Article Figures & Data
Figures
- Fig. 1.
PGE2 signaling regulates phosphorylation of proteins involved in TCR signaling. Phosphosites regulated by PGE2 in the four different phosphoproteomics studies were queried against proteins included in the GO term “T cell receptor signaling pathway” (gray). TCR signaling proteins (green) have phosphosites regulated by PGE2 or one of the EP receptor agonists in one or more of the phosphoproteomics studies. Asterisks indicate proteins not included in GO term TCR signaling (GRAP2 = GADS, NCK1) but known to be involved in TCR signaling and regulated in (Oberprieler et al. 2010)
- Fig. 2.
Overlap in phosphorylation sites regulated in the four studies. Venn diagrams showing the overlap between the four phosphoproteomics studies of PGE2 signaling in T cells. For the (Lone et al., 2021) study, all regulated sites, also from stimulation with individual EP agonists, were included. As evident from this illustration, some of the regulated sites are specific to each study, and some are shared between studies. Left panel does not include de Graaf et al. (2014), which was a targeted study of PKA substrates. Right panel includes all four studies described here.
- Fig. 3.
Schematic showing kinetics of phosphorylation for phosphosites at different relative positions in a phosphorylation cascade. Phosphorylation time courses may in some cases be used to infer the position of a phosphosite in a signaling pathway, with early phosphorylation suggesting a position near the top of a signaling cascade (red) and later phosphorylation suggesting a position further down in the cascade (blue).
Tables
- TABLE 1
Current clinical trials with EP4 antagonists.
This table gives an overview of current clinical trials with EP4 antagonists in cancer. To identify clinical trials, a search was performed on clinicaltrials.gov with the keyword “Prostaglandin E2,” selecting for interventional studies and condition = cancer/neoplasm/tumor. In addition, searches were also performed with the names of all EP4 antagonists listed in the database https://www.guidetopharmacology.org, as well as EP4 antagonists found by searching the NCI Drug Dictionary: https://www.cancer.gov/publications/dictionaries/cancer-drug. Abbreviations: NCI - National Cancer Institute, MSS - microsatellite stable, PD-1 - Programmed death 1, PD-L1 - Programmed Death 1 Ligand 1, NSCLC - Non small-cell lung cancer, DMARD - disease modifying antirheumatic drugs
Trial Number Title Conditions EP4 Antagonist Combination with Status Phase NCT04344795 Phase 1a/1b study of TPST-1495 alone and with Pembrolizumab in subjects with solid tumors Solid tumor, microsatellite stable colorectal cancer, adenocarcinoma of the lung, squamous cell carcinoma of head and neck, bladder cancer, triple-negative breast cancer, gastric cancer TPST-1495 Pembrolizumab Recruiting 1 NCT03658772 Grapiprant and Pembrolizumab in patients with advanced or progressive MSS colorectal cancer Microsatellite stable colorectal cancer Grapiprant Pembrolizumab Recruiting 1 NCT03696212 Grapiprant (ARY-007) and Pembrolizumab in patients with advanced or metastatic post-PD-1/L1 NSCLC adenocarcinoma Non–small-cell lung cancer adenocarcinoma Grapiprant and Pembrolizumab Recruiting 1, 2 NCT02538432 Phase 2 trial of EP4 receptor antagonist AAT-007 (RQ-07; CJ-023,423) in advanced solid tumors Prostate cancer non–small-cell lung cancer breast cancer RQ-00000007 Gemcitabine Withdrawn 2 NCT03163966 A study of the EP4 antagonist CR6086 in combination with methotrexate, in DMARD-naïve patients with early rheumatoid arthritis Rheumatoid arthritis, DMARD-naïve. and early disease patients CR6086 Methotrexate Unknown 2 NCT00957983 EP4 receptor antagonism and prostaglandin E2 in a human headache model Headache, migraine BGC20-1531 Completed 1, 2 - TABLE 2
List of phosphoproteomics studies of PGE2 signaling
The table gives an overview of the studies discussed in this review article. In addition to the four phosphoproteomics studies of PGE2 signaling in T cell, two related articles have also been included. Abbreviations: PMID - PubMed IDentifier, Ti4+ - titanium (IV) ion, IMAC - immobilized metal affinity chromatography.
