Home Prokineticins in central and peripheral control of human reproduction
Article
Licensed
Unlicensed Requires Authentication

Prokineticins in central and peripheral control of human reproduction

  • Wael Traboulsi , Sophie Brouillet , Frederic Sergent , Houssine Boufettal , Naima Samouh , Touria Aboussaouira , Pascale Hoffmann , Jean Jacques Feige , Mohamed Benharouga and Nadia Alfaidy EMAIL logo
Published/Copyright: November 17, 2015
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Hormone Molecular Biology and Clinical Investigation
From the journal Hormone Molecular Biology and Clinical Investigation Volume 24 Issue 2

Abstract

Prokineticin 1 (PROK1) and (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. PROKs activate two G-protein linked receptors (prokineticin receptor 1 and 2, PROKR1 and PROKR2). Both PROK1 and PROK2 have been found to regulate a stunning array of biological functions. In particular, PROKs stimulate gastrointestinal motility, thus accounting for their family name “prokineticins”. PROK1 acts as a potent angiogenic mitogen, thus earning its other name, endocrine gland-derived vascular endothelial factor. In contrast, PROK2 signaling pathway has been shown to be a critical regulator of olfactory bulb morphogenesis and sexual maturation. During the last decade, strong evidences established the key roles of prokineticins in the control of human central and peripheral reproductive processes. PROKs act as main regulators of the physiological functions of the ovary, uterus, placenta, and testis, with marked dysfunctions in various pathological conditions such as recurrent pregnancy loss, and preeclampsia. PROKs have also been associated to the tumor development of some of these organs. In the central system, prokineticins control the migration of GnRH neurons, a key process that controls reproductive functions. Importantly, mutations in PROK2 and PROKR2 are associated to the development of Kallmann syndrome, with direct consequences on the reproductive system. This review describes the finely tuned actions of prokineticins in the control of the central and peripheral reproductive processes. Also, it discusses future research directions for the use of these cytokines as diagnostic markers for several reproductive diseases.

Keywords: EG-VEGF; Kallmann; prokineticin; PROKR1; PROKR2; reproduction
Corresponding author: Nadia Alfaidy, Unité INSERM U1036. Laboratoire BCI -iRTSV, CEA Grenoble 17, rue des Martyrs, 38054 Grenoble cedex 9, France, Phone: +04 38 78 35 01, Fax: +04 38 78 50 58, E-mail: ; Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France; University Grenoble-Alpes, 38000, Grenoble, France; and Commissariat à l’Energie Atomique, iRTSV- Biology of Cancer and infection, Grenoble, France

Acknowledgments

Funding support was provided from Groupement des Entreprises Françaises pour la Lutte contre le Cancer Comité Isère to Dr. N. Alfaidy and from Cooperation between INSERM (France) and CNRT (Morroco). Fisrt autor, W. Traboulsi was funded by la Ligue Nationale contre le Cancer for his PhD thesis.

Disclosure: The authors have nothing to disclose.

References

1. LeCouter J, Ferrara N. EG-VEGF and the concept of tissue-specific angiogenic growth factors. Semin Cell Dev Biol 2002;13:3–8.10.1006/scdb.2001.0284Search in Google Scholar

2. Li M, Bullock CM, Knauer DJ, Ehlert FJ, Zhou QY. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol Pharmacol 2001;59:692–8.10.1124/mol.59.4.692Search in Google Scholar

3. Ngan ES, Shum CK, Poon HC, Sham MH, Garcia-Barcelo MM, Lui VC, Tam PK. Prokineticin-1 (Prok-1) works coordinately with glial cell line-derived neurotrophic factor (GDNF) to mediate proliferation and differentiation of enteric neural crest cells. Biochim Biophys Acta 2008;1783:467–78.10.1016/j.bbamcr.2007.09.005Search in Google Scholar

4. Cheng MY, Lee AG, Culbertson C, Sun G, Talati RK, Manley NC, Li X, Zhao H, Lyons DM, Zhou QY, Steinberg GK, Sapolsky RM. Prokineticin 2 is an endangering mediator of cerebral ischemic injury. Proc Natl Acad Sci USA 2012;109:5475–80.10.1073/pnas.1113363109Search in Google Scholar

5. Hu WP, Zhang C, Li JD, Luo ZD, Amadesi S, Bunnett N, Zhou QY. Impaired pain sensation in mice lacking prokineticin 2. Mole Pain 2006;2:35.10.1186/1744-8069-2-35Search in Google Scholar

