The balance of concentration between Prokineticin 2β and Prokineticin 2 modulates the food intake by STAT3 signaling

Miele

2022

Life

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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.

Section: Genetic and Mrna Splice Variantsmentioning

confidence: 99%

Prokineticin-Receptor Network: Mechanisms of Regulation

Miele

2022

Life

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“…Membranes were then incubated with an anti-mouse IgG HRP-linked secondary antibody. The immunoreactive signals were visualized using an enhanced chemiluminescence system [12].…”

Section: Analysis Of Stat3 and Erk Activation In Cho-r1 And Cho-r2 By...mentioning

confidence: 99%

“…PROK2 mRNA is detected in the testis, granulocytes, dendritic cells, macrophages, olfactory bulb, brain, lung, and spleen [7,11], whereas PROK2L mRNA expression is higher than PROK2 in the lung and spleen, and lower in the brain. Both PROK2 and PROK2L are present in adipocytes and the hypothalamus, where PROK2 and PROK2β regulate adipocyte differentiation and food intake [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…Depending on their cellular localization, both receptors can couple to a variety of G proteins and activate multiple intracellular signal transduction pathways [7]. Thus, receptor activation by both PROK2 and PROK2β has been shown to induce intracellular Ca 2+ mobilization, stimulate cAMP accumulation, and activate ERK1/2, but only PROK2 induces STAT3 phosphorylation [12].…”

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of a New Splicing Variant of Prokineticin 2

Maftei

Vincenzi

et al. 2022

Life

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Prokineticin 2 (PROK2) is a secreted bioactive peptide that regulates a variety of biological responses via two GPCRs, the prokineticin receptors (PROKRs). The aim of this study was to characterize a new alternatively spliced product of the prok2 gene consisting of four exons. The 40-amino acid peptide, designated PROK2C, is encoded by exon 1 and exon 4, and its expression was detected in the hippocampus and spinal cord of mice. PROK2C was expressed in a heterologous system, Pichia pastoris, and its binding specificity to the amino-terminal regions of PROKR1 and PROKR2 was investigated by GST pull-down experiments. In addition, the introduction of the unnatural amino acid p-benzoyl-L-phenylalanine using amber codon suppression technology demonstrated the role of tryptophan at position 212 of PROKR2 for PROK2C binding by photoactivatable cross-linking. The functional significance of this new isoform was determined in vivo by nociceptive experiments, which showed that PROK2C elicits strong sensitization of peripheral nociceptors to painful stimuli. In order to analyze the induction of PROK2C signal transduction, STAT3 and ERK phosphorylation levels were determined in mammalian CHO cells expressing PROKR1 and PROKR2. Our data show by in vivo and in vitro experiments that PROK2C can bind and activate both prokineticin receptors.

“…The anorexic effects of PK2 depend on the activation of Arcuate Nucleus (ARC) neurons that release melanocyte-stimulating hormone and are modulated by the specific physical interaction of the accessory melanocortin receptor 2 protein (MRAP2) with PKR1 [ 64 , 65 ]. In contrast, peripheral administration of PK2β shows a tendency to increase feeding, likely due to its limited ability to induce STAT3 phosphorylation [ 66 ].…”

Section: Control Of Energy Metabolismmentioning

confidence: 99%

Versatile Role of Prokineticins and Prokineticin Receptors in Neuroinflammation

Miele

2021

Biomedicines

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Prokineticins are a new class of chemokine-like peptides involved in a wide range of biological and pathological activities. In particular, prokineticin 2 (PK2), prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) play a central role in modulating neuroinflammatory processes. PK2 and PKRs, which are physiologically expressed at very low levels, are strongly upregulated during inflammation and regulate neuronal-glial interaction. PKR2 is mainly overexpressed in neurons, whereas PKR1 and PK2 are mainly overexpressed in astrocytes. Once PK2 is released in inflamed tissue, it is involved in both innate and adaptive responses: it triggers macrophage recruitment, production of pro-inflammatory cytokines, and reduction of anti-inflammatory cytokines. Moreover, it modulates the function of T cells through the activation of PKR1 and directs them towards a pro-inflammatory Th1 phenotype. Since the prokineticin system appears to be upregulated following a series of pathological insults leading to neuroinflammation, we will focus here on the involvement of PK2 and PKRs in those pathologies that have a strong underlying inflammatory component, such as: inflammatory and neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, obesity, diabetes, and gastrointestinal inflammation.