{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProkineticin‐1 (PROK1), also known as endocrine gland–derived vascular endothelial growth factor (EG‐VEGF), is a tissue‐specific secreted protein that plays a pivotal role in reproductive physiology. It is produced in the endometrium, first‐trimester decidua, and other steroidogenic tissues where it is tightly regulated by pregnancy hormones such as human chorionic gonadotropin, progesterone, and insulin. In these sites, PROK1 initiates a cascade of intracellular signals—via G protein–coupled receptors (PROKR1 and PROKR2) and pathways including Gq–Ca²⁺, c‐Src, and the MAPK/ERK cascade—to induce the expression of key cytokines (such as leukemia inhibitory factor and interleukin‑11) and regulators that promote decidualization, enhance trophoblast adhesion, and ensure successful embryo implantation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its key function in early pregnancy, PROK1 critically regulates angiogenesis and vascular remodeling in endocrine organs. Its selective mitogenic effects on endothelial cells have been documented in the ovary, placenta, testis, and prostate—supporting not only normal reproductive tissue homeostasis but also contributing to the neovascularization observed in certain hormone‐responsive tumors. Aberrant expression of PROK1 has been associated with the development and progression of several malignancies, including testicular, prostate, colorectal, and neuroblastoma tumors, and has been implicated in conditions such as fetal growth restriction and preeclampsia. The ability of PROK1 to modulate cell invasion via suppression or enhancement of matrix metalloproteinases further underscores its dual role in both normal placentation and pathological processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, PROK1 signals through its receptors to regulate a wide array of implantation‐ and angiogenesis‐related genes—including DKK1, CTGF, COX‑2, and various interleukins—and modulate key cellular processes such as proliferation, survival, adhesion, and invasion. Its expression and downstream signaling are modulated both by classical hormones (e.g. hCG, progesterone, insulin and androgens) and by environmental factors like hypoxia, thereby fine‐tuning the balance between pro‐ and anti‐invasive mechanisms. Furthermore, PROK1 has been implicated in inflammatory cascades that may precipitate labor and in the maintenance of tumor cell viability through activation of STAT3 and other survival pathways, making it a promising candidate for diagnostic biomarker development and targeted therapy in reproductive disorders, cancers, and even in conditions such as age‐related neovascular eye disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "S Battersby, H O D Critchley, K Morgan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) and their receptors in the human endometrium across the menstrual cycle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2003-032012"}], "href": "https://doi.org/10.1210/jc.2003-032012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15126578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15126578"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Elly S W Ngan, K Y Lee, William S B Yeung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endocrine gland-derived vascular endothelial growth factor is expressed in human peri-implantation endometrium, but not in endometrial carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2005-0543"}], "href": "https://doi.org/10.1210/en.2005-0543"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16210375"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16210375"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jemma Evans, Rob D Catalano, Kevin Morgan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prokineticin 1 signaling and gene regulation in early human pregnancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2007-1633"}], "href": "https://doi.org/10.1210/en.2007-1633"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18339712"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18339712"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jemma Evans, Rob D Catalano, Pamela Brown, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.08-124495"}], "href": "https://doi.org/10.1096/fj.08-124495"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19255255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19255255"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Tatiana Kisliouk, Nitzan Levy, Arye Hurwitz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presence and regulation of endocrine gland vascular endothelial growth factor/prokineticin-1 and its receptors in ovarian cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2003-030492"}], "href": "https://doi.org/10.1210/jc.2003-030492"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12915658"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12915658"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Michel Samson, Franklin V Peale, Gretchen Frantz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human endocrine gland-derived vascular endothelial growth factor: expression early in development and in Leydig cell tumors suggests roles in normal and pathological testis angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2003-032024"}], "href": "https://doi.org/10.1210/jc.2003-032024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15292351"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15292351"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Daniela Pasquali, Valentina Rossi, Stefania Staibano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The endocrine-gland-derived vascular endothelial growth factor (EG-VEGF)/prokineticin 1 and 2 and receptor expression in human prostate: Up-regulation of EG-VEGF/prokineticin 1 with malignancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2006-0614"}], "href": "https://doi.org/10.1210/en.2006-0614"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16763065"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16763065"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Elly S W Ngan, Francesco Y L Sit, KingLiu Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Implications of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 signaling in human neuroblastoma progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-06-2176"}], "href": "https://doi.org/10.1158/1078-0432.CCR-06-2176"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17289879"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17289879"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "S Brouillet, P Murthi, P Hoffmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-012-1141-z"}], "href": "https://doi.org/10.1007/s00018-012-1141-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22941044"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22941044"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Nadia Alfaidy, Pascale Hoffmann, Houssine Boufettal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The multiple roles of EG-VEGF/PROK1 in normal and pathological placental angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2014/451906"}], "href": "https://doi.org/10.1155/2014/451906"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24955357"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24955357"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Nobushige Tanaka, Masahito Ikawa, Nathan L Mata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Choroidal neovascularization in transgenic mice expressing prokineticin 1: an animal model for age-related macular degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Ther (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymthe.2005.08.024"}], "href": "https://doi.org/10.1016/j.ymthe.2005.08.