# PTGER4

## Overview
PTGER4 is a gene that encodes the prostaglandin E receptor 4 (EP4), a member of the G protein-coupled receptor (GPCR) family. This receptor is integral to various physiological processes, primarily through its interaction with prostaglandin E2 (PGE2). As a transmembrane receptor, EP4 is involved in modulating immune responses, inflammation, and maintaining mucosal integrity. It achieves these functions by coupling with different G proteins, such as Gs and Gi, and interacting with β-arrestins, which influence downstream signaling pathways (Lone2021Systems; Toyoda2018Ligand). The receptor's role extends to acting as a tumor suppressor in B cell lymphomas and influencing cell proliferation in conditions like clear cell renal cell carcinoma (Murn2008Prostaglandin; Zhou2024Cellular). Genetic variations in PTGER4 have been associated with diseases such as Crohn's disease, highlighting its significance in immune regulation and disease susceptibility (Glas2012PTGER4).

## Structure
The human prostaglandin E receptor 4 (PTGER4) is a G protein-coupled receptor (GPCR) characterized by its seven transmembrane alpha-helices, a common feature of GPCRs. The primary structure of PTGER4 includes specific amino acid sequences that are highly conserved among prostanoid receptors, as indicated by sequence alignment studies showing high similarity between human and mouse EP4 receptors (Toyoda2018Ligand). 

The receptor can couple with different G proteins, such as Gs and Gi, and is capable of forming complexes with β-arrestin, which are crucial for its signal transduction properties (Toyoda2018Ligand). Structural modifications, including the deletion of certain regions and the introduction of thermostabilizing mutations, have been employed to facilitate crystallization and study the receptor's structure (Toyoda2018Ligand). 

PTGER4 may undergo post-translational modifications like phosphorylation, which can influence its functional properties. The receptor also has splice variant isoforms, which may affect its activity and interactions. The structural analysis of EP4 includes a snake-plot diagram, which provides insights into the receptor's topology and the conservation of specific residues critical for its function (Toyoda2018Ligand).

## Function
PTGER4 encodes the EP4 receptor, a G-protein-coupled receptor that mediates the effects of prostaglandin E2 (PGE2) in various physiological processes. In healthy human cells, PTGER4 plays a crucial role in modulating immune responses and maintaining mucosal integrity. The EP4 receptor is involved in the regulation of B cell proliferation and survival, acting as a tumor suppressor by negatively regulating B cell receptor (BCR) signaling. This regulation involves counteracting transcriptional activities of NF-κB and AP-1 complexes, which are essential for B cell growth and proliferation (Murn2008Prostaglandin).

In the context of inflammation, PTGER4 is involved in the suppression of pro-inflammatory cytokines such as TNF-α and IL-1β in human monocytic cells, highlighting its role in modulating inflammatory responses (Kashmiry2018The). The EP4 receptor also plays a significant role in maintaining the mucosal barrier in the gastrointestinal tract, promoting epithelial regeneration, and suppressing innate immune responses by downregulating pro-inflammatory cytokines and chemokines (Kabashima2002The). These functions are crucial for maintaining immune homeostasis and protecting against excessive inflammatory damage in tissues.

## Clinical Significance
Alterations in the PTGER4 gene have been implicated in several diseases, particularly in the context of cancer and inflammatory conditions. In B cell lymphomas, PTGER4 acts as a tumor suppressor, with its down-regulation linked to increased tumorigenicity and poor prognosis. The gene's expression is inversely correlated with oncogenes like MYC, and its reduced expression is associated with increased B cell proliferation and lymphoma growth (Murn2008Prostaglandin).

In clear cell renal cell carcinoma (ccRCC), PTGER4 is involved in regulating cell proliferation and lipid metabolism. Low expression levels of PTGER4 in RCC cells are associated with enhanced tumor growth, while overexpression leads to suppressed proliferation and increased cellular senescence (Zhou2024Cellular).

PTGER4 polymorphisms have also been linked to Crohn's disease (CD). Specific single nucleotide polymorphisms (SNPs) in the PTGER4 gene, such as rs7720838, are associated with increased susceptibility to CD and influence disease behavior, particularly stricturing disease (Prager2014PTGER4; Glas2012PTGER4). These genetic variations may affect PTGER4 expression and its role in immune response regulation (Glas2012PTGER4).

## Interactions
PTGER4, also known as the prostaglandin E receptor 4, is a G-protein-coupled receptor that participates in various protein interactions, influencing multiple signaling pathways. One of the key interactions of PTGER4 is with G proteins, specifically Gαs and Gαi, which are involved in the activation of signaling pathways such as adenylyl cyclase and PI3K. This interaction is crucial for the receptor's role in modulating immune responses and inflammation (Lone2021Systems).

PTGER4 also interacts with β-arrestins, which are involved in receptor desensitization and internalization. This interaction can lead to the transactivation of the epidermal growth factor receptor (EGFR) through β-arrestin and Src activation, further triggering pathways like PI3K-Akt and Ras-Raf (Lone2021Systems). These interactions highlight the receptor's involvement in both G protein-dependent and independent signaling pathways.

In addition to these interactions, PTGER4 is implicated in the regulation of gene expression in B cells, where it acts as a candidate tumor suppressor. The receptor's signaling through PGE2 can inhibit B cell proliferation by promoting apoptosis and repressing activating genes, suggesting a complex network of interactions that regulate immune cell function (Murn2008Prostaglandin).