Study Cell Type Labeling Enrichment Data and Pathway Analysis Approaches Notes Oberprieler et al. (2010). High-resolution mapping of prostaglandin E2–dependent signaling networks identifies a constitutively active PKA signaling node in CD8+CD45RO+ T cells. PMID: 20558615 Primary CD3+ Stable isotope dimethyl labeling PhosphositePlus, NetworKIN, Scansite, Phosida, IceLogo Combined with phosphoflow Giansanti et al. (2013). Interrogating cAMP-dependent kinase signaling in Jurkat T cells via a protein kinase A targeted immune-precipitation phosphoproteomics approach. PMID: 23882029 Jurkat Stable isotope dimethyl labeling PKA motif antibody enrichment Ingenuity Pathway Analysis, Cytoscape, STRING, PhosphoSitePlus de Graaf et al., 2014. Single-step enrichment by Ti4+-IMAC and label-free quantitation enables in-depth monitoring of phosphorylation dynamics with high reproducibility and temporal Resolution. PMID: 24850871 Jurkat Label-free STRING, NetworKIN, IceLogo, Gene Ontology analysis Lone et al., 2021. Systems approach reveals distinct, joint signaling networks of the four PGE2 receptors in T Cells Primary CD4+, CD8+, Tregs Label-free NetworKIN, IceLogo, Phonemes, STRING, PhosphoSitePlus, Predict Functional Phosphosites Combined with phosphoflow
Individual stimulation of 4 PGE2 receptorsGerarduzzi et al. (2014). Quantitative phosphoproteomic analysis of signaling downstream of the prostaglandin E2/G-protein coupled receptor in human synovial fibroblasts: potential antifibrotic networks. PMID: 25223752 Primary synovial fibroblasts Label-free PKA motif antibody enrichment Ingenuity Pathway Analysis Related study Beltejar et al. (2017). Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells. PMID: 28634298 Jurkat Label-free NetPhorest, Predict Functional Phosphosites, STRING, Gene Ontology Analysis Related study.
Combined stimulation with PDE inhibitors and PGE2 - TABLE 3
Proteins from GO term T cell receptor signaling pathway whose phosphorylation is regulated by PGE2
The table shows proteins contained in GO term T cell receptor signaling pathway that have one or more phosphosites that are regulated by PGE2 or one of the EP receptor agonists in one or more of the phosphoproteomics studies reviewed here. Commonly used alternative names for the proteins are shown in parenthesis.
TCR Signaling Protein Oberprieler Giansanti de Graaf Lone Conditions Regulated in Lone BRAF ✓ CARD11 (Carma1) ✓ ✓ ✓ CD8 EP1, EP2, EP3, EP4, PGE2 CD247 (CD3ζ) ✓ ✓ CD8 EP1, EP2, EP3 CD3E ✓ ELF1 ✓ FYB1 (ADAP) ✓ ✓ ✓ CD8 EP2, EP4 FYN ✓ CD8 EP2 GATA3 ✓ LCK ✓ ✓ ✓ CD8 EP2 CD4 EP1, EP2, EP3, EP4, PGE2 LCP2 (SLP76) ✓ ✓ CD8 EP2 LIME1 ✓ CD8 EP1, EP2, EP3, EP4, PGE2 MAPK1 ✓ PLCG1 ✓ ✓ CD8 PGE2 PRKD2 ✓ ✓ ✓ CD4 EP4 PTPN22 (LYP) ✓ ✓ CD8 EP2 PTPRC (CD45) ✓ ✓ CD8 EP2 RFTN1 ✓ CD8 EP2 RNF31 ✓ SPN (CD43) ✓ ✓ ✓ CD8 EP1, EP2, EP3, EP4, PGE2 CD4 EP1, EP2, EP3, EP4, PGE2 TESPA1 ✓ CD8 EP2 TRAT1 (TRIM) ✓ WNK1 ✓ ✓ ✓ CD8 EP2, EP4
In this issue
PGE2 Signaling in T Cells
Jump to section
- Article
- Abstract
- Introduction
- Phosphoproteomics and Its Application to Signaling Studies
- Phosphoproteomics Studies of PGE2 Signaling in T Cells
- PKA Signaling and Interaction with TCR Signaling
- Non-PKA Signaling Nodes and Pathways
- Signaling Networks Regulated by PGE2
- Distinct PGE2 Responses Across T Cell Subtypes
- Temporal Patterns in PGE2 Signaling
- Functional Output of PGE2 Signaling in T Cells
- Perspectives and Future Directions
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
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