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  • 1
    Publication Date: 2014-02-21
    Description: Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paolino, Magdalena -- Choidas, Axel -- Wallner, Stephanie -- Pranjic, Blanka -- Uribesalgo, Iris -- Loeser, Stefanie -- Jamieson, Amanda M -- Langdon, Wallace Y -- Ikeda, Fumiyo -- Fededa, Juan Pablo -- Cronin, Shane J -- Nitsch, Roberto -- Schultz-Fademrecht, Carsten -- Eickhoff, Jan -- Menninger, Sascha -- Unger, Anke -- Torka, Robert -- Gruber, Thomas -- Hinterleitner, Reinhard -- Baier, Gottfried -- Wolf, Dominik -- Ullrich, Axel -- Klebl, Bert M -- Penninger, Josef M -- W 1101/Austrian Science Fund FWF/Austria -- England -- Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria. ; Lead Discovery Center GmbH, D-44227 Dortmund, Germany. ; Medical University Innsbruck, 6020 Innsbruck, Austria. ; Department of Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA. ; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Perth, Australia. ; Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany. ; 1] Medical University Innsbruck, 6020 Innsbruck, Austria [2] Internal Medicine III, University Hospital Bonn, 53127 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553136" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Animals ; Anticoagulants/pharmacology/therapeutic use ; Female ; Killer Cells, Natural/drug effects/*immunology/metabolism ; Male ; Mammary Neoplasms, Experimental/drug therapy/genetics/immunology/*pathology ; Melanoma, Experimental/drug therapy/genetics/immunology/*pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasm Metastasis/drug therapy/*immunology/prevention & control ; Proto-Oncogene Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-cbl/deficiency/genetics/*metabolism ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; Ubiquitination ; Warfarin/pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    German Medical Science; Düsseldorf, Köln
    In:  57. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie; 20060511-20060514; Essen; DOCSO.03.01 /20060508/
    Publication Date: 2006-07-31
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
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    Unknown
    German Medical Science; Düsseldorf, Köln
    In:  56. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3èmes journées françaises de Neurochirurgie (SFNC); 20050507-20050511; Strasbourg; DOC10.05.-09.02 /20050504/
    Publication Date: 2005-05-05
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
    ISSN: 1432-1912
    Keywords: Glibenclamide ; ATP ; GTP ; Diazoxide ; Pancreatic islet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In microsomes obtained from mouse pancreatic islets, the Mg complex of adenosine 5′-triphosphate (MgATP) increased the dissociation constant (K D) for binding of [3H]glibenclamide by sixfold. In the presence of Mg2+, not only ATP but also adenosine 5′-0-(3-thiotriphosphate) (ATPγS), adenosine 5′-diphosphate (ADP), guanosine 5′-triphosphate (GTP), guanosine 5′-diphosphate (GDP), guanosine 5′-0-(3-thiotriphosphate) (GTPγTS) and guanosine 5′-0-(2-thiodiphosphate) (GDPβ S) inhibited binding of [3H]glibenclamide. These effects were not observed in the absence of Mg2+. Half maximally effective concentrations of the Mg complexes of ATP, ADP, ATPγS and GDP were 11.6, 19.0, 62.3 and 90.1 μmol/l, respectively. The non-hydrolyzable analogues adenosine 5′-(β,γ-imidotriphosphate) (AMP-PNP) and guanosine 5′-(β,γ-imidotriphosphate) (GMP-PNP) did not alter [3H]glibenclamide binding in the presence of Mg2+. MgADP acted much more slowly than MgATP and both MgADP and MgADP did not inhibit [3H]glibenclamide binding when the concentrations of MgATP and MgATP were kept low by the hexokinase reaction. Development of MgATP-induced inhibition of [3H]glibenclamide binding and dissociation of [3H]-glibenclamide binding occurred at similar rates. However, the reversal of MgATP-induced inhibition of [3H]glibenclamide binding was slower than the association of [3H]glibenclamide with its binding site. Exogenous alkaline phosphatase accelerated the reversal of MgATP-induced inhibition of [3H]glibenclamide binding. MgATP enhanced displacement of [3H]glibenclamide binding by diazoxide. The data suggest that sulfonylureas and diazoxide exert their effects by interaction with the same binding site at the sulfonylurea receptor and that protein phosphorylation modulates the affinity of the receptor.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1912