6. LeCouter J, Zlot C, Tejada M, Peale F, Ferrara N. Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci USA 2004;101:16813–8.10.1073/pnas.0407697101Search in Google Scholar

7. Urayama K, Guilini C, Messaddeq N, Hu K, Steenman M, Kurose H, Ert G, Nebigil CG. The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis. FASEB J 2007;21:2980–93.10.1096/fj.07-8116comSearch in Google Scholar

8. Maldonado-Perez D, Evans J, Denison F, Millar RP, Jabbour HN. Potential roles of the prokineticins in reproduction. Trends Endocrinol Metab 2007;18:66–72.10.1016/j.tem.2006.12.002Search in Google Scholar

9. Schweitz H, Bidard JN, Lazdunski M. Purification and pharmacological characterization of peptide toxins from the black mamba (Dendroaspis polylepis) venom. Toxicon 1990;28:847–56.10.1016/S0041-0101(09)80007-XSearch in Google Scholar

10. Schweitz H, Pacaud P, Diochot S, Moinier D, Lazdunski M. MIT(1), a black mamba toxin with a new and highly potent activity on intestinal contraction. FEBS lett 1999;461:183–8.10.1016/S0014-5793(99)01459-3Search in Google Scholar

11. Joubert FJ, Strydom DJ. Snake venom. The amino acid sequence of protein A from Dendroaspis polylepis polylepis (black mamba) venom. Hoppe Seylers Z Physiol Chem 1980;361:1787–94.10.1515/bchm2.1980.361.2.1787Search in Google Scholar PubMed

12. Mollay C, Wechselberger C, Mignogna G, Negri L, Melchiorri P, Barra D, Kreil G. Bv8, a small protein from frog skin and its homologue from snake venom induce hyperalgesia in rats. Eur J Pharmacol 1999;374:189–96.10.1016/S0014-2999(99)00229-0Search in Google Scholar

13. Bullock CM, Li JD, Zhou QY. Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists. Mol Pharmacol 2004;65:582–8.10.1124/mol.65.3.582Search in Google Scholar

14. Eddie SL, Childs AJ, Kinnell HL, Brown P, Jabbour HN, Anderson RA. Prokineticin ligands and receptors are expressed in the human fetal ovary and regulate germ cell expression of COX2. J Clin Endocrinol Metab 2015;100:E1197–205.10.1210/jc.2015-2330Search in Google Scholar

15. Hoffmann P, Feige JJ, Alfaidy N. Expression and oxygen regulation of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 and its receptors in human placenta during early pregnancy. Endocrinology 2006;147:1675–84.10.1210/en.2005-0912Search in Google Scholar

16. Masumoto KH, Nagano M, Takashima N, Hayasaka N, Hiyama H, Matsumoto S, Inouye ST, Shigeyoshi Y. Distinct localization of prokineticin 2 and prokineticin receptor 2 mRNAs in the rat suprachiasmatic nucleus. Eur J Neurosci 2006;23:2959–70.10.1111/j.1460-9568.2006.04834.xSearch in Google Scholar

17. Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M, Soga T, Hiyama H, Matsumoto M, Takasaki J, Kamohara M, Matsuo A, Ishii H, Kobori M, Katoh M, Matsushime H, Furuichi K, Shigeyoshi Y. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci USA 2006;103:4140–5.10.1073/pnas.0508881103Search in Google Scholar

18. LeCouter J, Ferrara N. EG-VEGF and Bv8. a novel family of tissue-selective mediators of angiogenesis, endothelial phenotype, and function. Trends Cardiovasc Med 2003;13:276–82.10.1016/S1050-1738(03)00110-5Search in Google Scholar

19. LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L, Frantz G, Rangell L, DeGuzman L, Keller GA, Peale F, Gurney A, Hillan KJ, Ferrara N. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 2001;412:877–84.10.1038/35091000Search in Google Scholar PubMed

20. Kaser A, Winklmayr M, Lepperdinger G, Kreil G. The AVIT protein family. Secreted cysteine-rich vertebrate proteins with diverse functions. EMBO Rep 2003;4:469–73.10.1038/sj.embor.embor830Search in Google Scholar PubMed PubMed Central

