Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Circulating Nucleotides in Health and Disease
No full textThe concentration of adenosine nucleotides (ATP&ADP) in the circulation may impact health and disease by controlling cellular metabolic pathways in tissues throughout the body. Fasting plasma nucleotide levels are normally relatively low in healthy subjects, but can increase by orders of magnitude in disease. High circulating nucleotide levels promote chronic purinergic signaling, which may disrupt the normal cellular metabolism in the body and initiate immune and inflammatory consequences. Strategies to control nucleotide levels in the bloodstream may therefore have therapeutic importance to halt the progression of metabolic disorders
Posttranslational modifications of CXCR4: implications in cancer metastasis
Get PDFCXCR4, the most widely expressed chemokine receptor in solid malignancies, has been implicated in cancer metastasis. However, how the activity of CXCR4 is regulated during carcinogenesis especially at the metastatic stage remains largely unknown. As with other G protein-coupled receptors, CXCR4 is subjected to posttranslational medications such as phosphorylation, ubiquitination, glycosylation, and sulfation. These posttranslational modifications contribute significantly to the heterogeneity of CXCR4 in terms of intracellular location, signaling, and functionality. We have shown that the difference in the sulfation level of CXCR4 is responsible for, if not all, the difference in the activities of CXCR4 between the highly metastatic and non-metastatic nasopharyngeal carcinoma (NPC) cell lines. Molecular mechanistic studies revealed that the Epstein-Barr virus-encoded oncoprotein LMP1 induces the expression of tyrosylprotein sulfotransferase 1 (TPST-1) through nuclear translocation of the epidermal growth factor receptor. This LMP1-regulated TPST-1 expression accounts for tyrosine sulfation of CXCR4 and is associated with the metastatic phenotype of NPC cell lines. Finally, in NPC patient specimens, there was a positive correlation between the expression of LMP1 and TPST-1 and the metastatic potential of NPC. Our findings provide the first evidence that the posttranslational modification of a chemokine receptor plays a role in cancer metastatic progression. Understanding the role of posttranslational modifications of chemokine receptors in cancer biology may provide new insights for developing attractive therapeutic targets in cancer therapy
Salicylic acid receptor in plants and humans
Get PDFA NAD(P)H-reductase like protein that undergoes conformational changes in the presence of salicylic acid, aspirin, and 2,6-dihydroxybenzoic acid has been purified. The protein is evolutionarily conserved and was found in plants and humans. A strong relationship between the protein conformation and temperature of plants, human neuroblastoma cell line, SK-N-SH, and mouse brain tissue has been demonstrated. These findings create a common ground for studying thermoregulation in plants and humans
The pERK of being a target: Kinase regulation of the orphan nuclear receptor ERR?
Get PDFEstrogen-related receptors (ERRs) are orphan members of the nuclear receptor superfamily that are important regulators of mitochondrial metabolism with emerging roles in cancer. In the absence of an endogenous ligand, ERRs are reliant upon other regulatory mechanisms that include protein/protein interactions and post-translational modification, though the cellular and clinical significance of this latter mechanism is unclear. We recently published a study in which we establish estrogen-related receptor gamma (ERR?) as a target for extracellular signal-regulated kinase (ERK), and show that regulation of ERR? by ERK has important consequences for the function of this receptor in cellular models of estrogen receptor-positive (ER+) breast cancer. In this Research Highlight, we discuss the implications of these findings from a molecular and clinical perspective
Harnessing receptor clustering in lipid rafts to tailor the inhibitory effects of monoclonal antibodies to specific cell types
Get PDFCertain cell signaling pharmaceutical targets have the potential to provide substantial clinical benefit when inhibited on some cell types yet elicit unwanted collateral damage when impeded on others. Thus, the appropriate therapeutic strategy for this situation would be to block preferentially receptor activation on the desired cell set. Taking advantage of the clustering within lipid rafts of toll-like receptor 4 (TLR4) and Fc gamma receptors (Fc?R) during TLR4 activation, we have identified a mechanism that allows an antibody to block more favorably signaling on leukocytes, cells that underlie acute and chronic inflammatory processes. The anti-TLR4 monoclonal antibody (mAb), Hu 15C1, co-engages TLR4 and Fc?Rs to enhance its inhibitory potency via an avidity effect on Fc?R-bearing cells. This novel mechanism of action allows the mAb to block efficiently TLR4 activation on Fc?R-bearing inflammatory cells, while limiting the duration of effect on cells lacking Fc?Rs. As receptor clustering in lipid rafts is a common phenomenon, this mechanism could be exploited to anchor similar receptor-targeting mAbs or formats bearing an antibody Fc domain to desired cell types
Effect of the Sigma-1 receptor on neurite outgrowth
Get PDFNeurite outgrowth is one of the essential processes underlying development and plasticity of the nervous system. Enhancing neurite outgrowth, along with neural protection, is one of the most prominent therapeutic strategies against neuronal degeneration or damage. The sigma-1 receptor (Sig-1R) is a brain-enriched a receptor chaperone expressed in the ER membrane. As Sig-1R is involved in the mode of action of several neurotherapeutic drugs, it is important to elucidate the molecular mechanism of Sig-1R. This would increase our understanding of the pathology of neuronal diseases as well as aid in establishing new approaches for their treatment. In this review, we focus on the findings that Sig-1R contributes to neural protection and neurite outgrowth even in pathological conditions, such as in high glutamate concentration. Although a large part of molecular mechanisms of Sig-1R remains unknown, the interaction of Sig-1R and neurotrophin receptors has been recently reported. Activation of Sig-1R leads to an increase in the secretion of neurotrophin. Meanwhile, Sig-1R enhances neurotrophin receptor-mediated neurite outgrowth upon activation. We discuss the neurite outgrowth effect of Sig-1R, especially in relation to neurotrophin-mediated neurite outgrowth
