An update on the role of prokineticins in human reproduction-potential therapeutic implications


Objective: Prokineticin-1 (PROK1) is a recently described protein with a wide range of functions including tissue specific angiogenesis, modulation of inflammatory responses and regulation of haematopoiesis. PROK1 has been found in the steroidogenic organs like ovary, testis, adrenal and specially placenta and they have been found to have a role in development of the olfactory system and GnRH system. The aim was to update the role of PROK1 and PROK2 inhuman reproduction since the review was provided by Maldono-Perez (2007) on the potentials of prokineticins in reproduction. Design: A review of international scientific literature by a search of Pubmed and the authors files was done for citation of articles relevant to prokineticins in reproduction, be it its role in ovary, testis, uterus with special emphasis on implantation, normal pregnancy, in labour, pathophysiological states like tubal pregnancy, pcos, various genital tumours, and cases of isolated hypogonadotropic hypogonadism with mutations with PROK2/ PROKR2 and studies detailing functional mechanisms. Results: In the normal cycle, PROK1 has been found to have important roles in implantation, regulating several genes like COX-2, IL-8, IL-11, CTGF related to implantation. Initially murine studies revealed a critical role of PROK2 pathway on olfactory bulb morphogenesis and GnRH secretion which was accidentally discovered and since then several studies on mutations in PROK2/PROKR2 showed that they underlie some case of KS in humans. Although in mouse heterozygote state is not associated with clinical phenotype, most of human mutations are heterozygous. Conclusions: Role of PROK-1 in the process of implantation, with a deeper understanding of the process success rates in IVF and ART can be improved, besides understanding the pathophysiology of tubal pregnancy. Further presence in ovarian follicles of PROK1 can be used to plan a strategy for treating pcos. Development of antagonism of PROK’S may be a helpful strategy in treating preterm labour.

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Kaur, K. , Allahbadia, G. and Singh, M. (2013) An update on the role of prokineticins in human reproduction-potential therapeutic implications. Open Journal of Genetics, 3, 201-215. doi: 10.4236/ojgen.2013.33023.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Li, M., Bullock, C.M., Knauer, D.J., Ehlert, F.J. and Zhou, Q.Y. (2001) Identification of two prokineticin cDNAs: Recombinant proteins potently contract gastrointestinal smith muscle. Molecular Pharmacology, 59, 692-698.
[2] Mollay, C., Wechselberger, C., Mignogna, G., Neegri, L., Melchiorri, P., Barra, D. and Kreil, G. (1999) Bv8, a small protein from frog skin and its homologue from snake venom induce hyperalgesia in rats. European Journal of Pharmacology, 374, 189-196. doi:10.1016/S0014-2999(99)00229-0
[3] LeCouter, J., Kowalski, J., Foster, J., Hass, P., Zhang, Z., Dillard-Telm, L., Frantz, G., Rangell, L., Deguzman, L., Keller, G.A., Peale, F., Gurney, A., Hillan, K.J. and Ferrara, N. (2001) Identification of an angiogenic mitogen selective for endothelial gland endothelium. Nature, 412, 877-884. doi:10.1038/35091000
[4] LeeCouter, J.J., Lin, R., Frantz, G., Zhang, Z., Hillan, K. and Ferrara, N. (2003) Mouse endocrine gland-derived vascular endothelial growth factor: A distinct expression pattern from its human ortholog suggests different roles as a regulator of organ specific angiogenesis. Endocrinology, 144, 2606-2616. doi:10.1210/en.2002-0146
[5] Chen, J., Kuie, C., Sutton, S., Wilson, S., Yu, J.X., Kamme, F., Mazur, C., Lovenberg, T. and Liu, C. (2005) Identification and pharmacological characterization of prokineticin 2β as a selective ligand for prokineticin receptor 1. Molecular Pharmacology, 67, 2070-2076. doi:10.1124/mol.105.011619
[6] Urayama, K., Guilini, C., Messaddeq, N., Hu, K., Stteenman, M., Kuurose, H., Ert, G. and Nebigil, C.G. (2007) The prokinecitin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis. The FASEB Journal, 21, 2980-2993. doi:10.1096/fj.07-8116com
[7] Ng, K.L., Li, J.D., Cheng, M.Y., Leslie, F.M., Lee, A.G. and Zhou, Q.Y. (2005) Dependence of olfactory bulb neurogenesis on prokinecitin 2 signalling. Science, 308, 1923-1927. doi:10.1126/science.1112103
[8] Negri, L., Lattanzi, R., Giannini, E., Canestrelli, M., Nicotra, A. and Melchoorri, P. (2009) Chapter 11 Bv8/ prokineticins and their receptors: A new pronociceptive system. International Review of Neurobiology, 85, 145-157. doi:10.1016/S0074-7742(09)85011-3
[9] Monnier, J. and Samson, M. (2008) Cytokine properties of prokineticins. The FEBS Journal, 275, 4014-4021. doi:10.1111/j.1742-4658.2008.06559.x
[10] Maldonando-Perez, D., Evans, J., Denison, F., Millar, R.P. and Jabbour, H.N. (2007) Potential roles of the prokineticins in reproduction. Trends in Endocrinology & Metabolism, 18, 66-72. doi:10.1016/j.tem.2006.12.002
[11] Soga, T., Matsumoto, S., Oda, T., Saito, T., Hiyama, H., Takasaki, J., Kamohara, M., Ohishi, T., Matsushime, H. and Furuichi, K. (2002) Molecular cloning and characterization of prokineticin receptors. Biochemica et Biophysica Acta, 1579, 173-179.
