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1.
Prokineticins are a novel family of secreted peptides with diverse regulatory roles, one of which is their capacity to modulate immunity in humans and in other species. Prokineticins are small peptides of 8 kDa that mediate their biological activities by signaling through two homologous G-protein-coupled receptors (prokineticin receptor 1 and prokineticin receptor 2). This family of peptides is characterized by a completely conserved N-terminal hexapeptide crucial for their bioactivities and a unique structural motif comprising five disulfide bonds. Prokineticins and their receptors are highly expressed in bone marrow, in peripheral circulating leukocytes, in inflamed tissues and in resident organ immune cells. Their structure, size, signaling and biological activities are reminiscent of the chemokine superfamily. In this review, emphasis is placed on the properties of prokineticins as cytokines and their role in the immune system. 相似文献
2.
Prokineticin signaling comprises two secreted proteins (Prok-1 and Prok-2) and two cognate G-protein coupled receptors (PK-R1 and PK-R2) that are widely expressed in different tissues and of great versatility. Prokineticins were originally identified as the potent agents mediating gut motility in the digestive system, but were later shown to promote angiogenesis in steroidgenic glands, heart and reproductive organs. Prokineticins also modulate neurogenesis, circadian rhythms, nociception, haematopoiesis as well as immune response. Their diverse biological functions and functional complexity are exquisitely mediated by the distinct expression pattern and the multiple G-protein coupling of the receptors and ligands. Emerging evidence indicated that prokineticins are also associated with pathologies of the reproductive and nervous systems, myocardial infarction and tumorigenesis. The physiological and patho-physiological roles of prokineticin signaling are just beginning to be revealed and a better understanding of the system should lead to the development of useful therapies for various diseases. 相似文献
3.
Molecular cloning and characterization of prokineticin receptors 总被引:5,自引:0,他引:5
Soga T Matsumoto Si Oda T Saito T Hiyama H Takasaki J Kamohara M Ohishi T Matsushime H Furuichi K 《Biochimica et biophysica acta》2002,1579(2-3):173-179
Recent studies have identified two novel biofunctional proteins, termed prokineticin 1/EG-VEGF and prokineticin 2, which were mammalian homologues of mamba MIT1 and frog Bv8. Prokineticins have been demonstrated to exert their physiological functions through G-protein coupled receptors (GPCRs). In this study, we report the molecular identification of two endogenous prokineticin receptors, designated PK-R1 and PK-R2, through a search of the human genomic DNA database. PK-R1, locating in chromosome 2, and PK-R2, locating in chromosome 20p13, shared 87% homology, which was an extremely high value among known GPCRs. In functional assays, mammalian cells expressing PK-Rs responded to prokineticins in a concentration-dependent manner. Tissue distribution analysis revealed that expression of PK-R1 was observed in the testis, medulla oblongata, skeletal muscle and skin, while that of PK-R2 showed preferential expression in the central nervous system. The tissue distribution of PK-Rs reported in this paper suggests that the prokineticins play multifunctional roles in vivo. 相似文献
4.
Bv8/Prokineticin proteins and their receptors 总被引:1,自引:0,他引:1
The Bv8/Prokineticins (PKs) are a new family of peptides identified in frog, fish, reptiles and mammals that signal through two highly homologous G-protein coupled receptors, PKR1 and PKR2. Bv8/PK proteins possess a unique structural motif comprising five disulfide bonds and a completely conserved N-terminal hexapeptide sequence that is essential for the peptide's biological activities. Over the past few years, several biological functions of Bv8/PK proteins have been elucidated. This review considers all the published data on the action and physiological role of this new biological system implicated in angiogenesis and neurogenesis, in reproduction and cancer and in regulating physiological functions that underly circadian rhythms, such as the sleep/wake cycle, hormone secretion and ingestive behaviors. The high expression level of human Bv8/PK2 in bone marrow, lymphoid organs and leukocytes suggested an involvement of these peptides in hematopoiesis and in inflammatory and immunomodulatory processes. Our review highlights the role of the Bv8/PK and their receptor system in setting the pain threshold under normal and pathological conditions. 相似文献
5.