21. Boisbouvier J, Albrand JP, Blackledge M, Jaquinod M, Schweitz H, Lazdunski M, Marion D. A structural homologue of colipase in black mamba venom revealed by NMR floating disulphide bridge analysis. J Mol Biol 1998;283:205–19.10.1006/jmbi.1998.2057Search in Google Scholar PubMed

22. Negri L, Lattanzi R, Giannini E, Colucci MA, Mignogna G, Barra D, Grohovaz F, Codazzi F, Kaiser A, Kreil G, Melchiorri P. Biological activities of Bv8 analogues. Br J Pharmacol 2005;146:625–32.10.1038/sj.bjp.0706376Search in Google Scholar

23. Lin DC, Bullock CM, Ehlert FJ, Chen JL, Tian H, Zhou QY. Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J Biol Chem 2002;277:19276–80.10.1074/jbc.M202139200Search in Google Scholar

24. Masuda Y, Takatsu Y, Terao Y, Kumano S, Ishibashi Y, Suenaga M, Abe M, Fukusumi S, Watanabe T, Shintani Y, Yamada T, Hinuma S, Inatomi N, Ohtaki T, Onda H, Fujino M. Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors. Biochem Biophys Res Commun 2002;293:396–402.10.1016/S0006-291X(02)00239-5Search in Google Scholar

25. Soga T, Matsumoto S, Oda T, Saito T, Hiyama H, Takasaki J, Kamohara M, Ohishi T, Matsushime H, Furuichi K. Molecular cloning and characterization of prokineticin receptors. Biochim Biophys Acta 2002;1579:173–9.10.1016/S0167-4781(02)00546-8Search in Google Scholar

26. Brouillet S, Hoffmann P, Feige JJ, Alfaidy N. EG-VEGF: a key endocrine factor in placental development. Trends Endocrinol Metab 2012;23:501–8.10.1016/j.tem.2012.05.006Search in Google Scholar PubMed

27. Chen J, Kuei C, Sutton S, Wilson S, Yu J, Kamme F, Mazur C, Lovenberg T, Liu C. Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1. Mol Pharmacol 2005;67:2070–6.10.1124/mol.105.011619Search in Google Scholar PubMed

28. Boulberdaa M, Urayama K, Nebigil CG. Prokineticin receptor 1 (PKR1) signalling in cardiovascular and kidney functions. Cardiovasc Res 2011;92:191–8.10.1093/cvr/cvr228Search in Google Scholar PubMed

29. Ferrara N, LeCouter J, Lin R, Peale F. EG-VEGF and Bv8: a novel family of tissue-restricted angiogenic factors. Biochim Biophys Acta 2004;1654:69–78.10.1016/j.bbcan.2003.07.001Search in Google Scholar PubMed

30. Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, Weaver DR, Leslie FM, Zhou QY. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 2002;417:405–10.10.1038/417405aSearch in Google Scholar PubMed

31. Battersby S, Critchley HO, Morgan K, Millar RP, Jabbour HN. 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. J Clin Endocrinol Metab 2004;89:2463–9.10.1210/jc.2003-032012Search in Google Scholar PubMed

32. Fraser HM, Bell J, Wilson H, Taylor PD, Morgan K, Anderson RA, Duncan WC. Localization and quantification of cyclic changes in the expression of endocrine gland vascular endothelial growth factor in the human corpus luteum. J Clin Endocrinol Metab 2005;90:427–34.10.1210/jc.2004-0843Search in Google Scholar PubMed

33. Garnier V, Traboulsi W, Salomon A, Brouillet S, Fournier T, Winkler C, Desvergne B, Hoffmann P, Zhou QY, Congiu C, Onnis V, Benharouga M, Feige JJ, Alfaidy N. PPARgamma controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development. Am J Physiol Endoc Metab 2015;309:E357–69.10.1152/ajpendo.00093.2015Search in Google Scholar PubMed

34. Brouillet S, Hoffmann P, Chauvet S, Salomon A, Chamboredon S, Sergent F, Benharouga M, Feige JJ, Alfaidy N. Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors. Cell Mole Life Sci 2012;69:1537–50.10.1007/s00018-011-0889-xSearch in Google Scholar PubMed

35. Li JD, Hu WP, Zhou QY. The circadian output signals from the suprachiasmatic nuclei. Prog Brain Res 2012;199:119–27.10.1016/B978-0-444-59427-3.00028-9Search in Google Scholar PubMed