[12] Kaser, A., Winklmayr, M., Lepperdinger, G. and Kreil, G. (2003) The AVIT family. Secreted cysteine rich vertebrate proteins with diverse functions. EMBO Reports, 4, 469-473. doi:10.1038/sj.embor.embor830
[13] Zhang, L., Yang, N., Conejo-Garcia, J.R., Katsaros, D., Mohamed-Hadley, A., Fracchioli, S., Schlienger, K., Toll, A., Levine, B., Rubin, S.C. and Coukos, G. (2003) Expression of endocrine gland-vascular endothelial growth factor in ovarian carcinoma. Clinical Cancer Research, 9, 264-272.
[14] Ferrara, N., Frantz, G., LeCouter, J., Dillard-Telm, L., Pham, T., Dreaksharapu, A., Giordano, T. and Peale, F. (2003) Differential expression of the angiogenic factor genes vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF in normal and polycystic human ovaries. The American Journal of Pathology, 162, 1881-1893. doi:10.1016/S0002-9440(10)64322-2
[15] Fraser, H.M., Bell, J., Wilson, H., Taylor, P.D., Morgan, K., Anderson, R.A. and Duncan, W.C. (2005) Localization and quantification of cyclic changes in the expression of endocrine gland vascular endothelial growth factor in the human corpus luteum. The Journal of Clinical Endocrinology & Metabolism, 90, 427-434.
[16] Lin, D.C., Bullock, C.M., Ehlert, F.J., Chen, J.L., Tian, H. and Zhou, Q.Y. (2002) Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. The Journal of Biological Chemistry, 277, 19276-19280. doi:10.1074/jbc.M202139200
[17] Kisloiuk, T., Podlovni, H., Spanel-Borowski, K., Ovadia, O., Zhou, Q.Y. and Meidan, R. (2005) Prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) in the bovine ovary: Expression and role as mitogens and survival factors for corpus luteum-derived endothelial cells. Endocrinology, 146, 3950-3958. doi:10.1210/en.2005-0297
[18] Kisliouk, T., Podlovni, H. and Meidan, R. (2005) Unique expression and regulatory mechanisms of EG-VEGF/ prokineticin1 and its receptors in the corpus luteum. Annals of Anatomy, 187, 529-537. doi:10.1016/j.aanat.2005.07.005
[19] Kisliouk, T., Friedman, A., Klipper, E., Zhou, Q.Y., Schams, D., Alfraidy, N. and Meidan, R. (2007) Expression pattern of prokineticin 1 and its receptors in bovine ovaries during the estrous cycle: Involvememt in corpus luteum regression and follicular atresia. Biology of Reproduction, 76, 749-758. doi:10.1095/biolreprod.106.054734
[20] Plaks, V., Kachenko, V., Dekel, N. and Neeman, M. (2006) MRI analysis of angiogenesis during mouse embryo implantation. Magnetic Resonance in Medicine, 55, 1013-1022.
[21] Plaks, V., Bimberg, T., Beerkutzki, T., Sela, S., Ben Yashar, A., Kalchenko, V., Mor, G., Keshet, D., Dekel, N., Neeman, M. and Jung, S. (2008) Uterine DC’s are crucial for decidua formation during embryo implantation. Journal of Clinical Investigation, 118, 3954-3965.
