{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n GPR31 was recently deorphanized as a high‐affinity receptor for the arachidonate 12‐lipoxygenase metabolite 12(S)‑hydroxyeicosatetraenoic acid [12(S)-HETE]. Activation of GPR31 by 12(S)-HETE initiates G protein–mediated signaling cascades—including activation of ERK1/2, MEK, and NFκB—that promote cell invasion and enhance inflammatory responses in several cellular contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the liver, an ALOX12–12‑HETE–GPR31 signaling axis has been shown to trigger inflammatory cell recruitment and tissue damage during ischemia–reperfusion injury"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while in the kidney, activation of GPR31 by 12(S)-HETE contributes to gentamicin-induced nephrotoxicity by harnessing oxidative stress and proinflammatory kinase cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In the oncological sphere, high GPR31 expression is correlated with tumor aggressiveness and unfavorable clinical outcomes, as documented in prostate and colorectal cancers where increased GPR31 levels associate with enhanced invasion, metastasis, and impaired overall survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, in platelets, 12(S)-HETE engagement of GPR31 facilitates Gi-dependent signaling that amplifies PAR4-mediated activation and arterial thrombosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Beyond inflammation and cancer, GPR31 also participates in immunomodulatory functions; it mediates pyruvate-induced dendrite extension by intestinal CX3CR1^high myeloid cells, thereby enhancing the induction of regulatory T cells and oral tolerance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and it contributes to the adaptive gene expression response of epithelial cells under extracellular acidosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, distinct expression patterns of GPR31 in skin tumors—being frequently negative in basal cell carcinomas yet prevalent in squamous cell carcinomas—further underscore its potential as a diagnostic marker in oncology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yande Guo, Wenliang Zhang, Craig Giroux, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.216564"}], "href": "https://doi.org/10.1074/jbc.M110.216564"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21712392"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21712392"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kenneth V Honn, Yande Guo, Yinlong Cai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.201500076"}], "href": "https://doi.org/10.1096/fj.201500076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26965684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26965684"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiao-Jing Zhang, Xu Cheng, Zhen-Zhen Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.4451"}], "href": "https://doi.org/10.1038/nm.4451"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29227475"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29227475"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Isha Sharma, Yingjun Liao, Xiaoping Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of gentamicin-induced acute kidney injury by myo-inositol oxygenase via the ROS/ALOX-12/12-HETE/GPR31 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.155487"}], "href": "https://doi.org/10.1172/jci.insight.155487"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35315361"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35315361"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yu-Ming Rong, Xiao-Ming Huang, De-Jun Fan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of G protein-coupled receptor 31 as a poor prognosticator in human colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Gastroenterol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3748/wjg.v24.i41.4679"}], "href": "https://doi.org/10.3748/wjg.v24.i41.4679"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30416315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30416315"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Nicole Fehrenbacher, Mark R Philips "}, {"type": "b", "children": [{"type": "t", "text": "Targeting RAS - will GPR31 deliver us a new path forward?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Oncol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/23723556.2017.1359228"}], "href": "https://doi.org/10.1080/23723556.2017.1359228"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29209647"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29209647"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Layla Van Doren, Nga Nguyen, Christopher Garzia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lipid Receptor GPR31 (G-Protein-Coupled Receptor 31) Regulates Platelet Reactivity and Thrombosis Without Affecting Hemostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.120.315154"}], "href": "https://doi.org/10.1161/ATVBAHA.120.315154"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33267659"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33267659"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Qizhi Liu, Eiji Umemoto, Naoki Morita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pyruvate enhances oral tolerance via GPR31."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/intimm/dxac010"}], "href": "https://doi.org/10.1093/intimm/dxac010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35303081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35303081"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ian M Cartwright, Alexander S Dowdell, Jordi M Lanis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2023871118"}], "href": "https://doi.org/10.1073/pnas.2023871118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33972436"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33972436"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Antonia Förch, Susanne Wallner, Florian Zeman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of Proton-Sensitive GPR31, GPR151, TASK1 and TASK3 in Common Skin Tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells11010027"}], "href": "https://doi.org/10.3390/cells11010027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35011589"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35011589"}]}]}]}