovation programme (675585 Marie-Curie ITN ?SymBioSys?) and the JRC for Computational Biomedicine, which was partially funded by Bayer. Publisher Copyright: Copyright © 2021 The Authors, some rights reserved

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N2 - Prostaglandin E2 (PGE2) promotes an immunosuppressive microenvironment in cancer, partly by signaling through four receptors (EP1, EP2, EP3, and EP4) on T cells. Here, we comprehensively characterized PGE2 signaling networks in helper, cytotoxic, and regulatory T cells using a phosphoproteomics and phosphoflow cytometry approach. We identified ~1500 PGE2-regulated phosphosites and several important EP1–4 signaling nodes, including PKC, CK2, PKA, PI3K, and Src. T cell subtypes exhibited distinct signaling pathways, with the strongest signaling in EP2-stimulated CD8+ cells. EP2 and EP4, both of which signal through Gαs, induced similar signaling outputs, but with distinct kinetics and intensity. Functional predictions from the observed phosphosite changes revealed PGE2 regulation of key cellular and immunological processes. Last, network modeling suggested signal integration between the receptors and a substantial contribution from G protein–independent signaling. This study offers a comprehensive view of the different PGE2-regulated phosphoproteomes in T cell subsets, providing a valuable resource for further research on this physiologically and pathophysiologically important signaling system.

AB - Prostaglandin E2 (PGE2) promotes an immunosuppressive microenvironment in cancer, partly by signaling through four receptors (EP1, EP2, EP3, and EP4) on T cells. Here, we comprehensively characterized PGE2 signaling networks in helper, cytotoxic, and regulatory T cells using a phosphoproteomics and phosphoflow cytometry approach. We identified ~1500 PGE2-regulated phosphosites and several important EP1–4 signaling nodes, including PKC, CK2, PKA, PI3K, and Src. T cell subtypes exhibited distinct signaling pathways, with the strongest signaling in EP2-stimulated CD8+ cells. EP2 and EP4, both of which signal through Gαs, induced similar signaling outputs, but with distinct kinetics and intensity. Functional predictions from the observed phosphosite changes revealed PGE2 regulation of key cellular and immunological processes. Last, network modeling suggested signal integration between the receptors and a substantial contribution from G protein–independent signaling. This study offers a comprehensive view of the different PGE2-regulated phosphoproteomes in T cell subsets, providing a valuable resource for further research on this physiologically and pathophysiologically important signaling system.

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DO - 10.1126/scisignal.abc8579

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JF - Science Signaling

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M1 - eabc8579

ER -

Systems approach reveals distinct and shared signaling networks of the four PGE2 receptors in T cells

Abstract

Bibliographical note

UN SDGs

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