共查询到20条相似文献,搜索用时 13 毫秒
1.
Gabriele Eden Marco Archinti Ralitsa Arnaudova Giuseppina Andreotti Andrea Motta Federico Furlan Valentina Citro Maria Vittoria Cubellis Bernard Degryse 《Cellular and molecular life sciences : CMLS》2018,75(10):1889-1907
The urokinase receptor (uPAR) stimulates cell proliferation by forming a macromolecular complex with αvβ3 integrin and the epidermal growth factor receptor (EGFR, ErbB1 or HER1) that we name the uPAR proliferasome. uPAR transactivates EGFR, which in turn mediates uPAR-initiated mitogenic signal to the cell. EGFR activation and EGFR-dependent cell growth are blocked in the absence of uPAR expression or when uPAR activity is inhibited by antibodies against either uPAR or EGFR. The mitogenic sequence of uPAR corresponds to the D2A motif present in domain 2. NMR analysis revealed that D2A synthetic peptide has a particular three-dimensional structure, which is atypical for short peptides. D2A peptide is as effective as EGF in promoting EGFR phosphorylation and cell proliferation that were inhibited by AG1478, a specific inhibitor of the tyrosine kinase activity of EGFR. Both D2A and EGF failed to induce proliferation of NR6-EGFR-K721A cells expressing a kinase-defective mutant of EGFR. Moreover, D2A peptide and EGF phosphorylate ERK demonstrating the involvement of the MAP kinase signalling pathway. Altogether, this study reveals the importance of sequence D2A of uPAR, and the interdependence of uPAR and EGFR. 相似文献
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The laminin-binding integrin α6β4 plays key roles in both normal epithelial and endothelial cells and during tumor cell progression, metastasis, and angiogenesis. Previous cysteine mutagenesis studies have suggested that palmitoylation of α6β4 protein supports a few integrin-dependent functions and molecular associations. Here we took another approach and obtained strikingly different results. We used overexpression and RNAi knockdown in multiple cell types to identify protein acyl transferase DHHC3 as the enzyme responsible for integrin β4 and α6 palmitoylation. Ablation of DHHC3 markedly diminished integrin-dependent cellular cable formation on Matrigel, integrin signaling through Src, and β4 phosphorylation on key diagnostic amino acids (S1356 and 1424). However, unexpectedly, and in sharp contrast to prior α6β4 mutagenesis results, knockdown of DHHC3 accelerated the degradation of α6β4, likely due to an increase in endosomal exposure to cathepsin D. When proteolytic degradation was inhibited (by Pepstatin A), rescued α6β4 accumulated intracellularly, but was unable to reach the cell surface. DHHC3 ablation effects were strongly selective for α6β4. Cell-surface levels of ~10 other proteins (including α3β1) were not diminished, and the appearance of hundreds of other palmitoylated proteins was not altered. Results obtained here demonstrate a new substrate for the DHHC3 enzyme and provide novel opportunities for modulating α6β4 expression, distribution, and function. 相似文献
4.
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR 总被引:1,自引:0,他引:1
Kleinau G Jaeschke H Mueller S Worth CL Paschke R Krause G 《Cellular and molecular life sciences : CMLS》2008,65(22):3664-3676
Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications
are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated
receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant
mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling.
Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating
mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity
for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR
models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details
underlying mutations decreasing basal activity.
G. Kleinau, H. Jaeschke: These two authors contributed equally to this work.
Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008 相似文献
5.
Elisa Bisicchia Valerio Chiurchiù Maria Teresa Viscomi Laura Latini Filomena Fezza Luca Battistini Mauro Maccarrone Marco Molinari 《Cellular and molecular life sciences : CMLS》2013,70(12):2191-2204
Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB2) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB2 and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB2 and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRβ, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB2, but not GRα. Overall, our study demonstrates for the first time the existence of a CB2-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB2 as a new target for chronic inflammatory and neurodegenerative diseases. 相似文献
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R. Liljequist M. K. Paasonen E. Solatunturi 《Cellular and molecular life sciences : CMLS》1982,38(3):379-380
Summary 1% -alanine and -L-alanine, when given for 7 days as the only drinking fluid, inhibited the exploratory activity of adult male spontaneously-hypertensive rats (SHR)_but not that of the normotensive Wistar-Kyoto rats (WKR). -Alanine decreased the taurine level in the liver of both strains and in the platelets of SHR. -Alanine decreased the taurine level in the liver of WKR and in the platelets of SHR.This study was supported by the Sigrid Jusélius Foundation. 相似文献
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Summary The effects of selected -agonists and -antagonists on theophylline-induced lipolysis were investigate in isolated hamster white fat cells 2-Agonists (tramazoline, clonidine) inhibited theophylline-induced lipolysis while an 2-agonist (methoxamine) was without any effect. The inhibitory effect of 2-agonists was suppressed by yohimbine (2-antagonist), whereas 2-antagonists were inefficient. This result implies that the -adrenergic receptor of hamster fat cells is of the 2-type, although located postsynaptically.Acknowledgments. This work was supported by grants from CNRS (ERA 412) and DGRST (grant No. 787 1078). We thank M. Dauzats for excellent technical assistance. We thank Prof. H. Schmitt for tramazoline and AR-C 239 and for helpful discussion. 相似文献
9.