    Keywords: Key words μ- ; δ- ; κ-Opioid-Receptor ; Morphine ; Morphine-3-O-β-D-Glucuronide ; Morphine-6-O-β-D-Glucuronide ; Cerebral membranes ; In-vitro-binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We investigated the nature of interaction of morphine-3-O-β-D-glucuronide (M3G) and morphine-6-O-β-D-glucuronide (M6G) with opioid binding sites at the μ-, δ- and κ-opioid receptors (μ-OR, δ-OR and κ-OR) in cerebral membranes. Saturation binding experiments revealed a competitive interaction of M6G with all three opioid receptors. Inhibition binding experiments at the μ-OR employing combinations of morphine and M6G resulted in a rightward shift of the IC50 for morphine proportional to the M6G concentration, thus strengthening the finding of competitive interaction of M6G at the μ-opioid binding site. Data in absence and presence of M6G were included in a three-dimensional model. Compared to a model with one binding site a model with two binding sites significantly improved the fits. This might indicate that different μ-OR subtypes are involved. Hydrolysis of M6G to morphine was investigated and did not occur. Therefore the effects of M6G on binding to the μ-OR were due to M6G and not due to morphine. In contrast, M3G at the three opioid receptors was found to inhibit binding being about 300 times weaker than morphine. This effect was well explained by the amount of contaminating morphine (about 0.3%) identified by HPLC. We conclude that M6G binds to μ-, δ- and κ-OR in a competitive manner. Some of our results on the μ-OR suggest two binding sites for agonists at the μ-OR and that M6G binds to both sites. Our results suggest that the high potency of M6G as an analgesic is mediated through opioid receptors. In contrast, M3G does not interact with the μ-, δ- or κ-OR. We therefore doubt that any effect of M3G is mediated via opioid receptors.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1912
    Keywords: µ-, δ-, κ-Opioid-Receptor ; Morphine ; Morphine-3-O-β-D-Glucuronide ; Morphine-6-O-β-D-Glucuronide ; Cerebral membranes ; In-vitro-binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We investigated the nature of interaction of morphine-3-O-β-D-glucuronide (M3G) and morphine6-O-β-D-glucuronide (M6G) with opioid binding sites at the µ-, δ- and κ-opioid receptors (µ-OR, δ-OR and κ-OR) in cerebral membranes. Saturation binding experiments revealed a competitive interaction of M6G with all three opioid receptors. Inhibition binding experiments at the µ-OR employing combinations of morphine and M6G resulted in a rightward shift of the IC50 for morphine proportional to the M6G concentration, thus strengthening the finding of competitive interaction of M6G at the µ-opioid binding site. Data in absence and presence of M6G were included in a three-dimensional model. Compared to a model with one binding site a model with two binding sites significantly improved the fits. This might indicate that different µ-OR subtypes are involved. Hydrolysis of M6G to morphine was investigated and did not occur. Therefore the effects of M6G on binding to the μ-OR were due to M6G and not due to morphine. In contrast, M3G at the three opioid receptors was found to inhibit binding being about 300 times weaker than morphine. This effect was well explained by the amount of contaminating morphine (about 0.3%) identified by HPLC. We conclude that M6G binds to µ-, δ- and κ-OR in a competitive manner. Some of our results on the µ-OR suggest two binding sites for agonists at the μ-OR and that M6G binds to both sites. Our results suggest that the high potency of M6G as an analgesic is mediated through opioid receptors. In contrast, M3G does not interact with the µ-, δ- or κ-OR. We therefore doubt that any effect of M3G is mediated via opioid receptors.
    Type of Medium: Electronic Resource
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