## References


[1. (Prager2014PTGER4) Matthias Prager, Janine Büttner, and Carsten Büning. Ptger4 modulating variants in crohn’s disease. International Journal of Colorectal Disease, 29(8):909–915, May 2014. URL: http://dx.doi.org/10.1007/s00384-014-1881-3, doi:10.1007/s00384-014-1881-3. This article has 11 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00384-014-1881-3)

[2. (Murn2008Prostaglandin) Jernej Murn, Olivier Alibert, Ning Wu, Simon Tendil, and Xavier Gidrol. Prostaglandin e2 regulates b cell proliferation through a candidate tumor suppressor, ptger4. The Journal of Experimental Medicine, 205(13):3091–3103, December 2008. URL: http://dx.doi.org/10.1084/jem.20081163, doi:10.1084/jem.20081163. This article has 58 citations.](https://doi.org/10.1084/jem.20081163)

[3. (Zhou2024Cellular) Lijie Zhou, Youmiao Zeng, Yuanhao Liu, Kaixuan Du, Yongbo Luo, Yiheng Dai, Wenbang Pan, Lailai Zhang, Lei Zhang, Fengyan Tian, and Chaohui Gu. Cellular senescence and metabolic reprogramming model based on bulk/single-cell rna sequencing reveals ptger4 as a therapeutic target for ccrcc. BMC Cancer, April 2024. URL: http://dx.doi.org/10.1186/s12885-024-12234-5, doi:10.1186/s12885-024-12234-5. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12885-024-12234-5)

[4. (Glas2012PTGER4) Jürgen Glas, Julia Seiderer, Darina Czamara, Giulia Pasciuto, Julia Diegelmann, Martin Wetzke, Torsten Olszak, Christiane Wolf, Bertram Müller-Myhsok, Tobias Balschun, Jean-Paul Achkar, M. Ilyas Kamboh, Andre Franke, Richard H. Duerr, and Stephan Brand. Ptger4 expression-modulating polymorphisms in the 5p13.1 region predispose to crohn’s disease and affect nf-κb and xbp1 binding sites. PLoS ONE, 7(12):e52873, December 2012. URL: http://dx.doi.org/10.1371/journal.pone.0052873, doi:10.1371/journal.pone.0052873. This article has 39 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0052873)

[5. (Kashmiry2018The) Alaa Kashmiry, Rothwelle Tate, Giuliana Rotondo, Jillian Davidson, and Dino Rotondo. The prostaglandin ep4 receptor is a master regulator of the expression of pge2 receptors following inflammatory activation in human monocytic cells. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1863(10):1297–1304, October 2018. URL: http://dx.doi.org/10.1016/j.bbalip.2018.07.003, doi:10.1016/j.bbalip.2018.07.003. This article has 16 citations.](https://doi.org/10.1016/j.bbalip.2018.07.003)

[6. (Toyoda2018Ligand) Yosuke Toyoda, Kazushi Morimoto, Ryoji Suno, Shoichiro Horita, Keitaro Yamashita, Kunio Hirata, Yusuke Sekiguchi, Satoshi Yasuda, Mitsunori Shiroishi, Tomoko Shimizu, Yuji Urushibata, Yuta Kajiwara, Tomoaki Inazumi, Yunhon Hotta, Hidetsugu Asada, Takanori Nakane, Yuki Shiimura, Tomoya Nakagita, Kyoshiro Tsuge, Suguru Yoshida, Tomoko Kuribara, Takamitsu Hosoya, Yukihiko Sugimoto, Norimichi Nomura, Miwa Sato, Takatsugu Hirokawa, Masahiro Kinoshita, Takeshi Murata, Kiyoshi Takayama, Masaki Yamamoto, Shuh Narumiya, So Iwata, and Takuya Kobayashi. Ligand binding to human prostaglandin e receptor ep4 at the lipid-bilayer interface. Nature Chemical Biology, 15(1):18–26, December 2018. URL: http://dx.doi.org/10.1038/s41589-018-0131-3, doi:10.1038/s41589-018-0131-3. This article has 87 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41589-018-0131-3)

[7. (Kabashima2002The) Kenji Kabashima, Tomomi Saji, Takahiko Murata, Miyako Nagamachi, Toshiyuki Matsuoka, Eri Segi, Kazuhito Tsuboi, Yukihiko Sugimoto, Takuya Kobayashi, Yoshiki Miyachi, Atsushi Ichikawa, and Shuh Narumiya. The prostaglandin receptor ep4 suppresses colitis, mucosal damage and cd4 cell activation in the gut. Journal of Clinical Investigation, 109(7):883–893, April 2002. URL: http://dx.doi.org/10.1172/jci14459, doi:10.1172/jci14459. This article has 9 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci14459)

[8. (Lone2021Systems) Anna M. Lone, Piero Giansanti, Marthe Jøntvedt Jørgensen, Enio Gjerga, Aurelien Dugourd, Arjen Scholten, Julio Saez-Rodriguez, Albert J. R. Heck, and Kjetil Taskén. Systems approach reveals distinct and shared signaling networks of the four pge 2 receptors in t cells. Science Signaling, October 2021. URL: http://dx.doi.org/10.1126/scisignal.abc8579, doi:10.1126/scisignal.abc8579. This article has 5 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1126/scisignal.abc8579)