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Literature summary for 3.4.21.69 extracted from
- Activated protein C, protease activated receptor 1, and neuroprotection (2018), Blood, 132, 159-169 .
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| additional information | the physiologic mechanism for protein C activation involves proteolysis at Arg169 in EPCR-bound protein C by thrombomodulin-bound thrombin | Homo sapiens | |
| additional information | the physiologic mechanism for protein C activation involves proteolysis at Arg169 in EPCR-bound protein C by thrombomodulin-bound thrombin | Mus musculus |
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | enzyme mutant 3K3A-APC appears to be safe in ischemic stroke patients and reduced bleeding in the brain after tissue plasminogen activator therapy in a recent phase 2 clinical trial. Studies using human fetal neural stem and progenitor cells show that 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model. 3K3A-APC appears to be safe in ischemic stroke patients and reduced bleeding in the brain after tissue plasminogen activator therapy in a recent phase 2 clinical trial. Enzyme mutant 3K3A-APC may potentially be used for late treatment of stroke in patients in ongoing phase 1 (NCT01151124) and phase 2 (NCT02117635) clinical trials that involve directly injecting manufactured NSCs into the brain of patients that remain moderately to severely disabled following an ischemic stroke | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| K191A/K192A/K193A | engineering of APC by site-directed mutagenesis provided a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks over 90% anticoagulant activity but retains normal cell signaling activities. The 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein-coupled receptor, protease activated receptor 1 (PAR1). Potent neuroprotection in murine ischemic stroke models is linked to 3K3A-APC-induced signaling that arises due to APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site | Mus musculus |
| additional information | engineering of APC by site-directed mutagenesis provides a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks over 90% anticoagulant activity but retains normal cell signaling activities. The 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein-coupled receptor, protease activated receptor 1 (PAR1) | Homo sapiens |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| protease-activated receptor 1 + H2O | Homo sapiens | PAR1 | ? | - |
? |  |
| protease-activated receptor 1 + H2O | Mus musculus | PAR1 | ? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P04070 | - |
- |
| Mus musculus | P33587 | - |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| proteolytic modification | the physiologic mechanism for protein C activation involves proteolysis at Arg169 in EPCR-bound protein C by thrombomodulin-bound thrombin | Mus musculus |
| proteolytic modification | the physiologic mechanism for protein C activation involves proteolysis at Arg169in EPCR-bound protein C by thrombomodulin-bound thrombin. The half-life of endogenous circulating APC in humans is 15 to 0 minutes and is dominantly determined by its irreversible reaction with the plasma serine protease inhibitors, alpha1-antitrypsin, protein C inhibitor, and alpha2-macroglobulin | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| blood plasma | - |
Homo sapiens | - |
| blood plasma | - |
Mus musculus | - |
| fetal neural stem cell | - |
Homo sapiens | - |
| fetus | fetal neural stem and progenitor cells | Homo sapiens | - |
| additional information | APC-induced signaling, that involves PAR, is thought to occur in caveola, where EPCR-bound APC cleaves PAR1 | Homo sapiens | - |
| additional information | APC-induced signaling, that involves PAR, is thought to occur in caveola, where EPCR-bound APC cleaves PAR1 | Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| protease-activated receptor 1 + H2O | PAR1 | Homo sapiens | ? | - |
? | |
| protease-activated receptor 1 + H2O | PAR1 | Mus musculus | ? | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| Activated protein C | - |
Homo sapiens |
| Activated protein C | - |
Mus musculus |
| APC | - |
Homo sapiens |
| APC | - |
Mus musculus |
| PROC | - |
Homo sapiens |
| PROC | - |
Mus musculus |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site through the APC mutant 3K3A-APC causes biased signaling that provides a major explanation for APC's in vivo mechanism of action for neuroprotective activities. Structure-activity relationships of protein C is used to analyse protein C dysfunction in venous thrombosis patients who have protein C mutations | Homo sapiens |
| malfunction | potent neuroprotection in murine ischemic stroke models is linked to enzyme mutant 3K3A-APC-induced signaling that arises due to APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site. This cleavage causes biased signaling that provides a major explanation for APC's in vivo mechanism of action for neuroprotective activities. Mice carrying the 46QQ-PAR1 point mutation strongly support the concept that APC-induced, PAR1-dependent biased signaling following Arg46 cleavage is central to APC's in vivo neuroprotective benefits in this model of ischemic stroke | Mus musculus |
| metabolism | other cell receptors, especially endothelial cell protein C (EPCR) and PAR3 inter alia, may also significantly contribute to APC-initiated cell signaling. APC anticoagulant and cell signaling pathways and the structure of signaling-selective 3K3A-APC, overview | Mus musculus |
| metabolism | other cell receptors, especially endothelial cell protein C (EPCR) and PAR3 inter alia, may also significantly contribute to APC-initiated cell signaling. PAR1 internalization after activation by either thrombin or APC. APC anticoagulant and cell signaling pathways and the structure of signaling-selective 3K3A-APC, overview | Homo sapiens |
| physiological function | protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Enzyme APC shows cytoprotective and neurogenerative activities which most often, but not always, involve PAR1 and EPCR, often other receptors are required, such as PAR3, sphingosine phosphate 1 receptor 1 (S1P1), the integrin Mac-1 or other beta1 and beta3 integrins, apolipoprotein E receptor 2, epidermal growth factor receptor, and Tie-2 (tunica intima endothelial receptor tyrosine kinase 2). Neuroprotective effects of APC in the neurovascular space and in neurons, overview. APC's neuronal protective actions require PAR1 and PAR3. Enzyme mutant 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model, using human fetal neural stem and progenitor cells | Homo sapiens |
| physiological function | protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Enzyme APC shows cytoprotective and neurogenerative activities which most often, but not always, involve PAR1 and EPCR, often other receptors are required, such as PAR3, sphingosine phosphate 1 receptor 1 (S1P1), the integrin Mac-1 or other beta1 and beta3 integrins, apolipoprotein E receptor 2, epidermal growth factor receptor, and Tie-2 (tunica intima endothelial receptor tyrosine kinase 2). Neuroprotective effects of APC in the neurovascular space and in neurons, overview. APC's neuronal protective actions require PAR1 and PAR3. Enzyme mutant 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model, using human fetal neural stem and progenitor cells | Mus musculus |
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