Peptidergic hormones, neurotransmitters, and neuromodulators are extracellular signaling molecules that play central roles in physiological signal transmissions between various cells, tissues, and organs. These factors are primarily translated as inactive precursor proteins according to the genetic information. These precursor proteins are then cleaved by various proteases including signal peptidases and processing enzymes to produce matured bioactive factors. During these processes, various fragmented peptides are also produced from the same precursor proteins. Such fragmented peptides may have various unexpected biological activities that have not been identified yet because these peptides are considered to be produced and released along with mature factors at the same secretary pathways. Recently, we found that various fragmented peptides of mitochondrial proteins that are produced during the maturation processes, such as fragments of cytochrome c oxidase, activate neutrophils whose functions are distinct from their parent proteins. These findings suggest the existence of many different functional peptides whose functions have not been identified yet. These unidentified peptides may play a variety of roles in various regulatory mechanisms, and therefore, they are expected to provide novel regulatory and signaling mechanisms, "Peptide World". 相似文献
6.
Prokineticins are small (approximately 8 kDa), biologically active secretory proteins whose primary structures have been highly conserved throughout the Animal Kingdom. Representatives have been identified in the defensive skin secretions of several amphibians reflecting the immense structural/functional diversity of polypeptides in such. Here we describe the identification of a prokineticin homolog (designated Bo8) from the skin secretion of the Oriental fire-bellied toad (Bombina orientalis). Full primary structural characterization was achieved using a combination of direct Edman microsequencing, mass spectrometry and cloning of encoding skin cDNA. The latter approach employed a recently described technique that we developed for the cloning of secretory peptide cDNAs from lyophilized skin secretion, and this was further extended to employ lyophilized skin as the starting material for cDNA library construction. The Bo8 precursor was found to consist of an open-reading frame of 96 amino acid residues consisting of a putative 19-residue signal peptide followed by a single 77-residue prokineticin (Mr=7990 Da). Amino acid substitutions in skin prokineticins from the skin secretions of bombinid toads are confined to discrete sites affording the necessary information for structure/activity studies and analog design. 相似文献
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8.
Modulation of the ComA-dependent quorum response in Bacillus subtilis by multiple Rap proteins and Phr peptides
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In Bacillus subtilis, extracellular peptide signaling regulates several biological processes. Secreted Phr signaling peptides are imported into the cell and act intracellularly to antagonize the activity of regulators known as Rap proteins. B. subtilis encodes several Rap proteins and Phr peptides, and the processes regulated by many of these Rap proteins and Phr peptides are unknown. We used DNA microarrays to characterize the roles that several rap-phr signaling modules play in regulating gene expression. We found that rapK-phrK regulates the expression of a number of genes activated by the response regulator ComA. ComA activates expression of genes involved in competence development and the production of several secreted products. Two Phr peptides, PhrC and PhrF, were previously known to stimulate the activity of ComA. We assayed the roles that PhrC, PhrF, and PhrK play in regulating gene expression and found that these three peptides stimulate ComA-dependent gene expression to different levels and are all required for full expression of genes activated by ComA. The involvement of multiple Rap proteins and Phr peptides allows multiple physiological cues to be integrated into a regulatory network that modulates the timing and magnitude of the ComA response. 相似文献
9.
During the past decades, bioactive (regulatory) peptides have been identified as the major players in the regulation of many important biological processes. Dozens of peptides have found their application as pharmaceutical agents, which further stimulated research in this field making it one of the most rapidly developing areas on the edge of biological science and medicine. However, the fast accumulation of enormous amounts of experimental data has revealed a great difficulty in their analysis and demanded the development of a systematic approach for generalization of the obtained information. We propose a new computer-based algorithm for studying biological activities of regulatory peptides and their groups based on their representation as vectors in n -dimensional functional space. Our method allows the rapid analysis of databases containing thousands of polyfunctional regulatory peptides with overlapping spectra of physiological activity. The described method permits to perform several types of correlations which, when applied to the large databases, could reveal new important information about the system of regulatory peptides. It can select the groups of peptides with similar physiological role (peptide constellations) and search for the optimal peptide combinations with predetermined spectrum of effects and minimal side effects for their further pharmacological application. It can also reveal the role of regulatory peptides in induction of chain physiological reactions. 相似文献
10.
Mara Castelli Giada Amodeo Lucia Negri Roberta Lattanzi Daniela Maftei Cecilia Gotti Francesco Pistillo Valentina Onnis Cenzo Congu Alberto E. Panerai Paola Sacerdote Silvia Franchi 《PloS one》2016,11(1)
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease. 相似文献
11.
