3.4.21.69: Protein C (activated)
This is an abbreviated version!
For detailed information about Protein C (activated), go to the full flat file.
Word Map on EC 3.4.21.69
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3.4.21.69
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thrombosis
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venous
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leiden
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sepsis
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endothelial
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antithrombin
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thromboembolism
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thrombophilia
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clot
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thrombomodulin
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platelet
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procoagulant
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heparin
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arterial
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vein
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bleeding
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plasminogen
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hypercoagulable
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thromboplastin
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lupus
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fibrinogen
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fibrinolysis
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hemostatic
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viiia
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epcr
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intravascular
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contraceptive
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antiphospholipid
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antithrombotic
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prothrombotic
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fibrin
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k-dependent
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anticardiolipin
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d-dimers
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coagulopathy
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embolism
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prothrombinase
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amidolytic
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thrombin-antithrombin
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haemostasis
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par1
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profibrinolytic
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pharmacology
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goal-directed
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diagnostics
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drug development
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gamma-carboxyglutamic
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deep-vein
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time-based
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tafi
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hypofibrinolysis
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thromboprophylaxis
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medicine
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protac
- 3.4.21.69
- thrombosis
- venous
- leiden
- sepsis
- endothelial
- antithrombin
- thromboembolism
- thrombophilia
- clot
- thrombomodulin
- platelet
-
procoagulant
- heparin
- arterial
- vein
-
bleeding
- plasminogen
-
hypercoagulable
- thromboplastin
-
lupus
- fibrinogen
-
fibrinolysis
-
hemostatic
- viiia
- epcr
-
intravascular
-
contraceptive
-
antiphospholipid
-
antithrombotic
-
prothrombotic
- fibrin
-
k-dependent
-
anticardiolipin
-
d-dimers
- coagulopathy
- embolism
- prothrombinase
-
amidolytic
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thrombin-antithrombin
-
haemostasis
- par1
-
profibrinolytic
- pharmacology
-
goal-directed
- diagnostics
- drug development
-
gamma-carboxyglutamic
-
deep-vein
-
time-based
- tafi
-
hypofibrinolysis
-
thromboprophylaxis
- medicine
- protac
Reaction
degradation of blood coagulation factors Va and VIIIa =
Synonyms
Activated blood coagulation factor XIV, Activated protein C, anticoagulant activated protein C, anticoagulant protein C/protein S system, anticoagulant serine protease-activated protein C, anticoagulant-activated protein C, APC, Autoprothrombin II-A, Autoprothrombin IIA, Blood coagulation factor XIV, Blood-coagulation factor XIV, activated, Blood-coagulation factor XIVa, ghrelin endopeptidase, GSAPC, hAPC, PROC, Protein Ca, rhAPC
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General Information
General Information on EC 3.4.21.69 - Protein C (activated)
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malfunction
metabolism
physiological function
additional information
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severe thrombophilia occurs with deficiencies in phosphatidylcholine or phosphatidylserine and with a mutation in factor Va that prevents its inactivation by APC, known as Factor V Leiden
malfunction
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naturally occuring mutation G216D in the specificity pocket of the enzyme causes protein C deficiency. Superposition of the integrin binding motifs in wild-type and mutant forms suggests that the interaction with integrin can still occur and thus the mutant is likely to retain its antiseptic function related to the neutrophyl integrin binding
malfunction
a recombinant APC variant (APCN329Q) mimicking the naturally occurring APC-beta plasma glycoform exhibits superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling.Mutant APCN329Q also enhances integrin aMb2-dependent PAR1 proteolysis to exert significantly improved anti-inflammatory activity on macrophages compared with wild-type APC
malfunction
a recombinant APC variant (APCN329Q) mimicking the naturally occurring APC-beta plasma glycoform exhibits superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling.Mutant APCN329Q also enhances integrin aMb2-dependent PAR1 proteolysis to exert significantly improved anti-inflammatory activity on macrophages compared with wild-type APC. Enhanced cytoprotective PAR1 signaling by APC-beta is a consequence of accelerated EPCR-dependent PAR1 proteolysis