[22] Battersby, S., Critchley, H.O., Morgan, K., Millar, R.P. and Jabbour, H.N. (2004) Expression and regulation of the prokineticins (endocrine gland derived vascular endothelial growth factor and Bv8) and their recptors in the human endometrium across the menstrual cycle. The Journal of Clinical Endocrinology & Metabolism, 89, 2463-2469. doi:10.1210/jc.2003-032012
[23] Evans, J., Catalano, R.D., Morgan, K., Critchley, H.O., Millar, R.P. and Jabbour, H.N. (2008) Prokineticin 1 signalling and gene regulation in early human pregnancy. Endocrinology, 149, 2877-2887. doi:10.1210/en.2007-1633
[24] Evans, J., Catalano, R.D., Brown, P., Sherwin, R., Critchley, H.O., Fazleabas, A.T. and Jabbour, H.N. (2009) Prokineticin 1 mediates fetal-maternal dialogue regarding endometrial leukemia inhibitory factor. The FASEB Journal, 23, 2165-2175. doi:10.1096/fj.08-124495
[25] Maldonado-Perez, D., Evans, J., Denison, F., Millar, R.P., Thompson, E.A. and Jabbour, H.N. (2009) Prokineticin 1 modulates IL-8 expression via the calcineurin/NFAT signaling pathway. Biochimica et Biophysica Acta, 1793, 1315-1324. doi:10.1016/j.bbamcr.2009.03.008
[26] Ngan, E.S., Lee, K.Y., Yeung, W.S., Ngan, H.Y., Ng, E.H. and Ho, P.C. (2006) Endocrine gland-derived vascular endothelial growth factor is expressed in human periimplantation endometrium, bit not in endometrial carcinoma. Endocrinology, 147, 88-95. doi:10.1210/en.2005-0543
[27] Cook, I.H., Evans, J., Maldonaldo-Perez, D., Critchley, H.O., Sales, K.J. and Jabbour, H.N. (2010) Prokineticin 1 (PROK1) modulates interleukin (IL)-11 expression via prokineticin receptor 1 (PROKR1) and the calcineurin/ NFAT signaling pathway. Basic Science of Reproductive Medicine, 16, 158-169. doi:10.1093/molehr/gap084
[28] Dimitriadis, S., Robb, L. and Salamonsen, L.A. (2002) Interleukin 11 advances progesterone induced decidualization of human endometrial stromal cells. Basic Science of Reproductive Medicine, 8, 636-643. doi:10.1093/molehr/8.7.636
[29] Dimitriadis, E., Stoikos, C., Baca, M., Fairlie, W.D., McCoubrie, J.E. and Salamonsen, L.A. (2005) Relaxin and prostaglandin E2 regulate interleukin 11 during human endometrial stromal cell decidualization. The Journal of Clinical Endocrinology & Metabolism, 90, 3458-3465. doi:10.1210/jc.2004-1014
[30] Roh, C.R., Budhraja, V., Kim, H.S., Nelson, D.M. and Sadosky, Y. (2005) Microarrey based identification of differentially expressed genes in hypoxic term human trophoblasts and in placental villi of pregnancies with growth restricted fetuses. Placenta, 26, 319-328. doi:10.1016/j.placenta.2004.06.013
[31] Rimon, E., Chen, B., Shanks, A.L., Nelson, D.M. and Sadovsky, Y. (2008) Hypoxia in human trophoblasts stimulates the expression and secretion of connective tissue growth factor. Endocrinology, 149, 2852-2958. doi:10.1210/en.2007-1099
[32] Oh, S.Y., Song, S.E., Seo, E.S., Kim, K.H., Choi, S.J., Suh, Y.L., Sadovsky, Y. and Roh, C.R. (2009) The expression of connective tissue growth factor in pregnancies complicated by severe preeclampsia or fetal growth restriction. Placanta, 30, 981-987. doi:10.1016/j.placenta.2009.08.006
[33] Waddell, J.M., Evans, J., Jabbour, H.N. and Denison, F.C. (2011) CTGF expression is upregulated by PROK1 in early pregnancy and influence ahtr-8/Syneo Cell adhesion and network formation. Human Reproduction, 26, 67-75.
