Prokineticin
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PROVIDER: S-EPMC2884588 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
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Project description:BackgroundAngiogenesis is integral for embryogenesis, and targeting angiogenesis improves the outcome of many pathological conditions in patients. TBX20 is a crucial transcription factor for embryonic development, and its deficiency is associated with congenital heart disease. However, the role of TBX20 in angiogenesis has not been described.MethodsLoss- and gain-of-function approaches were used to explore the role of TBX20 in angiogenesis both in vitro and in vivo. Angiogenesis gene array was used to identify key downstream targets of TBX20.ResultsUnbiased gene array survey showed that TBX20 knockdown profoundly reduced angiogenesis-associated PROK2 (prokineticin 2) gene expression. Indeed, loss of TBX20 hindered endothelial cell migration and in vitro angiogenesis. In a murine angiogenesis model using subcutaneously implanted Matrigel plugs, we observed that TBX20 deficiency markedly reduced PROK2 expression and restricted intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or its cognate receptor prokr1a also limited angiogenesis. In contrast, overexpression of prok2 or prokr1a rescued the impaired angiogenesis in tbx20-deficient animals.ConclusionsOur study identifies TBX20 as a novel transcription factor regulating angiogenesis through the PROK2-PROKR1 (prokineticin receptor 1) pathway in both development and disease and reveals a novel mode of angiogenic regulation whereby the TBX20-PROK2-PROKR1 signaling cascade may act as a "biological capacitor" to relay and sustain the proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.
| S-EPMC6139092 | biostudies-literature
Project description:Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.
| S-EPMC1617130 | biostudies-literature
Project description:Successful pregnancy establishment in mammals depends on proper embryo-maternal communication. Prokineticin 1 (PROK1) is a secretory protein that exerts pleiotropic functions in various tissues. Despite the studies that have primarily been performed with human cell lines and mice, the function of PROK1 in trophoblasts has still not been fully elucidated. Hence, the aim of this study was to establish the role of PROK1 in trophoblasts during implantation and placentation. Prokineticin 1 mRNA was elevated in porcine trophoblasts during implantation and the early placentation period. Furthermore, we reveal that PROK1-PROKR1 signaling induces the expression of genes involved in the regulation of angiogenesis, immunological response, trophoblast cell adhesion, invasion, and proliferation, as well as stimulating phosphorylation of MAPK and PTK2. Ingenuity Pathway Analysis identified the aforementioned and also other functions associated with PROK1-regulated genes/proteins, such as cell-to-cell contact, epithelial tissue differentiation, Ca2+ release, lipid synthesis, and chemotaxis. We also showed evidence that PROK1 acting via PROKR1 increased trophoblast cell proliferation and adhesion. The PROK1-stimulated cell proliferation was mediated by PI3K/AKT/mTOR, MAPK, and cAMP, whereas adhesion was mediated by MAPK and/or PI3K/AKT signaling pathways. Concluding, our study suggests that PROK1 plays a pleiotropic role in trophoblast function during implantation and early placentation.
| S-EPMC8253840 | biostudies-literature
Project description:Prokineticins are a new class of chemokine-like peptides that bind their G protein-coupled receptors, PKR1 and PKR2, and promote chemotaxis and the production of pro-inflammatory cytokines following tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms of prokineticins pathway regulation that, like other chemokines, include: genetic polymorphisms; mRNA splice modulation; expression regulation at transcriptional and post-transcriptional levels; prokineticins interactions with cell-surface glycosaminoglycans; PKRs degradation, localization, post-translational modifications and oligomerization; alternative signaling responses; binding to pharmacological inhibitors. Understanding these mechanisms, which together exert substantial biochemical control and greatly enhance the complexity of the prokineticin-receptor network, leads to novel opportunities for therapeutic intervention. In this way, besides targeting prokineticins or their receptors directly, it could be possible to indirectly influence their activity by modulating their expression and localization or blocking the downstream signaling pathways.
| S-EPMC8877203 | biostudies-literature
Project description:ContextMice deficient in prokineticin 2(PROK2) and prokineticin receptor2 (PROKR2) exhibit variable olfactory bulb dysgenesis and GnRH neuronal migration defects reminiscent of human GnRH deficiency.ObjectivesWe aimed to screen a large cohort of patients with Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (IHH) for mutations in PROK2/PROKR2, evaluate their prevalence, define the genotype/phenotype relationship, and assess the functionality of these mutant alleles in vitro.DesignSequencing of the PROK2 and PROKR2 genes was performed in 170 KS patients and 154 nIHH. Mutations were examined using early growth response 1-luciferase assays in HEK 293 cells and aequorin assays in Chinese hamster ovary cells.ResultsFour heterozygous and one homozygous PROK2 mutation (p.A24P, p.C34Y, p.I50M, p.R73C, and p.I55fsX1) were identified in five probands. Four probands had KS and one nIHH, and all had absent puberty. Each mutant peptide impaired receptor signaling in vitro except the I50M. There were 11 patients who carried a heterozygous PROKR2 mutation (p.R85C, p.Y113H, p.V115M, p.R164Q, p.L173R, p.W178S, p.S188L, p.R248Q, p.V331M, and p.R357W). Among them, six had KS, four nIHH, and one KS proband carried both a PROKR2 (p.V115M) and PROK2 (p.A24P) mutation. Reproductive phenotypes ranged from absent to partial puberty to complete reversal of GnRH deficiency after discontinuation of therapy. All mutant alleles appear to decrease intracellular calcium mobilization; seven exhibited decreased MAPK signaling, and six displayed decreased receptor expression. Nonreproductive phenotypes included fibrous dysplasia, sleep disorder, synkinesia, and epilepsy. Finally, considerable variability was evident in family members with the same mutation, including asymptomatic carriers.ConclusionLoss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH.