Membrane-bound peptidases play a key role in the control of growth, differentiation, and signal transduction of many cellular systems by degrading bioactive peptides. Thus, abnormal changes in their expression pattern and catalytic function result in altered peptide activation, which contributes to neoplastic transformation or progression. In this review, we describe our recent findings along with work from other groups on the expression and biological functions of membrane-bound peptidases in cancer, focusing on the regulatory roles of three peptidases, aminopeptidase A (APA), neutral endopeptidase (NEP) and placental leucine aminopeptidase (P-LAP), in the progression of gynecologic malignancies. APA, NEP and P-LAP are differentially expressed and localized in various gynecologic malignancies including cervical cancer, endometrial cancer, ovarian cancer and choriocarcinoma in a tumor-type specific pattern. The expression levels are up- or down-regulated depending on histological grade or disease progression. These peptidases play regulatory roles in tumor cell proliferation, invasion or angiogenesis via degradation/inactivation of target peptides such as angiotensin II, endothelin-1 and oxytocin, which act on cancer cells as stimulatory or inhibitory factors. Thus, membrane-bound peptidases may become not only a new diagnostic/prognostic marker, but also a novel molecular target for the treatment of gynecologic malignancies. 相似文献
12.
PKs是最近发现的多功能分泌蛋白,由PK1和PK2组成.在不同的系统中,它们通过两个高度同源G-蛋白偶联受体发挥各种生物学功能.它们与神经和血管的形成以及免疫应答的调节有关,并且对生殖系统的正常生理和促性腺激素释放激素系统的发育都有很大的影响. 相似文献
13.
Diversity in mammalian tachykinin peptidergic neurons: multiple peptides, receptors, and regulatory mechanisms 总被引:31,自引:0,他引:31
The tachykinins comprise a family of closely related peptides that participate in the regulation of diverse biological processes. The tachykinin peptides substance P, neurokinin A, neurokinin A(3-10), neuropeptide K, and neuropeptide gamma are produced from a single preprotachykinin gene as a result of differential RNA splicing and differential posttranslational processing. Another tachykinin, neurokinin B, is produced from a separate preprotachykinin gene. These preprotachykinin mRNAs and peptide products are differentially distributed throughout the nervous system. Three distinct G protein-coupled tachykinin receptors exist for these tachykinin peptides. The three receptors interact differentially with the tachykinin peptides and are uniquely distributed throughout the nervous system. The NK-1 receptor preferentially interacts with substance P, the NK-2 receptor prefers neurokinin A, neuropeptide K, and neuropeptide gamma, and the NK-3 receptor interacts best with neurokinin B. Examples of the roles of tachykinin peptidergic neuronal systems are taken from the spinal cord sensory system and the nigrostriatal extrapyramidal motor system. Analysis of the functional significance of multiple tachykinin peptide systems, receptor-second messenger coupling mechanisms, and developmental and regulatory mechanisms underlying peptide mRNA and receptor expression represent areas of current and future investigation. 相似文献
14.
Xionghui Lin Marian Novotny Kenneth S?derh?ll Irene S?derh?ll 《The Journal of biological chemistry》2010,285(37):28577-28586
Hematopoiesis is the process by which hemocytes mature and subsequently enter the circulation. Vertebrate prokineticins (PKs) are known to take part in this process, as are the invertebrate prokineticin domain proteins, astakines. In Pacifastacus leniusculus, astakine 1 is essential for the release of new hemocytes into the open circulatory system of these animals. In addition to astakine 1, we have now cloned a homologue of astakine 1 with an insert of 13 amino acids, named as astakine 2. Both crustacean astakines lack the N-terminal AVIT motif, which is present in vertebrate PKs, and hence receptor binding differs from that of vertebrate PKs. We have found astakine-like sequences in 19 different invertebrate species, and the sequences show that some motifs are conserved among invertebrate groups. Previously we showed that astakine 1 is directly involved in hematopoiesis, and now we show that astakine 1 and astakine 2 have different roles in hemocyte lineage differentiation. Astakine 1 can stimulate proliferation of hematopoietic tissue (Hpt) cells (precursor of hemocytes) as well as specifically induce differentiation of Hpt cells along the semigranular cell lineage, whereas astakine 2 plays a role in granular cell differentiation. Moreover, we discuss the impact of the putative structures of different astakines in comparison with the vertebrate prokineticins. 相似文献
15.
