Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID: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. 1976 62

The best-known function of the serine protease tissue-type plasminogen activator (tPA) is as a thrombolytic enzyme. However, it is also found in structures of the brain that are highly vulnerable to hypoxia-induced cell death, where its association with neuronal survival is poorly understood. Here, we have demonstrated that hippocampal areas of the mouse brain lacking tPA activity are more vulnerable to neuronal death following an ischemic insult. We found that sublethal hypoxia, which elicits tolerance to subsequent lethal hypoxic/ischemic injury in a natural process known as ischemic preconditioning (IPC), induced a rapid release of neuronal tPA. Treatment of hippocampal neurons with tPA induced tolerance against a lethal hypoxic insult applied either immediately following insult (early IPC) or 24 hours later (delayed IPC). tPA-induced early IPC was independent of the proteolytic activity of tPA and required the engagement of a member of the LDL receptor family. In contrast, tPA-induced delayed IPC required the proteolytic activity of tPA and was mediated by plasmin, the NMDA receptor, and PKB phosphorylation. We also found that IPC in vivo increased tPA activity in the cornu ammonis area 1 (CA1) layer and Akt phosphorylation in the hippocampus, as well as ischemic tolerance in wild-type but not tPA- or plasminogen-deficient mice. These data show that tPA can act as an endogenous neuroprotectant in the murine hippocampus.
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PMID:Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus. 2044 70