| S-EPMC2567850 | biostudies-literature
Project description:Recurrent implantation failure(RIF) is an urgent problem to be solved in reproduction.Currently, endometrium decidualization damage is considered as one of the important causes, but the mechanism is still unclear. Prokineticin 2(PK2) is a newly discovered secreted protein with multiple biological functions, and its role in the endometrium is unknown.Our previous study showed that PK2 was significantly increased in RIF patients, but endometrial decidualization markers PRL and IGFBP1 were lower compared with the control group. We performed transcriptome sequencing, we found there were significant differences between the PK2 overexpression group and the control group. Differential genes mainly involved in decidualization process including adhesion, immunity, chemotaxis, ect.
2020-12-29 | GSE163936 | GEO
Project description:Psoriasis is histologically characterized by keratinocytes (KC) hyperproliferation, inflammation, and increased angiogenesis, but the pathological factor responsible for these symptoms is unknown. Here, a neuroendocrine peptide (prokineticin 2, PK2), is highly expressed in human and mouse psoriatic skins but no significant change in other autoimmune diseases, suggesting that PK2 is a psoriasis-specific factor. Bacterial products significantly up-regulated PK2, implying that infection induces PK2 over-expression. PK2 promoted KC and macrophage to produce interleukin-1 (IL-1), the central player of inflammation and psoriasis, which acts on adjacent fibroblast to induce inflammatory cascades and KC hyperproliferation. IL-1 feeds back on macrophages to induce PK2 production to perpetuate PK2-IL-1 positive feedback loop. PK2 also promoted angiogenesis, another psoriatic symptom. In mouse models, PK2 over-expression aggravated psoriasis while its knock-down inhibited pathological development. The results indicate that PK2 over-production perpetuates psoriatic symptoms by creating PK-2-IL-1 vicious loop. PK2 is a central player in psoriasis and a promising psoriasis-specific target.
| S-EPMC5264273 | biostudies-literature
Project description:ObjectiveTo investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease.MethodsWe investigated the expression of PK2 in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro.ResultsPk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demyelination, and decreased the production of interferon (IFN)-γ and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-γ and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen.ConclusionThese data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy.
| S-EPMC4396530 | biostudies-literature
Project description:Preeclampsia (PE) is the most threatening pathology of human pregnancy. Placenta from PE patients releases harmful factors that contribute to the exacerbation of the disease. Among these factors is the prokineticin1 (PROK1) and its receptor, PROKR2 that we identified as a mediators of PE. Here we tested the effects of PKRA, an antagonist of PROKR2, on the attenuation of PE symptoms. We used the genetic PE mouse model, STOX1 that overexpresses Stox1 gene in a heterozygosis manner in the placenta. This model allowed exploiting two genotypes of the offspring, those that overexpress the Stox1 gene, and the WT that grow in a PE environment (STE). We characterised the effect PKRA (1 μM) on the attenuation of PE symptoms and compared its effects on STOX1 and STE placentas. We also used STOX1 overexpressing trophoblast cells to decipher the PROK1-underlying mechanism. We demonstrated that (i) antagonisation of PROKR2 attenuated PE-mediated hypertension and proteinuria, (ii) STE placentas and foetuses exhibited better outcomes in response to PKRA, (iii) the secretome of STOX1-trophoblasts impacted the integrity of the fetal vasculature that was attenuated by PKRA treatment. This study demonstrates the direct involvement of the PROK1 in PE and identifies PKRA as a promising therapy for PE.
| S-EPMC11736873 | biostudies-literature
Project description:The prokineticins (PKs) were discovered approximately 20 years ago as small peptides inducing gut contractility. Today, they are established as angiogenic, anorectic, and proinflammatory cytokines, chemokines, hormones, and neuropeptides involved in variety of physiologic and pathophysiological pathways. Their altered expression or mutations implicated in several diseases make them a potential biomarker. Their G-protein coupled receptors, PKR1 and PKR2, have divergent roles that can be therapeutic target for treatment of cardiovascular, metabolic, and neural diseases as well as pain and cancer. This article reviews and summarizes our current knowledge of PK family functions from development of heart and brain to regulation of homeostasis in health and diseases. Finally, the review summarizes the established roles of the endogenous peptides, synthetic peptides and the selective ligands of PKR1 and PKR2, and nonpeptide orthostatic and allosteric modulator of the receptors in preclinical disease models. The present review emphasizes the ambiguous aspects and gaps in our knowledge of functions of PKR ligands and elucidates future perspectives for PK research. SIGNIFICANCE STATEMENT: This review provides an in-depth view of the prokineticin family and PK receptors that can be active without their endogenous ligand and exhibits "constitutive" activity in diseases. Their non- peptide ligands display promising effects in several preclinical disease models. PKs can be the diagnostic biomarker of several diseases. A thorough understanding of the role of prokineticin family and their receptor types in health and diseases is critical to develop novel therapeutic strategies with safety concerns.
| S-EPMC10595023 | biostudies-literature