Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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The cycling peroxisomal targeting signal type 1 - receptor Pex5p: reaching the circle’s end with ubiquitin
Get PDFPeroxisomes are single-membrane bound organelles that are found nearly ubiquitiously in eukaryotic cells. Their main task is the breakdown of fatty acids by beta-oxidation and the detoxification of hydrogen peroxide. However, these so called “multi-purpose organelles” also display several other metabolic functions, which can differ between species, tissues or growth conditions of the cells. This high plasticity of peroxisomal functions is enabled by an adjustment of the protein composition, which in turn is regulated by the dynamically operating protein import receptors. Subsequent to their synthesis on free ribosomes in the cytosol, peroxisomal matrix proteins are recognizes by import receptors by means of a peroxisomal targeting sequence (PTS). Most peroxisomal matrix proteins harbor a PTS-type 1 (PTS1) signal, which is bound by the PTS1-receptor Pex5p in the cytosol. The PTS1-receptor/cargo-complex reaches a docking complex at the peroxisome, where Pex5p is thought to become a building block of a transiently opened translocation pore. After the translocation of the folded cargo proteins over the membrane into the peroxisomal matrix, Pex5p is exported back to the cytosol for further rounds of matrix protein import. This dislocation step comprises the only energy-consuming reactions of the entire receptor cycle, because Pex5p has to be monoubiquitinated at a conserved cysteine before it can be extracted from the membrane by the AAA-type ATPases Pex1p and Pex6p. In case this recycling pathway is hampered, Pex5p gets polyubiquitinated on lysine residues and degraded by the proteasome. This review focuses on the PTS1-receptor Pex5p and discusses recent data and concepts regarding the molecular mechanism of cargo recognition, pore formation, cargo release and ubiquitination-dependent export and highlights the clinical relevance of Pex5p in health and disease
The Couple G Protein-Coupled Receptor-G Protein: Preassembly versus Agonist-Induced Interaction
Get PDFThe investigation of the physical and functional interaction of the G protein-coupled receptors (GPCRs) with their cognate heterotrimeric G proteins constitutes one of the most evolved aspects in this family of cell surface receptors. The development of the energy transfer-based approaches, bioluminescence or fluorescence resonance energy transfer (BRET or FRET, respectively), has strongly contributed to such advance. Using protease-activated receptors 1 and 2 (PAR1 and 2) as model for their multiple G protein coupling profiles, we revealed a preassembly between the two receptors and G?i1 and G?o proteins whereas their association with G?12 occurred only upon receptor activation. Kinetic analysis in real-time and live cells showed important differences in the activation between these two modes of coupling which may be consistent with their implication in the physiological responses of PARs. Together, our finding indicate that preassembly or agonist-promoted association depend on receptor-G protein pair representing the key mechanisms of temporal and spatial regulation and integration of the multiple G protein coupling and signaling of GPCRs
Fibronectin signaling via toll-like receptprs: a novel paradigm for persistent fibrosis in scleroderma
Get PDFScleroderma is a systemic autoimmune disease with unknown etiology. Fibrosis, the hallmark of scleroderma, is the transformation of self-limited wound healing into a self-sustaining non-healing process. The factors responsible for maintaining persistent fibroblast activation in scleroderma and other conditions with chronic fibrosis are not well understood. We recently showed that TLR4 and fibronectin extra domain A (FnEDA), an endogenous TLR4 ligand, both are markedly elevated in the lesional skin biopsies from scleroderma patients and were shown to be involved in scleroderma disease pathogenesis. Here, we highlight the role of the FnEDA-TLR4 signaling axis in fibrosis, and the mechanisms involved in driving persistence of fibrosis in scleroderma
The High mobility group box 1/Toll-like Receptor 2 axis plays a non-inflammatory role in the self-renewal of mammary cancer stem cells
Get PDFThe lack of effective treatment in several metastatic cancers raises the question of whether current therapies target the right cells. These treatments may be missing cancer stem cells (CSC), a sub-population of stem cell-like cells that are able to play a critical role in cancer progression. A profound understanding of the mechanisms that regulate CSC selfrenewal is therefore essential for the identification of new CSC antigens that may turn out to be the ideal target for more effective anticancer strategies. In the light of these considerations, we have performed the transcription profiling of the murine ErbB2+ breast tumor cell line TUBO versus its derived CSC-enriched mammospheres. Of the all antigens that have been identified, we have focused our attention on toll-like receptor (TLR)2 which has been identified as being overexpressed in CSC. Moreover, TLR2 plays a central role in CSC biology; it is a key molecule for CSC selfrenewal as its signaling inhibition impairs in vitro mammosphere generation and blocks tumorigenesis and lung metastases development in vivo. Our in-depth analysis of the downstream signal driven by TLR2 has demonstrated that it is activated by endogenous high mobility-group box (HMGB)1 with an autocrine loop, which induces IkB? phosphorylation, IL-6 and TGF? secretion and consequently STAT3 and Smad3 activation
Ly49 and C-type lectin receptors on dendritic cells regulate T-cell differentiation as co-stimulatory molecules