Wu RC Wang Z Liu MJ Chen DF Yue XS 《Cellular and molecular life sciences : CMLS》2004,61(16):2071-2082
In this study with cycloheximide (CHX, an inhibitor of protein synthesis) and the human leukaemic cell line U937, a novel form of chemoresistance, which we termed sudden drug resistance (SDR), was identified using Hoechst33258 staining, Western blott and DNA Ladder. CHXhigh (10–100 g/ml)-induced apoptosis can spontaneously subside after 4–6 h or can be inhibited by short-term preincubation with CHXlow (2.5 g/ml). Unlike typical multidrug resistance, SDR is not caused by reduced drug accumulation or altered protein expression, and may be associated with a non-P-glycoprotein mechanism. To uncover this underlying mechanism, we focused on U937 cell aggregation promoted by CHX, because cell adhesion has been suggested to influence cell survival and prevent apoptosis. EDTA, or anti-CD18 monoclonal antibody, but not EGTA, acetylsalicylic acid or RGDS tetrapeptide, abrogated this homotypic aggregation and greatly increased CHX-induced apoptosis in a time-dependent manner, while fibrinogen and soluble intercellular adhesion molecule-1 exerted opposite effects. These results establish that 2-integrin engagement is a key mediator of SDR, although it may be non-exclusive. This finding supplements the classical basis of chemoresistance and may provide another opportunity for improved leukemia therapy.Received 15 April 2004; received after revision 18 May 2004; accepted 21 June 2004 相似文献
10.
A key statement of the 1965 Monod-Wyman-Changeux (MWC) model for allosteric proteins concerns the distinction between the ligand-binding function (
) and the relevant state function (
). Sequential models predict overlapping behavior of the two functions. In contrast, a straightforward experimental consequence of the MWC model is that for an oligomeric protein the parameters which characterize the two functions should differ significantly. Two situations, where
\bar Y$$
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and the system ishyper-responsive or where
and the system ishypo-responsive, have been encountered. Indeed, the hyper-responsive pattern was first observed for the enzyme aspartate transcarbamoylase, by comparing
with
monitored by a change in sedimentation. Extensions of the theory to ligand-gated channels led to the suggestion that, on the one hand, hyper-responsive properties also occur with high-affinity mutants. On the other hand, native channels of the acetylcholine neuronal7 receptor and low-affinity mutants of the glycine receptor can be interpreted in terms of the hypo-responsive pattern. For the ligand-gated channels, whereas
is detected directly by ion flux, ligand binding has rarely been measured and the formation of desensitized states may complicate the analysis. However, stochastic models incorporating both binding and channel opening for single molecules predict differences that should be measurable with new experimental approaches, particularly fluorescence correlation spectroscopy. 相似文献
11.
Lena Golick Youngah Han Yoo Kim Sang Won Park 《Cellular and molecular life sciences : CMLS》2018,75(10):1857-1869
Reduced hepatic expression levels of bromodomain-containing protein 7 (BRD7) have been suggested to play a role in the development of glucose intolerance in obesity. However, the molecular mechanism by which BRD7 regulates glucose metabolism has remained unclear. Here, we show that BRD7 increases phosphorylation of glycogen synthase kinase 3β (GSK3β) in response to activation of the insulin receptor-signaling pathway shortly after insulin stimulation and the nutrient-sensing pathway after feeding. BRD7 mediates phosphorylation of GSK3β at the Serine 9 residue and this effect on GSK3β occurs even in the absence of AKT activity. Using both in vitro and in vivo models, we further demonstrate that BRD7 mediates phosphorylation of ribosomal protein S6 kinase (S6K) and leads to increased phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and, therefore, relieves its inhibition of the eukaryotic translation initiation factor 4E (eIF4E). However, the increase in phosphorylation of 4E-BP1 with BRD7 overexpression is blunted in the absence of AKT activity. In addition, using liver-specific BRD7 knockout (LBKO) mice, we show that BRD7 is required for mTORC1 activity on its downstream molecules. These findings show a novel basis for understanding the molecular dynamics of glucose metabolism and suggest the unique function of BRD7 in the regulation of glucose homeostasis. 相似文献
12.