[34] Macdonald, L.J., Sales, K.J., Grant, V., Brown, P., Jabboir, H.N. and Catalano, R.D. (2011) Prokineticin 1 induces Diccopf1 expression and regulates cell proliferation and decidualization in the human endometrium. Basic Science of Reproductive Medicine, 17, 626-636. doi:10.1093/molehr/gar031
[35] Wallace, A.E., Catalano, R.D., Anderson, R.A. and Jabbour, H.N. (2011) Chemokine (C-C) motif ligand 20 os regulated by PGF (2alpha)-F-prostanoid receptor signaling in endometrial adenocarcinoma and promote cell proliferation. Molecular and Cellular Endocrinology, 331, 129-135. doi:10.1016/j.mce.2010.08.018
[36] Tulac, S., Overgaard, M.T., Hamilton, A.E., Jumbe, N.L., Suchanek, E. and Giudice, L.C. (2006) Diccopf-1 an inhibitor of Wnt signaling, is regulated by progesterone in human endometrial stromal cells. The Journal of Clinical Endocrinology & Metabolism, 91, 1453-1461. doi:10.1210/jc.2005-0769
[37] Kane, N., Jones, M., Brosens, J.J., Saunders, P.T., Kelly, R.W. and Critchley, H.O. (2008) Transforming growth factor-bera1 attenuates expression of both the progesterone receptor and dickkopf in differentiated human endometrial stromal cells. Molecular Endocrinology, 22, 716-728. doi:10.1210/me.2007-0316
[38] Salker, M., Teklenburg, G., Molokhia, M., Lavery, S., Trew, G., Aojanepang, T., Mardon, H.J., Lokugamage, A.U., Rai, R., et al. (2010) Natural selection of human embryos: Impaired decidualization of endometrium disables embryo-maternal interaction and causes recurrent pregnancy loss. PLoS One, 5, e10287. doi:10.1371/journal.pone.0010287
[39] Tiberi, F., Tropea, A., Romani, F., Apa, R., Marana, R. and Lanzone, A. (2010) Prokineticin 1, homeobox A10 and progesterone receptor messenger ribonucleic acid expression in primary cultures of endometrial stromal cells isolated from endometrium of healthy women and from eutopic endometrium of women with endometriosis. Fertility and Sterility, 94, 2558-2563. doi:10.1016/j.fertnstert.2010.03.006
[40] Su, M.T., Lin, S.H., Lee, I.W., Chen, Y.C., Hsu, C.C., Pan, H.A. and Kuo, P.L. (2010) Polymorphisms of endocrine gland-derived vascular endothelial growth factor geneand its receptor genes are associated with recurrent pregnancy loss. Human Reproduction, 25, 2923-2930. doi:10.1093/humrep/deq256
[41] Haouzi, D., Mahmoud, K., Fourar, M., Bendhaou, K., Dechaud, H., Vos, J.D., Rerne, T., Dewailly, D. and Hamamah, S. (2009) Identification of new biomarkers of human endometrial receptivity in the natural cycle. Human Reproduction, 24,198-205. doi:10.1093/humrep/den360
[42] Hoffmann, P., Feige, J.J. and Alfaidy, N. (2006) Expression and oxygen regulation of endocrine gland derived vascular endothelial growth factor/prokineticin-1 and its recptors in human placenta during early pregnancy. Endocrinology, 147, 1675-1684. doi:10.1210/en.2005-0912
[43] Hoffmann, P., Feige, J.J. and Alfaidy, N. (2007) Placental expression of EG-VEGF and its receptors PKR1 (prokineticin receptor-1) and PKR2 throughout mouse gestation. Placenta, 28, 1049-1058. doi:10.1016/j.placenta.2007.03.008
[44] Hoffmann, P., Saoudi, Y., Benharouga, M., Graham, C.H., Schaal, J.P., Mazouni, C., Feige, J.J. and Alfaidy, N. (2009) Role of EG-VEGF in human placentation: Physiological and pathological implications. Journal of Cellular and Molecular Medicine, 13, 2224-2235. doi:10.1111/j.1582-4934.2008.00554.x
[45] Dorsch, M., Qiu, Y., Soler, D., Frank, N., Duong, T., Gooearl, A., O’Neil, S., Lora, J. and Fraser, C.C. (2005) PK1/EG-VEGF-induces monocyte differentiation and activation. Journal of Leukocyte Biology, 78, 426-434. doi:10.1189/jlb.0205061
[46] Shojaei, F., Singh, M., Thompson, J.D. and Ferrara, N. (2008) Role of bv8 in neutrophil dependent angiogenesis in a transgenic model of cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 105, 2675-2684. doi:10.1073/pnas.0712185105
[47] Zhong, C., Qu, X., Tan, M., Meng, Y.G. and Ferrara, N. (2009) Characterization and regulation of bv8 in human blood cells. Clinical Cancer Research, 15, 2675-2684. doi:10.1158/1078-0432.CCR-08-1954
[48] Denison, F.C., Battersby, S., King, A.E., Szuber, M. and Jabbour, H.N. (2008) Prokineticin-1 a novel mediator of of the inflammatory response in third trimester human placenta. Endocrinology, 149, 3470-3477. doi:10.1210/en.2007-1695
[49] Bollapragada, S., Youssef, R., Jordan, F., Greer, I., Norman, J. and Nelson, S. (2009) Term labour is associated with core inflammatory response in human fetal membranes, myometrium and cervix. American Journal of Obstetrics and Gynecology, 200, 104. e1-e11.