Conformation-activity relationships of opioid peptides with selective activities at opioid receptors
The discovery of endogenous opioid peptides 25 years ago opened up a new chapter in efforts to understand the origins and control of pain, its relationships to other biological functions, including inflammatory and other immune responses, and the relationships of opioid peptides and their receptors to a variety of undesirable or toxic side effects often associated with the nonpeptide opiates such as morphine including addiction, constipation, a variety of neural toxicities, tolerance, and respiratory depression. For these investigations the need for potent and highly receptor selective agonists and antagonists has been crucial since they in principle allow one to distinguish unequivocally the roles of the different opioid receptors (mu, delta, and kappa) in the various biological and pathological roles of the opioid peptides and their receptors. Conformational and topographical constraint of the linear natural endogenous opioid peptides has played a major role in developing peptide ligands with high selectivity for mu, delta, and kappa receptors, and in understanding the conformational, topographical, and stereoelectronic structural requirements of the opioid peptides for their interactions with opioid receptors. In turn, this had led to insights into the three-dimensional pharmacophore for opioid receptors. In this article we review and discuss some of the developments that have led to potent, selective, and stable peptide and peptidomimetic ligands that are highly potent and selective, and that have delta agonist, mu antagonist, and kappa agonist biological activities (other authors in this issue will discuss the development of other types of activities and selectivities). These have led to ligands that provide unique insight into opioid pharmacophores and the critical roles opioid ligands and receptor scan play in pain, addiction, and other human maladies. 相似文献
16.
Lin DC Bullock CM Ehlert FJ Chen JL Tian H Zhou QY 《The Journal of biological chemistry》2002,277(22):19276-19280
We previously described two mammalian secreted proteins, prokineticin 1 and prokineticin 2, that potently contract gastrointestinal smooth muscle. Prokineticin 1 has also been shown to promote angiogenesis by stimulating proliferation, migration, and fenestration of endocrine organ-derived endothelial cells. Here we report the cloning and characterization of two closely related G protein-coupled receptors as receptors for prokineticins. Expression of prokineticin receptors in heterologous systems shows that these receptors bind to and are activated by nanomolar concentrations of recombinant prokineticins. Activation of prokineticin receptors leads to mobilization of calcium, stimulation of phosphoinositide turnover, and activation of p44/p42 MAPK signaling pathways that are consistent with the effects of prokineticins on smooth muscle contraction and angiogenesis. mRNA expression analysis reveals that prokineticin receptors are expressed in gastrointestinal organs, endocrine glands, and other tissues. 相似文献
17.
18.
Guvakova MA 《The international journal of biochemistry & cell biology》2007,39(5):890-909
Insulin-like growth factors I and II (IGF-I and IGF-II) have an ancient origin and play essential roles in fundamental biological processes. Although IGFs are principally known for their roles in regulating cell growth and survival, their ability to influence cell motility is just as significant. In the past 20 years, research has provided indisputable evidence for the regulatory role of IGFs in the migration of various cell types. Cell migration is crucial for reproduction, development, and tissue regeneration; IGFs play an important role in coordinating these processes. Moreover, studies continue to uncover the IGFs' role in stimulating cancer cell migration, invasion and metastasis. This review surveys current knowledge on the cell migration-modulating properties of IGFs and the biochemical pathways by which these peptides regulate cell movement in both physiological and pathological conditions. 相似文献
19.
MOTIVATION: Favorable interaction between the regulatory subunit of the cAMP-dependent protein kinase (PKA) and a peptide in A-kinase anchoring proteins (AKAPs) is critical for translocating PKA to the subcellular sites where the enzyme phosphorylates its substrates. It is very hard to identify AKAPs peptides binding to PKA due to the high sequence diversity of AKAPs. RESULTS: We propose a hierarchical and efficient approach, which combines molecular dynamics (MD) simulations, free energy calculations, virtual mutagenesis (VM) and bioinformatics analyses, to predict peptides binding to the PKA RIIα regulatory subunit in the human proteome systematically. Our approach successfully retrieved 15 out of 18 documented RIIα-binding peptides. Literature curation supported that many newly predicted peptides might be true AKAPs. Here, we present the first systematic search for AKAP peptides in the human proteome, which is useful to further experimental identification of AKAPs and functional analysis of their biological roles. 相似文献
20.
Identification of short coding sequences is challenging, both experimentally and in silico , and functional natural peptides (< 50 amino acids) have to a large extent been overlooked in Gram-negative bacteria. Recent results have converged to highlight the role of hydrophobic peptides that form a novel class of active molecules in Escherichia coli and Salmonella enterica serovar Typhimurium. These peptides can play a regulatory role by interacting with protein partners at the inner membrane and by modulating protein partner activity or stability. Genome-wide analyses in both bacterial species have identified several conserved short open reading frames encoding a single transmembrane segment. We discuss the known and predicted membrane-associated peptides and the tools for their identification. Besides the identification of novel regulatory networks, characterization of peptides with a single transmembrane helix segment and proteins that interact with them provides a powerful opportunity to study interactions between alpha helices within biological membranes. In addition, some bioactive membrane peptides could provide a basis for engineering membrane protein antagonists. 相似文献