| Characteristic response of astrocytes to plasminogen/plasmin to upregulate transforming growth factor beta 3 (TGFbeta3) production/secretion through proteinase-activated receptor-1 (PAR-1) and the downstream phosphatidylinositol 3-kinase (PI3K)-Akt/PKB signaling cascade. | |
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MedLine Citation:
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PMID: 19765562 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The effects of microglia-derived plasminogen (PLGn) on the neurotrophic role of astrocytes were investigated in vitro. The treatment of astrocytes with rat PLGn led to a significant increase in transforming growth factor beta3 (TGFbeta3) in the conditioned medium (CM). This response of astrocytes to PLGn was characteristic and different from that to other stimulators, including lipopolysaccharide, phorbol-12-myristate-13-acetate, interferon-gamma, and ATP. In surveying the signaling molecules that respond to PLGn in astrocytes, we found that Akt/PKB phosphorylation is promoted. The pretreatment of astrocytes with an Akt inhibitor prior to PLGn stimulation resulted in a significant decrease in TGFbeta3 amounts in the CM, suggesting an association of Akt with TGFbeta3 production/secretion. Further survey revealed that phosphatidylinositol 3 kinase (PI3K) is closely associated with TGFbeta3 production/secretion in astrocytes. In fact, PI3K inhibitor clearly depressed the phosphorylation of Akt, indicating that PI3K is localized upstream of Akt. Moreover, the effects of PLGn to increase TGFbeta3 were depressed by pretreatment with a proteinase-activated receptor-1 (PAR-1) inhibitor. Plasmin could mimic the PLGn effects to upregulate TGFbeta3, and the plasmin effects were suppressed by pretreatment with the PAR-1 inhibitor, suggesting the association of PLGn/plasmin effects with PAR-1. In addition, Akt phosphorylation caused by plasmin was inhibited in the presence of PAR-1 inhibitor. We have therefore demonstrated that PLGn/plasmin, probably plasmin, facilitates the production/secretion of TGFbeta3 in astrocytes through both PAR-1 and the subsequent signaling cascade including PI3K and Akt. |
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Authors:
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Shyuichi Maeda; Kazuyuki Nakajima; Yoko Tohyama; Shinichi Kohsaka |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-09-16 |
Journal Detail:
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Title: Brain research Volume: 1305 ISSN: 1872-6240 ISO Abbreviation: Brain Res. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-25 Completed Date: 2010-01-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0045503 Medline TA: Brain Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1-13 Citation Subset: IM |
Affiliation:
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Department of Bioinformatics, Faculty of Engineering, Soka University, 1-236 Tangi-machi, Hachioji, Tokyo 192-8577, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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metabolism* Analysis of Variance Animals Astrocytes / drug effects, metabolism* Blotting, Western Cells, Cultured Chromones / pharmacology Culture Media, Conditioned Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Fibrinolysin / metabolism*, pharmacology Fibrinolytic Agents / pharmacology Fibroblast Growth Factors / metabolism Flavonoids / pharmacology Immunohistochemistry Microglia / metabolism Morpholines / pharmacology Nerve Growth Factors / metabolism Neurons / metabolism Phosphorylation / drug effects Plasminogen / metabolism*, pharmacology Proto-Oncogene Proteins c-akt / metabolism* Pyrroles / pharmacology Quinazolines / pharmacology RNA, Messenger / metabolism Rats Receptor, PAR-1 / metabolism* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects, physiology Transforming Growth Factor beta3 / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Chromones; 0/Culture Media, Conditioned; 0/Enzyme Inhibitors; 0/Fibrinolytic Agents; 0/Flavonoids; 0/Morpholines; 0/N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; 0/Nerve Growth Factors; 0/PD 98059; 0/Pyrroles; 0/Quinazolines; 0/RNA, Messenger; 0/Receptor, PAR-1; 0/Transforming Growth Factor beta3; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 62031-54-3/Fibroblast Growth Factors; 9001-91-6/Plasminogen; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.21.7/Fibrinolysin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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