[50] Gorowiec, M.R., Catalano, R.D., Norman, J.E., Denison, F.C. and Jabbour, H.N. (2011) Prokineticin 1 induces inflammatory response in human myometrium: A Potential role in initiating term and preterm parturition. The American Journal of Pathology, 179, 2709-2719. doi:10.1016/j.ajpath.2011.08.029
[51] Catalano, R.D., Lannagan, T.R.M., Gorowiec, M., Denison, F.C., Norman, J.E. and Jabbour, H.N. (2010) Prokineticins: Novel mediators of inflammatory and contractile pathways at parturition? Molecular Human Reproduction, 16, 311-319. doi:10.1093/molehr/gaq014
[52] Brouillet, S., Hoffmann, P., Benharouga, M., Salomon, A., Schaal, J.P., Feige, J.J. and Alfaidy, N. (2010) Molecular characterization of EG-VEGF-mediated angiogenesis: Differential effects on microvascular and macrovascular endothelial cells. Molecular Biology of Cell, 21, 2832-2843. doi:10.1091/mbc.E10-01-0059
[53] Brouillet, S., Hoffmann, P., Chauvet, S., Salomon, A., Chamboredon, S., Sergent, F., Benharouga, M., Feige, J.J. and Alfaidy, M. (2012) Revisiting the role of hCG: New regulation of the angiogenic factor EG-VEGF and its receptors. Cellular and Molecular Life Sciences, 69, 1537-1550. doi:10.1007/s00018-011-0889-x
[54] Nugent, J.L., Wareing, M., Palin, V., Sibley, C.P., Baker, P.N., Ray, D.W., Farrow, S.N. and Jones, R.L. (2013) Chronic glucocorticoid exposure potentiates placental chorionic plate artey constriction: Implications for aberrant fetoplacental vascular resistance in fetal growth restriction. Endocrinology, 154, 876-887. doi:10.1210/en.2012-1927
[55] Feflea, S., Maria, A., Cimpean, A.M., Ceausu, R.A., Gaje, P. and Raica, M. (2012) Effects of antibodies to EGVEGF on angiogenesis in the chick embryo chorioallantoic membrane. In Vivo, 26, 793-797.
[56] Jabbour, H.N., Kelly, R.W., Fraser, H.M. and Critchley, H.O. (2006) Endocrine regulation of menstruation. Endocrine Reviews, 27, 17-46.
