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Prokineticin 2 in cancer-related inflammation
No full textInflammation, which triggers the release of a variety of growth factors, cytokines, and chemokines, is a critical component of tumor progression. Prokineticin 2 belongs to a new family of chemokines bound to two G-protein -coupled receptors called prokineticin receptor 1 and 2 that exert various tissue-specific biological functions. Under pathological conditions, prokineticin 2 can induce the proliferation, migration, and angiogenesis of endothelial cells, suggesting that this molecule plays a role in tumor growth, angiogenesis, and metastasis.The aim of this review is to provide a complete compendium of the involvement of prokineticin 2 in some cancers and to evaluate its role not only in the tumor microenvironment as an angiogenic factor and a mediator of immune cell migration, but also in modulating tumor growth and spread as a suppressor of tumor cell apoptosis, and as a trigger of their proliferation and movements required for metastasis. The involvement of prokineticin 2 in tumor pain and resistance responses is also described, and finally, the potential role of pro-kineticin 2 as a novel prognostic tumor biomarker is highlighted
Special Issue “GPCR: Roles in Cell Development and Disease”
Full text linkWe are pleased to present the following Special Issue of the International Journal of Molecular Sciences (IJMS), entitled “GPCR: Roles in Cell Development and Disease” [...
Non-Peptide Agonists and Antagonists of the Prokineticin Receptors
Full text linkThe prokineticin family comprises a group of secreted peptides that can be classified as chemokines based on their structural features and chemotactic and immunomodulatory functions. Prokineticins (PKs) bind with high affinity to two G protein-coupled receptors (GPCRs). Prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) are involved in a variety of physiological functions such as angiogenesis and neurogenesis, hematopoiesis, the control of hypothalamic hormone secretion, the regulation of circadian rhythm and the modulation of complex behaviors such as feeding and drinking. Dysregulation of the system leads to an inflammatory process that is the substrate for many pathological conditions such as cancer, pain, neuroinflammation and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The use of PKR’s antagonists reduces PK2/PKRs upregulation triggered by various inflammatory processes, suggesting that a pharmacological blockade of PKRs may be a successful strategy to treat inflammatory/neuroinflammatory diseases, at least in rodents. Under certain circumstances, the PK system exhibits protective/neuroprotective effects, so PKR agonists have also been developed to modulate the prokineticin system
Interaction of prokineticin receptors with accessory proteins
Full text linkG protein-coupled receptors (GPCRs) are transmembrane proteins that mediate the intracellular pathway of signals not only through heterotrimeric GTP-binding proteins (G proteins) but also through their associations with a variety of additional partner proteins. Prokineticin receptors 1 (PKR1) and 2 (PKR2) are new members of the GPCRs whose ligands are the novel chemokines prokineticin 1 (PK1) and prokineticin 2 (PK2). The multiplicity of G proteins coupled to PKRs, the ability of PKR2 to heterodimerize, the interaction of PKR2 with accessory proteins, and the existence of alternative splice isoforms of PKR2/PK2 explain the complexity of the system in the signal transduction pathway and, consequently, in the modulation of various physiological and pathological functions. Knowledge of these mechanisms provides the basis for the development of targeted drugs with therapeutic efficacy in PK-dependent diseases
Identification and characterization of prokineticin receptor 2 splicing variant and its modulation in an animal model of alzheimer's disease
Full text linkProkineticin 2 is a peptide that is widely distributed in the nervous system and influences a variety of brain functions, such as pain, food intake and circadian rhythms. We previously demonstrated that, in the animal model of Alzheimer’s disease, induced by the intracerebroventricular administration of Aβ1-42, there is a modulation of the prokineticin system in rat hippocampus.
Prokineticin 2 is a able to mediate its signaling through two different G-protein coupled receptors, designated PKR1 and PKR2, belonging to the neuropeptide Y receptor class. These two receptors have different tissue distributions: PKR1 is expressed in diverse peripheral organs with relatively high levels in the small intestines and lung, whereas PKR2 is predominantly expressed in the central nervous system. The PKRs activate multiple intracellular signal-transduction pathways: they are Gαq-coupled receptors and promoting intracellular calcium mobilization but they also couple to Gαi (especially PKR2) and Gαs proteins.