36. Pitteloud N, Zhang C, Pignatelli D, Li JD, Raivio T, Cole LW, Plummer L, Jacobson-Dickman EE, Mellon PL, Zhou QY, Crowley WF, Jr. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 2007;104:17447–52.10.1073/pnas.0707173104Search in Google Scholar PubMed PubMed Central

37. Guimiot F, Teixeira L, Dode C, Delezoide AL, Hardelin JP. [Kallmann syndrome – a fetopathological sequence]. Medecine sciences: M/S 2011;27:135–7.10.1051/medsci/2011272135Search in Google Scholar PubMed

38. Monnier J, Samson M. Prokineticins in angiogenesis and cancer. Cancer lett 2010;296:144–9.10.1016/j.canlet.2010.06.011Search in Google Scholar PubMed

39. Samson M, Peale FV, Jr., Frantz G, Rioux-Leclercq N, Rajpert-De Meyts E, Ferrara N. 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. J Clin Endocrinol Metab 2004;89:4078–88.10.1210/jc.2003-032024Search in Google Scholar PubMed

40. Pasquali D, Rossi V, Staibano S, De Rosa G, Chieffi P, Prezioso D, Mirone V, Mascolo M, Tramontano D, Bellastella A, Sinisi AA. 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. Endocrinology 2006;147:4245–51.10.1210/en.2006-0614Search in Google Scholar PubMed

41. Tu LH, Yu LL, Xiong CL, Zhang HP. Potential role of prokineticin 2 in experimental varicocele-induced rat testes. Urology 2012;80:952.e15–9.10.1016/j.urology.2012.05.033Search in Google Scholar PubMed

42. Gao MZ, Zhao XM, Sun ZG, Hong Y, Zhao LW, Zhang HQ. Endocrine gland-derived vascular endothelial growth factor concentrations in follicular fluid and serum may predict ovarian hyperstimulation syndrome in women undergoing controlled ovarian hyperstimulation. Fertil Steril 2011;95:673–8.10.1016/j.fertnstert.2010.09.044Search in Google Scholar PubMed

43. Macdonald LJ, Sales KJ, Grant V, Brown P, Jabbour HN, Catalano RD. Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium. Mol Hum Reprod 2011;17626–36.10.1093/molehr/gar031Search in Google Scholar PubMed PubMed Central

44. Evans J, Catalano RD, Brown P, Sherwin R, Critchley HO, Fazleabas AT, Jabbour HN. Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor. FASEB J 2009;23:2165–75.10.1096/fj.08-124495Search in Google Scholar PubMed PubMed Central

45. Evans J, Catalano RD, Morgan K, Critchley HO, Millar RP, Jabbour HN. Prokineticin 1 signaling and gene regulation in early human pregnancy. Endocrinology 2008;149:2877–87.10.1210/en.2007-1633Search in Google Scholar PubMed PubMed Central

46. Haouzi D, Mahmoud K, Fourar M, Bendhaou K, Dechaud H, De Vos J, Reme T, Dewailly D, Hamamah S. Identification of new biomarkers of human endometrial receptivity in the natural cycle. Hum Reprod 2009;24:198–205.10.1093/humrep/den360Search in Google Scholar PubMed

47. Shaw JL, Denison FC, Evans J, Durno K, Williams AR, Entrican G, Critchley HO, Jabbour HN, Horne AW. Evidence of prokineticin dysregulation in fallopian tube from women with ectopic pregnancy. Fertil Steril 2010;94:1601–8.e1.10.1016/j.fertnstert.2009.10.061Search in Google Scholar PubMed PubMed Central

48. Salker M, Teklenburg G, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Macklon NS, Brosens JJ. Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss. PloS one 2010;5:e10287.10.1371/journal.pone.0010287Search in Google Scholar PubMed PubMed Central

49. Su MT, Lin SH, Chen YC, Kuo PL. Gene-gene interactions and risk of recurrent miscarriages in carriers of endocrine gland-derived vascular endothelial growth factor and prokineticin receptor polymorphisms. Fertil Steril 2014;102:1071–7.e3.10.1016/j.fertnstert.2014.06.042Search in Google Scholar PubMed

50. Su MT, Lin SH, Chen YC, Wu LW, Kuo PL. Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy. Reproduction 2013;146: 63–73.10.1530/REP-13-0043Search in Google Scholar PubMed