[57] Shaw, J.L., Oliver, E., Lee, K.F., Entrican, G., Jabbour, H.N., Critchley, H.O. and Horne, A.W. (2010) Cotinine exposure increases fallopian tube PROKR1 expression via nicotinic AchR(alpha)-7: A potential mechanism explaining the link between smoking and tubal ectopic pregnancy. The American Journal of Pathology, 177, 2509-2515. doi:10.2353/ajpath.2010.100243
[58] Shaw, J.L., Wills, G.S., Lee, K.E., Horner, P.J., McClure, M.O., Abrahams, V.M., Wheelhouse, N., Jabbour, H.N., Critchley, H.O., Entrican, G. and Horne, A.W. (2011) Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFkappaB activation resulting in a microenvironment predisposed to ectopic pregnancy. The American Journal of Pathology, 178, 253-260. doi:10.1016/j.ajpath.2010.11.019
[59] Ji, Y.F., Chen, L.Y., Xu, K.H., Yao, J.F. and Shi, Y.F. (2009) Locally elevated leukemia inhibitory factor in the inflamed fallopian tube resembles that found in tubal pregnancy. Fertility and Sterility, 91, 2308-2314. doi:10.1016/j.fertnstert.2008.01.110
[60] LeCouter, J., Lin, R., Tejada, M., Frantz, G., Peale, F., Hillan, K.J. and Ferrara, N. (2003) The endocrine-glandderived VEGF homologue bv8 promotes angiogenesis in the testis: Localization of bv8 receptors to endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 2685-2690. doi:10.1073/pnas.0337667100
[61] Wechselnberger, C., Puglisi, R., Engel, E., Lepperdinger, G., Boitani, C. and Kreil, G. (1999) The mammalian homologues of frog bv8 are mainly expressed in spermatocytes. FEBS Letters, 462, 177-181. doi:10.1016/S0014-5793(99)01473-8
[62] Sampson, M., Peale Jr., F.V., Frantz, G., Rioux-Leclercq, N., Rajpert De Meyts, E. and Ferrara, N. (2004) 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. The Journal of Clinical Endocrinology & Metabolism, 89, 4078-4088. doi:10.1210/jc.2003-032024
[63] Lin, R., LeCouter, J., Kowalski, J. and Ferrara, N. (2002) Characterization of endocrine gland derived vascular endothelial growth factor signaling in adrenal cortex capillary endothelial cells. The Journal of Biological Chemistry, 277, 8724-8729. doi:10.1074/jbc.M110594200
[64] Aston, K.L. and Carrell, D.I. (2009) Genome-wide study of single-nucleotide polymorphisms associated with azoospermia and severe oligozoospermia. Journal of Andrology, 30, 711-725. doi:10.2164/jandrol.109.007971
[65] Tu, L.H., Yu, L.L., Xiong, C.L. and Zhang, H.P. (2012) Potential role of prokineticin 2 in experimental varicocoele-induced rat testes. Urology, 80, 952.e15-e19.
[66] Pasquali, D., Rossi, V., Staibano, S., DeRosa, G., Chieffi, P., Prezioso, D., Mirone, V., Mascolo, M., Tramantano, D., Bellastella, A. and Sinisi, A.A. (2006) The endocrine gland-derived vascular endothelial growth factor (EGVEGF/prokineticin 1 and 2 and receptor expression in human prostate: Upregulation of EG-VEGF/prokineticin 1 with malignancy. Endocrinology, 147, 4245-4251. doi:10.1210/en.2006-0614
[67] De la Iglesia, H.O. and Schwaerz, W.J. (2006) Minireview: Timely ovulation: Circadian regulation if the femalehypothalamo-pituitary-gonadalaxis. Endocrinology, 2147, 1148-1153.
[68] Ward, D.R., Dear, F.M., Ward, J.A., Anderson, S.I., Spergel, D.J., Smith, P.A. and Ebling, F.J. (2009) Innervation of gonadotropin-releasing hormones neurons by peptidergic neurons conveying circadian or energy balance information in the mouse. PLoS One, 4, e5.322.
[69] Pitteloud, N., Zhang, C., Pognatelli, D., Li, J.D., Raivio, T., Cole, L.W., Plumer, L.W., Jacobson-Dickman, E.E., Mellon, P.L., Zhou, Q.Y. and Crowley Jr., W.F. (2007) Loss of function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proceedings of the National Academy of Sciences of the United States of America, 104, 17447-17452. doi:10.1073/pnas.0707173104
[70] Matsumoto, S., Yamazaki, C., Masumoto, K.H., Nagano, M., Naito, M., Soga, T., Hiyama, H., Matsumoto, M., Tkasaki, J., Kamohara, M., Matsuo, A., Ishii, H., Kabori, M., et al. (2006) Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proceedings of the National Academy of Sciences of the United States of America, 103, 4140-4145. doi:10.1073/pnas.0508881103
[71] Martin, C., Balasubramanium, R., Dwyer, A.A., Au, M.G., Sidis, Y., Kaiser, U.B., Seminara, S.B., Pitteloud, N., Zhou, Q.Y. and Crowley Jr., W.F. (2011) The role of the prokineticin 2 pathway in human reproduction: Evidence from the study of human and murine mutations. Endocrine Reviews, 32, 225-246. doi:10.1210/er.2010-0007
[72] Dode, C., Teixeira, L., Levvilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.L., Lespinasse, J., LienhartRoussie, A., Mathew, M., Mierman, A., et al. (2006) Kalmann syndrome: Mutations in the genes encoding prokineticin 2 and prokineticin receptor 2. PLoS Gene, 2, e175.