Get PDFThe C-type lectin receptors (CLRs) expressed on dendritic cells (DCs) participate in T-cell polarization by recognizing pathogen-associated molecular patterns and activating signaling pathways for cytokine production. In addition, some CLRs expressed on DCs function as co-stimulatory molecules via recognition of endogenous ligands on T cells and regulate proliferation and/or differentiation of T cells. We recently showed that killer cell lectin-like receptor Ly49s3 is expressed in rat thymic DCs and recognizes MHC class I molecules on T cells, for differentiation into naturally occurring regulatory T cells (nTregs). Upon binding to MHC class I molecules on T cells, Ly49s3 seems to stimulate signal transduction pathway(s) leading to up-regulation of the MHC class II genes and then functions as a co-stimulatory molecule. The signaling pathway(s) is supposed to involve Dap12, Syk/Zap70, Lat, Plc-gamma, PKC, PU.1 and C2ta proteins to attain MHC class II expression. Other than Ly49s3, Ly49Q and Ly49B have been shown to be expressed in myeloid cells including DCs and macrophages, raising the possibility that they may be involved in the regulation of T-cell differentiation through recognition of MHC class I molecules on T cells. In humans, immunoglobulin (Ig)-like receptors binding to MHC class I molecules take the place of Ly49 receptors. Among them, expression of the KIR2DL4 gene has been reported to be induced in antigen-presenting cells, although its biological significance is obscure, and immunoglobulin-like transcript 4 (ILT4) expressed in DCs has been shown to down-regulate expression of MHC class II molecules on the same cells, upon binding to MHC class I molecules. They may also be involved in regulation of T-cell differentiation. Some other CLRs are expressed on DCs and possibly function as co-stimulatory molecules. For example, dectin-1, dectin-2 and Dcal-1 have been shown to promote T-cell proliferation, Treg differentiation and IL-4 production of T cells, respectively, through binding to unidentified ligands on T cells. DC-Sign, which recognizes ICAM3 on T cells, is also suggested to be involved in T-cell differentiation. Further investigation of the functional roles of CLRs on DCs will provide insight into the regulatory mechanisms of T-cell differentiation, essential processes for regulating immune responses
Stress and mu opioid receptor in the management of gilthead sea bream (Sparus aurata) aquaculture
Get PDFThe growing consumption of aquaculture products requires always new techniques to increase the production yield. Generally, the intensification of aquaculture practices is associated with a stress level rise of bred fishes. Sensitivity to stress, leading to disease, reduced growth and mortality, is higher in larvae than in adult fish. The stress induced effects can be reduced acting on opiod receptors. In this light we evaluated the efficacy of naloxone, an opioid receptor antagonist, directly added to the water during Sparus aurata larval development. We found that in larvae subjected to artificial induced stressors, such as overcrowding, reduced pH, increased temperature and salinity, naloxone was useful to decrease the negative effects caused. In this Research highlight we discuss the finding of our recent study and research advancements
A metabolomics multivariate statistical approach for obtaining data-driven information in neuropharmacological research
Get PDFBrain metabolism is exquisitely responsive to activation or inhibition of brain activity, including activation or inhibition of receptors. By multivariate statistical analysis of the metabolic labelling patterns produced following one hour incubation with [3-13C]pyruvate in the presence of receptor ligands of known activity, we have developed a metabolic “footprint” of the GABAergic system. Using this experimental paradigm, any compounds potentially acting on the GABAergic system can then be compared against the footprint and their mode of action as well as the preferred receptor sites identified and characterized. It seems obvious that such an approach would be most valuable for drugs of uncertain pharmacological profiles acting on multiple targets. This approach has already proven useful for ?-hydroxybutyrate (GHB) and was recently applied to ethanol [1]. We showed that the effects of ethanol on reducing glucose metabolism are not via substitution of ethanol for other substrates, or by production of acetate but likely occur via action at GABA receptors, specifically ?4?3? receptors
The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity
Get PDFIncidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it develops in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in the ad libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitum-fed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype
The Study of Novel diamide Insecticides: Chiral Sulfilimines
Get PDFNovel insecticidal chiral phthalamides containing N-cyano and N-trifluroacetyl sulfiliminyl moieties were firstly described, coupled with their insecticidal activity against oriental armyworm (Pseudaletia separata Walker) and diamondback moth (Plutella xylostella (L.)). The chirality of carbon and sulfur impact on bioactivity was systemically studied
Trastuzumab-induced HER2 phosphorylation: exploring the mechanisms and implications
Get PDFTargeting of ErbB family of receptor tyrosine kinases (RTKs) is frequently used to inhibit the oncogenic signaling in different malignancies. Lapatinib, a dual selective tyrosine kinase inhibitor (TKI) of EGFR and HER2, inhibits their tyrosine kinase activities and receptor tyrosine phosphorylation. Cetuximab, a chimeric monoclonal antibody (mAb) directed against the extracellular domain of EGFR, prevents EGF-mediated receptor kinase activation and tyrosine phosphorylation. However, trastuzumab, a humanized mAb directed against HER2, induces EGFR and HER2 receptor tyrosine phosphorylation and this agonistic effect is correlated with its inhibition of cancer cell proliferation. This review will focus on the current understanding of molecular mechanisms and implications of trastuzumab-induced tyrosine phosphorylation of HER2