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16263331"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16263331"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Tatiana Kisliouk, Helena Podlovni, Rina Meidan "}, {"type": "b", "children": [{"type": "t", "text": "Unique expression and regulatory mechanisms of EG-VEGF/prokineticin-1 and its receptors in the corpus luteum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Anat (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.aanat.2005.07.005"}], "href": "https://doi.org/10.1016/j.aanat.2005.07.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16320832"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16320832"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yin-Lau Lee, Yuk-Ling Chan, Wan-Ngai Chow, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endocrine gland-derived vascular endothelial growth factor stimulates proliferation and tube formation in human uterine microvascular endothelial cell through the mitogen-activated protein kinase but not through the Akt pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Fertil Steril (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.fertnstert.2008.03.076"}], "href": "https://doi.org/10.1016/j.fertnstert.2008.03.076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18571163"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18571163"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ian H Cook, Jemma Evans, David Maldonado-Pérez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prokineticin-1 (PROK1) modulates interleukin (IL)-11 expression via prokineticin receptor 1 (PROKR1) and the calcineurin/NFAT signalling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gap084"}], "href": "https://doi.org/10.1093/molehr/gap084"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19801577"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19801577"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Qing-Fang Li, Hai-Yan Zhu, Yue-Feng Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prokineticin-1/endocrine gland-derived vascular endothelial growth factor is a survival factor for human multiple myeloma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leuk Lymphoma (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/10428194.2010.512963"}], "href": "https://doi.org/10.3109/10428194.2010.512963"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20795791"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20795791"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Mei-Tsz Su, Sheng-Hsiang Lin, I-Wen Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms of endocrine gland-derived vascular endothelial growth factor gene and its receptor genes are associated with recurrent pregnancy loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Reprod (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/humrep/deq256"}], "href": "https://doi.org/10.1093/humrep/deq256"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20847187"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20847187"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Jennifer M Waddell, Jemma Evans, Henry N Jabbour, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CTGF expression is up-regulated by PROK1 in early pregnancy and influences HTR-8/Svneo cell adhesion and network formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Reprod (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/humrep/deq294"}], "href": "https://doi.org/10.1093/humrep/deq294"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21098624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21098624"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Linsay J Macdonald, Kurt J Sales, Vivien Grant, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gar031"}], "href": "https://doi.org/10.1093/molehr/gar031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21546446"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21546446"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Takanori Goi, Toshiyuki Nakazawa, Yasuo Hirono, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prokineticin 1 expression in gastrointestinal tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Res (2013)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24324064"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24324064"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Mei-Tsz Su, Sheng-Hsiang Lin, Yi-Chi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene-gene interactions and gene polymorphisms of VEGFA and EG-VEGF gene systems in recurrent pregnancy loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Assist Reprod Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10815-014-0223-2"}], "href": "https://doi.org/10.1007/s10815-014-0223-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24671265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24671265"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Nadia Alfaidy, Pascale Hoffmann, Pierre Gillois, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PROK1 Level in the Follicular Microenvironment: A New Noninvasive Predictive Biomarker of Embryo Implantation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2015-1988"}], "href": "https://doi.org/10.1210/jc.2015-1988"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26401590"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26401590"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Dorina Ujvari, Ivika Jakson, Cecilia Oldmark, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prokineticin 1 is up-regulated by insulin in decidualizing human endometrial stromal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.13305"}], "href": "https://doi.org/10.1111/jcmm.13305"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28782224"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28782224"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Xiaogang Yan, Yongfeng Hui, Yongqiang Hua, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EG-VEGF silencing inhibits cell proliferation and promotes cell apoptosis in pancreatic carcinoma via PI3K/AKT/mTOR signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2018.10.125"}], "href": "https://doi.org/10.1016/j.biopha.2018.10.125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30551529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30551529"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Dorina Ujvari, Carlota Graells Brugalla, Angelica Lindén Hirschberg "}, {"type": "b", "children": [{"type": "t", "text": "Dihydrotestosterone potentiates insulin to up-regulate prokineticin-1 in decidualizing human endometrial stromal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.14923"}], "href": "https://doi.org/10.1111/jcmm.14923"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31991505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31991505"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "XiaoYan Zhang, YouMing Sheng, BingWei Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ovarian cancer derived PKR1 positive exosomes promote angiogenesis by promoting migration and tube formation in vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biochem Funct (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbf.3583"}], "href": "https://doi.org/10.1002/cbf.3583"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32876972"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32876972"}]}]}]}