[73] Cole, L.W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignarelli, D., Hughes, V.A., Dwyer, A.A., Raivio, T., Hayes, F.J., Seminara, S.B., Huot, C., Alos, N., Speiser, P., Takeshita, A., et al. (2008) Mutations in prokineticin2 and prokineticin receptor genes in human gonadotrophin-releasing hormone deficiency: Molecular genetics and clinical spectrum. The Journal of Clinical Endocrinology & Metabolism, 93, 3551-3559. doi:10.1210/jc.2007-2654
[74] Leroy, C., Fouveaut, C., Leclercq, S., Jacquemont, S., Boullay, H.D., Lespinasse, J., Delpech, M., Dupont, J.M., Hardelin, J.P. and Dode, C. (2008) Biallelic mutations in the prokineticin gene in two sporadic case of Kallmann syndrome. European Journal of Human Genetics, 16, 865-868. doi:10.1038/ejhg.2008.15
[75] Sinisi, A.A., Asci, R., Bellastella, G., Maione, L., Esposito, D., Elefante, A., DeBellis, A., Bellastella, A. and Iolascon, A. (2008) Homozygous mutation in the prokineticin receptor 2 gene (Val 274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: Case report. Human Reproduction, 23, 2380-2384. doi:10.1093/humrep/den247
[76] Abreu, A.P., Trarbach, E.B., de Castro, M., Frade-Costa, E.M., Versiani, B., Matias-Baptista, M.T., Garmes, H.M., Mendonca, B.B. and Latronico, A.C. (2008) Loss of function mutations in the genes encoding prokineticin 2 or prokineticin receptor 2 cause autosomal recessive Kallmann syndrome. The Journal of Clinical Endocrinology & Metabolism, 93, 4113-4118. doi:10.1210/jc.2008-0958
[77] Canto, P.M., Munguia, P., Soderlund, D., Castro, J.J. and Mendez, J.P. (2009) Genetic analysis in patients with Kallmann syndrome: Coexisrence of mutations prokineticin receptor 2 and KAL1. Journal of Andrology, 30, 41-45. doi:10.2164/jandrol.108.005314
[78] Sarfati, J., Guiochon-Mantel, A., Rondard, P., Arnulf, L., Garcio-Pinero, A., Wolczynski, S., Brailly-Tabard, S., Bidet, M., Ramos-Arroyo, M., Mathieu, M., LienhardtRoussie, A., Morgan, G., et al. (2010) A comparative phenotypic study of Kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. The Journal of Clinical Endocrinology & Metabolism, 85, 659-669. doi:10.1210/jc.2009-0843
[79] Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.P., Hardelin, J.P. and Rondard, P. (2009) PROKR2 missense mutations associated with Kallmann syndrome impair receptor signaling activity. Human Molecular Genetics, 18, 75-81. doi:10.1093/hmg/ddn318
[80] Balasubramaniam, R., Plummer, L., Sidis, Y., Pitteloud, N., Cecila, N., Zhou, Q.Y. and Crowley Jr., W.F. (2011) The puzzles of the prokineticin 2 pathway in human reproduction. Molecular and Cellular Endocrinology, 346, 44-50. doi:10.1016/j.mce.2011.05.040
[81] Plana, A.M., Villanueva, C., Laccourreye, O., Bonfils, P. and de Roux, N. (2013) PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency. European Journal of Endocrinology, 168, 31-37. doi:10.1530/EJE-12-0578
[82] Lewkowitz-Shupntoff, H.M., Hughes, V.A., Plummer, L., Au, M.G., Doty, R.L., Seminara, S.B., Chan, Y.M., Potteloud, N., Crowley Jr., W.F. and Balasubramaniam, R. (2012) Olfactory phenotypic spectrums in idiopathic hypogonadotropic hypogonadism: Pathophysiological and genetic implications. The Journal of Clinical Endocrinology & Metabolism, 97, E136-E144. doi:10.1210/jc.2011-2041
[83] Hardelin, J.P. and Dode, C. (2008) The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sexual Development, 2, 181-193. doi:10.1159/000152034