Prostaglandin E and F receptors in the uterus
Get PDFProstaglandins (PGs) are necessary for normal female reproduction. PGs act via their respective receptors and execute various functions in their target tissues depending on which type of receptor being activated. PG receptors are G-protein coupled receptors mediating various vital processes in the uterus throughout the reproductive cycle and pregnancy. They are essential for the normal functioning of uterine endometrium, myometrium and cervix. In this mini review, we explore the expression, functions and regulations of EP1-4 and FP in uterus. Recent reports show that PG receptors are regulated spatio-temporally in endometrium throughout the reproductive cycle. In myometrium, EPs and FP are differentially expressed and have prominent roles in the contraction and relaxation of the smooth muscle. In the cervix, PG receptors are essential for normal cervical ripening. PG receptors are important in several reproductive functions including reproductive cyclicity, embryo implantation, embryo spacing, uterine contraction or relaxation, and cervical ripening. Flawed regulation or signaling by PG receptors lead to many pathological conditions of the female reproductive tract such as dysmenorrhea, menorrhagia, endometriosis, cancer and pre-term or post-term pregnancies. Although several studies have shown the expression of PG receptors in different cell types of the uterus, we still do not fully understand their functions in different cell types, how they are regulated and their implications in normal health and diseases. Better understanding of the PG receptor signaling mechanism would offer valuable insight that could be used for diagnosis and therapy
Nogo-B Receptor (NgBR): A New Receptor that Modulates Blood Vessel Formation
Get PDFNogo-B is an isoform of reticulon-4 (RTN4) that distributes mainly in the endoplasmic reticulum. Nogo-B binds to its receptor, Nogo-B receptor (NgBR), to modulate blood vessel formation. Animal with Nogo-B knockout is phenotypically normal. NgBR is a type I receptor with a single transmembrane domain that binds Nogo-B and probably other angiogenic factors. NgBR knockout in zebra fish leads to abnormal formation of intersomite vessels suggesting NgBR plays a more important role in the Nogo-B/NgBR signaling pathway. It is reported that NgBR plays a role in dolichol biosynthesis, protein N-glycosylation, stabilizes Niemann-Pick type C2 protein, regulates intracellular cholesterol trafficking, controls blood vessel development, and modulates breast cancer progression. However, the research in NgBR remains in its early stage and needs further exploration
Combinatorial Transcription Regulation of Oncogene CDC6 in Androgen-Sensitive Prostate Cancer Cells
Get PDFPrevious studies showed that CDC6 gene transcription is mainly regulated by E2F transcription factors. We recently reported [1] a novel regulatory mechanism of aberrant CDC6 gene transcription in androgen-responsive prostate cancer (PCa) cells where FOXM1 transcription factor positively regulates CDC6 gene transcription and DNA replication. In addition to direct binding to the CDC6 promoter, FOXM1 regulates CDC6 gene transcription by elevating AR gene expression. Furthermore, FOXM1 and AR collaborate to regulate CDC6 gene transcription in a cell cycle-dependent manner. Supporting the significance of this mechanism, siomycin A, a proteasome inhibitor known to inhibit FOXM1 expression and activity, inhibited PCa cell proliferation, and the effect of siomycin A was additive to that of bicalutamide, an antiandrogen commonly used to treat PCa patients
Collateral Sensitivity of sigma-2 Receptor ligands: Potentials in the Treatment of Multidrug Resistant Tumors
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Tumors remain one of the main causes of human illnesses and death with MultiDrug Resistance (MDR) being the most severe limitation to the success of chemotherapy. MDR is mainly due to the overexpression of drug efflux transporters, such as P-glycoprotein (P-gp), but attempts to inhibit P-gp have not been clinically successful so far. Lately, some agents were found to be more effective against P-gp overexpressing cells, showing a property termed “collateral sensitivity” (CS). The molecular bases of CS are poorly understood and hypersensitivity to reactive oxygen species (ROS) is one of the hypotheses that accounts for it. We recently identified a few sigma-2 (s2) receptors ligands endowed with CS, likely because of their interaction with P-gp. In fact, a number of CS agents are P-gp substrates: they are actively effluxed by P-gp, and it is believed that they activate a futile ATP cycle, increase oxidative phosphorylation leading to higher ROS production and oxidative stress. Therefore, we verified ROS involvement to study the CS properties of s2 receptors ligands/P-gp substrates (F408 and siramesine) whose activity was measured in three parental and Pg-p-overexpressing cell line pairs. We also demonstrated the major consumption of ATP induced by these compounds in P-gp overexpressing vs the parental cells. We analyzed the effects of siramesine and F408 on mitochondrial respiratory chain (source of ROS and intracellular ATP). Siramesine and F408 decreased both the electron flux rate and the ATP levels, with MDR cells undergoing a much more pronounced decrease than parent cells. Therefore, we demonstrated depletion of mitochondrial ATP supply by siramesine and F408 as the mechanism by which these s2 ligands likely induce CS. In conclusion, CS and s2 ligands-mediated actions warrant further investigation as a way to face MDR