51. Su MT, Lin SH, Lee IW, Chen YC, Hsu CC, Pan HA, Kuo PL. Polymorphisms of endocrine gland-derived vascular endothelial growth factor gene and its receptor genes are associated with recurrent pregnancy loss. Hum Reprod 2010;25:2923–30.10.1093/humrep/deq256Search in Google Scholar PubMed

52. Dunand C, Hoffmann P, Sapin V, Blanchon L, Salomon A, Sergent F, Benharouga M, Sabra S, Guibourdenche J, Lye SJ, Feige JJ, Alfaidy N. Endocrine gland-derived endothelial growth factor (EG-VEGF) is a potential novel regulator of human parturition. Biol Reprod 2014;91:73.10.1095/biolreprod.114.119990Search in Google Scholar

53. Hoffmann P, Saoudi Y, Benharouga M, Graham CH, Schaal JP, Mazouni C, Feige JJ, Alfaidy N. Role of EG-VEGF in human placentation: Physiological and pathological implications. J Cell Mol Med 2009;13:2224–35.10.1111/j.1582-4934.2008.00554.xSearch in Google Scholar

54. Brouillet S, Hoffmann P, Benharouga M, Salomon A, Schaal JP, Feige JJ, Alfaidy N. Molecular characterization of EG-VEGF-mediated angiogenesis: differential effects on microvascular and macrovascular endothelial cells. Mol Biol Cell 2010;21:2832–43.10.1091/mbc.e10-01-0059Search in Google Scholar

55. Guilini C, Urayama K, Turkeri G, Dedeoglu DB, Kurose H, Messaddeq N, Nebigil CG. Divergent roles of prokineticin receptors in the endothelial cells: angiogenesis and fenestration. Am J Physiol Heart Circ Physiol 2010;298:H844–52.10.1152/ajpheart.00898.2009Search in Google Scholar

56. Rigourd V, S TC, Vaiman D. [Preeclampsia]. Med Sci 2008;24: 1017–9.10.1051/medsci/200824121017Search in Google Scholar

57. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99.10.1016/S0140-6736(05)17987-2Search in Google Scholar

58. Brouillet S, Murthi P, Hoffmann P, Salomon A, Sergent F, De Mazancourt P, Dakouane-Giudicelli M, Dieudonne MN, Rozenberg P, Vaiman D, Barbaux S, Benharouga M, Feige JJ, Alfaidy N. EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR). Cell Mol Life Sci 2013;70:511–25.10.1007/s00018-012-1141-zSearch in Google Scholar PubMed

59. Catalano RD, Lannagan TR, Gorowiec M, Denison FC, Norman JE, Jabbour HN. Prokineticins: novel mediators of inflammatory and contractile pathways at parturition? Mol Hum Reprod 2010;16:311–9.10.1093/molehr/gaq014Search in Google Scholar PubMed

Received: 2015-8-20
Accepted: 2015-10-2
Published Online: 2015-11-17
Published in Print: 2015-11-1

©2015 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Topic B: Neuroendocrine Control, Gonadal Function, PCOS/Insulin Sensitivity and Reproduction
  3. Review Articles
  4. Prokineticins in central and peripheral control of human reproduction
  5. Role of the teneurins, teneurin C-terminal associated peptides (TCAP) in reproduction: clinical perspectives
  6. Original Articles
  7. Pro-nerve growth factor in the ovary and human granulosa cells
  8. Insulin sensitivity affects corticolimbic brain responses to visual food cues in polycystic ovary syndrome patients
https://doi.org/10.1515/hmbci-2015-0040
Keywords for this article
EG-VEGF; Kallmann; prokineticin; PROKR1; PROKR2; reproduction

Articles in the same Issue

  1. Frontmatter
  2. Topic B: Neuroendocrine Control, Gonadal Function, PCOS/Insulin Sensitivity and Reproduction
  3. Review Articles
  4. Prokineticins in central and peripheral control of human reproduction
  5. Role of the teneurins, teneurin C-terminal associated peptides (TCAP) in reproduction: clinical perspectives
  6. Original Articles
  7. Pro-nerve growth factor in the ovary and human granulosa cells
  8. Insulin sensitivity affects corticolimbic brain responses to visual food cues in polycystic ovary syndrome patients
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 7.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hmbci-2015-0040/html
Scroll to top button