[84] Chan, Y.M., De Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H.B., Crowley Jr., W.F., Amory, K., Pitelloud, N. and Seminara, S.B. (2009) GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proceedings of the National Academy of Sciences of the United States of America, 106, 11703-11708. doi:10.1073/pnas.0903449106
[85] Peng, Z., Tang, Y., Luo, H., Jiang, F., Sun, L. and Li, J.D. (2011) Disease causing mutation in PKR2 receptor reveals a critical role of positive charges in the second intracellular loop for G-protein coupling and receptor trafficking. The Journal of Biological Chemistry, 286, 16615-16622. doi:10.1074/jbc.M111.223784
[86] Abreu, A.P., Noel, S.D., Xu, S., Carroll, R.S., Ltronico, A.C. and Kaiser, U.B. (2012) Evidence of the first intracellular loop of prokineticin receptor 2 in receptor function. Molecular Endocrinology, 26, 1417-1427. doi:10.1210/me.2012-1102
[87] Abreu, A.P., Kaiser, U.B. and Latronico, A.C. (2010) The role of prokineticins in the pathogenesis of hypogonado tropic hypogonadism. Neuroendocrinology, 91, 81-90. doi:10.1159/000308880
[88] Kishi, T., Kitajima, T., Tsunoka, T., Okumura, T., Ikeda, M., Okochi, T., Kinoshita, Y., Kawashima, K., Yamanouchi, Y., Ozaki, N. and Iwara, N. (2009) Possible association of prokineticin receptor 2 gene (PROKR2) with mood disorders in the Japanese population. Neuromolecular Medicine, 11, 114-122.
[89] Caronia, L.M., Martin, C., Welt, K.C., Sykiotis, G.P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer-Hughes, V.A., Seminara, S.B., et al. (2011) A genetic basis for functional hypothalamic amenorrhea. The New England Journal of Medicine, 364, 215-225. doi:10.1056/NEJMoa0911064
[90] Reynaud, R., Jayakody, S.A., Monnier, C., Saveanu, A., Bouligand, J., Guedj, A.M., Simonin, G., Lecomte, M., Barlier, A., Rondard, P., Martinez-Barbera, J.P., Guiochon-Mantel, A. and Brue, T. (2012) PROKR2 variants in multiple hypopituitarism with pituitary stalk interrupttion. The Journal of Clinical Endocirnology & Metabolism, 97, E1068-E1073. doi:10.1210/jc.2011-3056
[91] McCabe, M.J., Gaston-Massuet, C., Gregory, L.C., Alatzoglu, K.S., Tziaferi, V., Sbai, O., Rondard, P., Masumoto, K.H., Nagano, M., Shigeyoshi, Y., Pfiefer, M., Hulse, T., Buchanan, C.R., Potteloud, N., Martinez-Barbera, J.P. and Dattani, M.T. (2013) Variations in PROKR2 but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. The Journal of Clinical Endocirnology & Metabolism, 98, E547-E557.
[92] Raica, M., Coculescu, M., Cimpean, M. and Ribatti, D. (2010) Endocrine gland derived-VEGF is downregulated in human pituitary adenoma. Anticancer Research, 30, 3981-3986.
[93] Levit, A., Yarnitzky, T., Wiener, A., Meidan, R. and Niv, M.Y. (2011) Modeling of human prokineticin receptors: Interactions with novel small molecules binders and potential off-target drugs. PLoS One, 6, e27990.1-17.
[94] Alvarez, C., Alonso-Muriel, I., Garcia, G., Crespo, J., Bellever, J., Simon, C. and Pellicer, A. (2007) Implantation is apparently unaffected by the dopamine agonist Cabergoline when administered to prevent ovarian hyperstimulation syndrome in women undergoing assisted reproduction treatment: A pilot study. Human Reproduction, 22, 3210-3214. doi:10.1093/humrep/dem315
[95] Sykiotis, G.P., Plummer, L., Hughes, V.A., Au, M., Durrani, S., Young, S.N., Dwyer, A.A., Quinton, R., Hall, J.E., Gusella, J.F., Seminara, S.B., Crowley Jr., W.F. and Pitteloud, N. (2010) Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proceedings of the National Academy of Sciences of the United States of America, 107, 15140-15144. doi:10.1073/pnas.1009622107

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