In rat hippocampus we identified a mRNA encoding for a PKR2 splice variant, that lacking the second exon, gives rise to a four-transmembrane protein denominated TM 4-7. Expression of this splicing variant in yeast, allowed us to demonstrate that TM 4-7 dimerizes with PKR2 long form and that this heterodimer binds to G protein subtypes with different specificity respect to PKR2 wild-type. Moreover we evidenced that, following Aβ1-42 intracerebroventricular injection in rat, the PKR2 hippocampal levels slightly increased respect to control animals whereas there was a strong up-regulation of the PKR2 splicing variant, TM 4-7. We showed that the increased levels of TM 4-7 determined a modulation of PKR2 signal transduction hindering STAT3 activation
A GATA-type transcription factor regulates expression of the high-affinity iron uptake system in the methylotrophic yeast Pichia pastoris
No full textThe ferroxidase Fet3 and the permease Ftr1 constitute a well-conserved high-affinity iron uptake system in yeast. We have investigated the mechanism of transcriptional regulation of Fet3 in the methylotrophic yeast Pichia pastoris. Isolation and functional analysis of the Fet3 promoter indicate that a GATA sequence element plays a role in iron-dependent expression of Fet3. A GATA-type transcription factor, which we have named Fep1, has been partially cloned and it is shown to belong to the family of iron-responsive fungal GATA-factors. These factors share the presence of two Cys2-Cys2 zinc-finger motifs and a set of four conserved cysteines, and are involved in the regulation of siderophore biosynthesis and/or high-affinity iron uptake. Disruption of the FEP1 gene in P. pastoris leads to constitutively high expression of Fet3, irrespective of iron levels, indicating that Fep1 is a transcriptional repressor. EMSA analyses evidence that Fep1 binds to DNA only in the presence of iron. © 2007 Elsevier Inc. All rights reserved
Defence peptides in the amphibian immune system
No full textAmphibian skin is a rich source of biologically
active compounds, such as amines, complex alkaloids
or peptides and proteins which are produced by
holocrine-type serous glands, where they are stored
and released upon stimulation. In particular, a high
number of gene-encoded antimicrobial peptides have
been isolated and characterised from amphibian skin
secretions, containing 10-50 amino acid residues.
Several of these peptides are characterised by posttranslational
modifications, such as amidation at the
C-terminal end or isomerization of an L-amino acid to the corresponding D-isomer. Here, the structural and functional properties of amphibian antimicrobial peptides, as well as the mechanisms regulating their synthesis are reviewed
Sequence of a gene from Bombina orientalis coding for the antimicrobial peptide BLP-7
No full textThe structure of a gene coding for bombinin-like peptides (BLP) in Bombina orientalis was determined. It comprises two exons separated by a 1337 bp intron. Exon 1 codes for the signal peptide, while exon 2 contains the genetic information for BLP-7 and a bombinin H-type peptide (GH-2). The promoter region contains putative recognition sites for nuclear factors, such as NF-IL6 and NF-kappaB. The analysis of the structure of this gene, compared with that of the previously reported BLP-3 gene sequence, suggests the occurrence of a gene duplication event, rather than an alternative splicing mechanism, which leads to the generation of both inter- and intra-families variability in this class of cytolytic peptides. Furthermore, walking chromosome analysis indicates that this gene family is not densely clustered. (C) 2000 Elsevier Science Inc. All rights reserved
Identification of transmembrane domains that regulate spatial arrangements and activity of prokineticin receptor 2 dimers
Full text linkThe chemokine prokineticin 2 (PK2) activates its cognate G protein-coupled receptor (GPCR) PKR2 to elicit various downstream signaling pathways involved in diverse biological processes. Many GPCRs undergo dimerization that can modulate a number of functions including membrane delivery and signal transduction. The aim of this study was to elucidate the interface of PKR2 protomers within dimers by analyzing the ability of PKR2 transmembrane (TM) deletion mutants to associate with wild type (WT) PKR2 in yeast using co-immunoprecipitation and mammalian cells using bioluminescence resonance energy transfer. Deletion of TMs 5-7 resulted in a lack of detectable association with WT PKR2, but could associate with a truncated mutant lacking TMs 6-7 (TM1-5). Interestingly, TM1-5 modulated the distance, or organization, between protomers and positively regulated Gαs signaling and surface expression of WT PKR2. We propose that PKR2 protomers form type II dimers involving TMs 4 and 5, with a role f
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