{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nP2RY14 is a G‐protein–coupled receptor that, although bearing prominent structural similarities to other P2Y receptors, exhibits a distinct pharmacological profile by selectively responding to UDP–sugars such as UDP–glucose. Its cloning and subsequent classification into the P2Y receptor family established the receptor as a unique sensor for extracellular sugar nucleotides released by damaged or stressed cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hematopoietic and immune cell populations, P2RY14 has been shown to mark a primitive, quiescent subset of stem cells in the bone marrow and to be differentially expressed during dendritic cell development. Activation of the receptor in these contexts triggers intracellular calcium fluxes and chemotactic responses that are essential for cell cycle regulation and initiating immune activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond stem cell regulation, P2RY14 plays a multifaceted role in mediating proinflammatory and chemotactic responses across diverse cell types. Studies using a selective high‐affinity antagonist (PPTN) confirmed that the receptor’s activation by UDP–sugars promotes inhibition of adenylyl cyclase and chemotaxis in models ranging from glioma and HL–60 cells to freshly isolated human neutrophils. In mucosal and epithelial compartments, including the female reproductive tract and the epidermis, receptor activation induces the production of key chemokines such as IL–8 and stimulates signaling pathways (involving JAK2–STAT3, RhoA, and ERK) that facilitate cell migration, hyaluronan synthesis, and innate inflammatory responses. In addition, similar proinflammatory actions have been observed in mast cells and in the epididymis, while in liver injury, activation of the receptor by damage–associated UDP–sugars links epithelial cell death to fibrogenic activation of hepatic stellate cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWhile P2RY14 protein is demonstrably expressed on platelets, functional studies indicate that its activation by UDP–glucose does not appreciably contribute to classical platelet responses such as aggregation or adenylate cyclase modulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further implicates P2RY14 in pathological conditions where immune cell mobilization is critical. For instance, in the context of COVID–19–induced systemic inflammation, modulation of this receptor has been proposed as a strategy to limit exaggerated neutrophil recruitment, NETosis, and the resultant tissue damage. Additionally, appropriate receptor expression appears to be important in cardiac progenitor cells from heart failure patients, where its upregulation may counteract cellular senescence, and in placental trophoblasts where it may contribute to immunological defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Maria P Abbracchio, Jean-Marie Boeynaems, Eric A Barnard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the UDP-glucose receptor (re-named here the P2Y14 receptor) adds diversity to the P2Y receptor family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Pharmacol Sci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0165-6147(02)00038-X"}], "href": "https://doi.org/10.1016/S0165-6147(02"}, {"type": "t", "text": "00038-X) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12559763"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12559763"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Byeong-Chel Lee, Tao Cheng, Gregor B Adams, et al. "}, {"type": "b", "children": [{"type": "t", "text": "P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bone-marrow hematopoietic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1071503"}], "href": "https://doi.org/10.1101/gad.1071503"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12842911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12842911"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lisa Skelton, Mike Cooper, Marianne Murphy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human immature monocyte-derived dendritic cells express the G protein-coupled receptor GPR105 (KIAA0001, P2Y14) and increase intracellular calcium in response to its agonist, uridine diphosphoglucose."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.171.4.1941"}], "href": "https://doi.org/10.4049/jimmunol.171.4.1941"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12902497"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12902497"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Matthew O Barrett, Juliana I Sesma, Christopher B Ball, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A selective high-affinity antagonist of the P2Y14 receptor inhibits UDP-glucose-stimulated chemotaxis of human neutrophils."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.113.085654"}], "href": "https://doi.org/10.1124/mol.113.085654"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23592514"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23592514"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Toru Arase, Hiroshi Uchida, Takashi Kajitani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The UDP-glucose receptor P2RY14 triggers innate mucosal immunity in the female reproductive tract by inducing IL-8."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0900001"}], "href": "https://doi.org/10.4049/jimmunol.0900001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19454705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19454705"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Juliana I Sesma, Silvia M Kreda, Natacha Steinckwich-Besancon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The UDP-sugar-sensing P2Y(14) receptor promotes Rho-mediated signaling and chemotaxis in human neutrophils."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00138.2012"}], "href": "https://doi.org/10.1152/ajpcell.00138.2012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22673622"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22673622"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Tiina A Jokela, Riikka Kärnä, Katri M Makkonen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extracellular UDP-glucose activates P2Y14 Receptor and Induces Signal Transducer and Activator of Transcription 3 (STAT3) Tyr705 phosphorylation and binding to hyaluronan synthase 2 (HAS2) promoter, stimulating hyaluronan synthesis of keratinocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.551804"}], "href": "https://doi.org/10.1074/jbc.M114.551804"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24847057"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24847057"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ingmar Mederacke, Aveline Filliol, Silvia Affo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.abe5795"}], "href": "https://doi.org/10.1126/scitranslmed.abe5795"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35385339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35385339"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Edyta Gendaszewska-Darmach, Edyta Węgłowska, Aurelia Walczak-Drzewiecka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nucleoside 5'-O-monophosphorothioates as modulators of the P2Y14 receptor and mast cell degranulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.12541"}], "href": "https://doi.org/10.18632/oncotarget.12541"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27732965"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27732965"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Larissa Berloffa Belardin, Christine Légaré, Robert Sullivan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of the pro-inflammatory P2Y14 receptor in the non-vasectomized and vasectomized human epididymis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Andrology (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/andr.13284"}], "href": "https://doi.org/10.1111/andr.13284"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36029226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36029226"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Natalia Dovlatova, Yanushi D Wijeyeratne, Susan C Fox, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Detection of P2Y(14) protein in platelets and investigation of the role of P2Y(14) in platelet function in comparison with the EP(3) receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thromb Haemost (2008)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18690346"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18690346"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lyvia Lintzmaier Petiz, Talita Glaser, Julio Scharfstein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "P2Y14 Receptor as a Target for Neutrophilia Attenuation in Severe COVID-19 Cases: From Hematopoietic Stem Cell Recruitment and Chemotaxis to Thrombo-inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Rev Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12015-021-10129-7"}], "href": "https://doi.org/10.1007/s12015-021-10129-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33575962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33575962"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Farid G Khalafalla, Waqas Kayani, Arwa Kassab, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Empowering human cardiac progenitor cells by P2Y"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "14"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": " nucleotide receptor overexpression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/JP274980"}], "href": "https://doi.org/10.1113/JP274980"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28980705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28980705"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Satomi Katakura, Tomoka Takao, Toru Arase, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UDP-glucose, a cellular danger signal, and nucleotide receptor P2Y14 enhance the invasion of human extravillous trophoblast cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Placenta (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.placenta.2020.09.061"}], "href": "https://doi.org/10.1016/j.placenta.2020.09.061"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33011563"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33011563"}]}]}]}