Prokineticin 1 Signaling and Gene Regulation in Early Human Pregnancy

Abstract

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 hematopoiesis. The objective of this study was to investigate the role of PROK1 and prokineticin receptor 1 (PROKR1) in human endometrium during early pregnancy. PROK1 and PROKR1 expression is significantly elevated in first-trimester decidua, compared with nonpregnant endometrium. Expression of PROK1 and PROKR1 was localized in glandular epithelial and various cellular compartments within the stroma. To investigate the signaling pathways and target genes activated by PROK1, we generated an endometrial epithelial cell line stably expressing PROKR1 (Ishikawa PROKR1 cells). PROK1-PROKR1 interaction induced inositol phosphate mobilization and sequential phosphorylation of c-Src, epidermal growth factor receptor, and ERK 1/2. Gene microarray analysis on RNA extracted from Ishikawa PROKR1 cells treated with 40 nm PROK1 for 8 h revealed 49 genes to be differentially regulated. A number of these genes, including cyclooxygenase (COX)-2, leukemia inhibitory factor, IL-6, IL-8, and IL-11 are regulated in the endometrium during implantation and early pregnancy. We subsequently investigated the effect of PROK1 on expression of COX-2 in Ishikawa PROKR1 cells and first-trimester decidua. COX-2 mRNA and protein expression, and prostaglandin synthesis, were elevated in response to treatment with PROK1. Moreover, expression of COX-2 by PROK1 was dependent on activation of the Gq-phospholipase C-beta-cSrc-epidermal growth factor receptor-MAPK/ERK kinase pathway. These data demonstrate that PROK1 and PROKR1 expression is elevated in human decidua during early pregnancy and that PROK1-PROKR1 interaction regulates expression of a host of implantation-related genes.

Cotinine Exposure Increases Fallopian Tube PROKR1 Expression via Nicotinic AChRα-7

“…10 The difficulty in studying implantation is that tissues are collected after an implantation event has occurred, making it hard to ascertain whether differences observed are the result of a predisposing factor or implantation itself. However, our previous findings, 10 together with the purported roles of PROK1 in intrauterine implantation, [13][14][15] led us to hypothesize that dysregulated PROKR1 expression might predispose the tubal environment to ectopic pregnancy.…”

“…PROK1 has been demonstrated to regulate the expression of genes important for implantation, such as cyclooxygenase 2 (COX2), dickkhopf-1 (DKK1), and LIF, in the human endometrium. 13 Furthermore, PROK1 was recently reported to enhance the adhesion of human trophoblast cells to extracellular matrix proteins. 15 This effect was shown to be mediated through PROK1 upregulation of LIF, suggesting that increased PROK1 activity may result in enhanced endometrial receptivity.…”

Role of EG-VEGF in Human Placentation: Physiological and Pathological Implications

“…The group of Jabbour (Cook et al, 2010,Evans et al, 2008, Maldonado-Perez et al, 2007 has reported the localization of EG-VEGF and that of its receptors in term placenta and decidua; studied its signaling pathways, and demonstrated the effect of EG-VEGF on the expression of two inflammatory and vascular mediators, the cyclooxygenase (COX)-2 and IL-8 in thirdtrimester placentas. IL-8 is a potent neutrophil chemoattractant and angiogenic factor, promoting endothelial cell chemotaxis (Winkler, 2003), whereas COX-2 is the inducible isoform of the enzyme involved in the synthesis of prostaglandins from arachidonic acid.…”

“…The labor onset is known to be associated with inflammatory cascades in the uteroplacental unit, and EG-VEGF has been shown to regulate the production of proinflammatory cytokines and to be involved in the inflammatory response in the placenta (Catalano et al, 2010, Denison et al, 2008, Evans et al, 2008. Therefore, antagonism of prokineticin action may provide a therapy for preterm labor caused by early inflammation and contractile pathways.…”

Role of Prokineticin in Epicardial Progenitor Cell Differentiation to Regenerate Heart

“…Prokineticin-1 via PKR1 regulates expression of host implatation-related gene. (Evans, et al, 2008) Dysregulation of Prokineticin signaling in fallopian tube could affect fallopian tube smooth muscle cells contractility and embryo-tubal transport providing a potential cause for ectopic pregnancy (Shaw, et al, 2010) Prokineticin-1 and its receptor gene polymorphism and haplotype were associated with idiopathic recurrent pregnancy loss. These three gene contribute to recurent pregnancy loss in the Taiwanese Han population (Su, et al) Kallman syndrome Insufficient prokineticin signaling leads to abnormal development of the olfactory system and reproductive axis in man (Dode, et al, 2006) Mutation in prokineticin-2 and PKR2 genes underlie both Kallman sydrome and idiopathic hypogonadotropic hypogonadism (Cole, et al, 2008) Behaviour Prokineticin-2 may play a role in the pathophysiology of mood disorders in the Japanese population (Kishi, et al, 2009) Prokineticin-2 may play a role in the pathophysiology of methamphetamine dependance in the Japanese population (Kishi, et al, 2010) …”