Ling Zhang Rolf Postina Yingqun Wang 《Cellular and molecular life sciences : CMLS》2009,66(24):3923-3935
Receptor for advanced glycation end products (RAGE) mediates diverse physiological and pathological effects and is involved
in the pathogenesis of Alzheimer’s disease (AD). RAGE is a receptor for amyloid β peptides (Aβ), mediates Aβ neurotoxicity
and also promotes Aβ influx into the brain and contributes to Aβ aggregation. Soluble RAGE (sRAGE), a secreted RAGE isoform,
acts as a decoy receptor to antagonize RAGE-mediated damages. Accumulating evidence has suggested that sRAGE represents a
promising pharmaceutic against RAGE-mediated disorders. Recent studies revealed proteolysis of RAGE as a previously unappreciated
means of sRAGE production. In this review we summarize these findings on the proteolytic cleavage of RAGE and discuss the
underlying regulatory mechanisms of RAGE shedding. Furthermore, we propose a model in which proteolysis of RAGE could restrain
AD development by reducing Aβ transport into the brain and Aβ production via BACE. Thus, the modulation of RAGE proteolysis
provides a novel intervention strategy for AD. 相似文献
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Résumé Dans les curs de lapins traités par l'-méthyldopa, la déplétion de la noradrénaline s'accompagne d'une fixation importante d'-méthylnoradrénaline. Sous l'effet de stimulation sympathique ou d'iodure de diméthylphényl-pipérazinium, ces curs libèrent conjointement de la noradrénaline et de l'-méthylnoradrénaline.Les quantités respectives de noradrénaline et d'-méthylnoradrénaline libérées par stimulation sympathique sont les mêmes que celles libérées par l'iodure de diméthyl-phényl-pipérazinium et que celles trouvées dans le myocarde lui-même. 相似文献
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A. Scriabine C. T. Ludden G. Morgan J. J. Baldwin 《Cellular and molecular life sciences : CMLS》1979,35(12):1634-1637
Summary Two new-adrenoceptor blocking drugs with acute antihypertensive and positive inotropic effects are described: Compound A (2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole) and MK-761 (2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride). In SH rats both compounds, given orally, lowered arterial pressure and were more potent than hydralazine. The antihypertensive effect of compound A but not of MK-761 was antagonized by timolol. Both compounds had positive inotropic activity on cat heart papillary muscles; these effects were antagonized by timolol. The pretreatment of animals with reserpine greatly reduced the positive inotropic effect of MK-761 but not of compound A. The acute antihypertensive and positive inotropic effects of compound A are likely to be at least partially due to stimulation of-adrenoceptors, e.g. intrinsic sympathomimetic activity. The effects of MK-761 on the same parameters appear to be mediated by different mechanisms. 相似文献
16.
G. D. Prestwich 《Cellular and molecular life sciences : CMLS》1978,34(6):682-684
Summary The defense secretions of 3 allopatric populations of the nasute termiteTrinervitermes gratiosus were analyzed. One population afforded a new trinervitene, isotrinervi-2-ol, a missing link in the hypothetical biosynthesis of the trinervitenes. Populations could be readily distinguished on the basis of the chromatographic profiles of their major and minor soldier frontal gland secretions.These studies were initiated (1975–76) with partial financial support by the International Centre of Insect Physiology and Ecology, Nairobi, Kenya and NIH Postdoctoral Fellowship AI-05076. Support by the Department of Chemistry of the State University of New York at Stony Brook and the technical assistance of Mr J. Engstrom allowed completion of this investigation. 相似文献
17.
J. N. Chatterjea 《Cellular and molecular life sciences : CMLS》1956,12(1):18-19
Résumé On décrit une methode pour la synthèse des -brazan et -brazanquinone deKruber. 相似文献
18.
Summary Highly purified human 2 macroglobulin (1.2–10 mg/ml) was shown to inhibit phytohemagglutinin-induced or antibody-induced lysis of chicken erythrocytes by polymorphonuclear neutrophils. Inhibition was not associated with impaired contact between effector and target cells but rather with the antiprotease activity of 2 macroglobulin.This study was supported by D.G.R.S.T. contract No 77-7-1381. 相似文献
19.
Sally A. Nicholas Vladimir V. Bubnov Inna M. Yasinska Vadim V. Sumbayev 《Cellular and molecular life sciences : CMLS》2011,68(1):151-158
Inflammatory reactions to ssRNA viruses are induced by the endosomal Toll-like receptors (TLRs) 7 and 8. TLR7/8-mediated inflammatory
reaction results in activation of the Nalp3 inflammasome via an unknown mechanism. Here we report for the first time that
TLR7/8 mediate activation of xanthine oxidase (XOD) in an HIF-1α-dependent manner. XOD produces uric acid and reactive oxygen
species, which could activate Nalp3 and therefore induce activation of caspase 1, known to convert inactive pro-IL-1β into
active IL-1β. Specific inhibition of the XOD activity attenuates TLR7/8-mediated activation of caspase 1 and IL-1β release.
These results were obtained using human THP-1 myeloid macrophages. The findings were verified by conducting in vivo experiments
on mice. 相似文献
20.
J. Kobayashi Y. Ohizumi H. Nakamura Y. Hirata K. Wakamatsu T. Miyazawa 《Cellular and molecular life sciences : CMLS》1986,42(9):1064-1065
Summary A novel bromine-containing alkaloid, hymenin, has been isolated from the Okinawan marine spongeHymeniacidon sp. as a potent -adrenoceptor blocking agent and its structure determined to be1 on the basis of the spectral data. 相似文献