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
malfunction
blocking Tie2 restricts endothelial barrier integrity. On blocking the Tie2 receptor, binding between APC and Tie2 is inhibited significantly irrespective of APC concentration
malfunction
coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice. aPC resistance of factor (f)V due to the R506Q Leiden mutation protects against detrimental anticoagulant effects of aPC therapy but also abrogates the anti-inflammatory and mortality reducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function. aPC resistance of fV Leiden suppresses in vitro regulation of inflammatory gene expression by aPC, overview
malfunction
Mac-1 inhibition prevents APC attenuation of pro-inflammatory cytokine release from lipopolysaccharide (LPS)-stimulated murine macrophages. Furthermore, APC administration does not significantly reduce mortality in Mac-1 deficient endotoxemic mice, suggestive of an important role for Mac-1-dependent PAR1 activation on myeloid cells for the ability of APC to limit mortality in murine endotoxemia
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
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the procoagulant role of the protein C pathway may have important implications for the regulation of TF- and TFPI-dependent biologic responses and for fine tuning of the hemostatic balance in the vascular system
metabolism
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the protein C pathway plays a key role in blood coagulation and inflammation
metabolism
activated protein C is the key effector molecule of the natural protein C pathway. Biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of factor V are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection, overview
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
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
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activated protein C and its cofactor, protein S in the presence of a membrane surface cleaves and inactivates the cofactors of the intrinsic and prothrombinase complexes, factor VIIIa and factor Va, respectively
physiological function
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activated protein C downregulates thrombin formation through proteolytic inactivation of factor Va and factor VIIIa, the anticoagulant activity may be important for in vivo regulation of thrombin formation
physiological function
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activated protein C has anti-apoptotic effects and improves survival in sepsis, activated protein C prevents endothelial cell apoptosis, induced by serum from patients with malaria or sepsis. Activated protein C alone lowers the endothelial cell apoptosis rate from 48% to 38% in the presence of patient serum, In combination with ascorbic acid, activated protein C lowers the apoptosis rate to 25% and in combination with ulinastatin to 23%
physiological function
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activated protein C inhibits bisphosphonate-induced endothelial cell death via the endothelial protein C receptor and nuclear factor-kappaB pathways, protective effects and mechanism, overview. APC inhibits induction of cell death by alendronate, zoledronate, and pamidronate, and diminishes activation of caspase-3 by the bisphosphonates
physiological function
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activated protein C inhibits high mobility group box 1 signaling in endothelial cells, protective effects of APC are mediated through endothelial cell protein C receptor and protease-activated receptor 1, PAR-1. APC potently inhibits the release of HMGB1, downregulates the expression of HMGB1 receptors, and downregulates the adhesion of the monocytic cell line, THP-1, to HMGB1-activated endothelial cells, and it also down-regulates the cell surface expression of all 3 HMGB1 receptors in endothelial cells
physiological function
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activated protein C is a natural anticoagulant protease that displays cytoprotective and antiinflammatory activities and has been demonstrated to reduce mortality of patients with severe sepsis. Protective cross talk between activated protein C and TNF signaling in vascular endothelial cells, overview. APC signaling causes a moderate but significant induction of cell adhesion molecules including VCAM-1 at mRNA and protein levels. Activation of the noncanonical NF-kappaB and ERK1/2 are both pivotal to APC signaling leading to VCAM-1 expression, PAR1 and EPCR equally mediate APC signaling that triggers VCAM-1 expression. APC upregulates TNF receptor-associated factor 2, TRAF2, and phosphorylates NF-kappaB p65 at Ser276 and Ser536 independently of IkappaB degradation, and it shows a regulatory effect on VCAM-1 expression, detailed overview. Ability of APC to activate ERK1/2 in resting cells and to enhance ERK activation in TNF-treated cells, activated ERK1/2 MAPK serves as an antiinflammatory signal in endothelial cells
physiological function
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activated protein C is a natural anticoagulant with anti-inflammatory and endothelial barrier protective properties, which significantly increases the barrier impedance of keratinocyte monolayers, overview. APC also increases junction proteins zona occludens, claudin-1 and VE-cadherin. APC activates Tie2, via a mechanism requiring, in sequential order, the receptors, endothelial protein C receptor, protease activated receptor-1, and EGF receptor, which selectively enhances the PI3K/Akt signaling to enhance junctional complexes and reduce keratinocyte permeability. Inhibition of Tie2 by its peptide inhibitor or small interfering RNA abolishes the barrier protective effect of APC on keratinocytes, as well as inhibition of the activation of Akt, but not ERK
physiological function
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activated protein C is a serine protease that downregulates coagulation by proteolytically inactivating cofactors FVa and factor VIIIa, activated protein C proteolytically inactivates factor Va and thereby down regulates prothrombinase. Prothrombinase is inactivated by aPC during prothrombin activation much more slowly than Factor Va is inactivated in the absence of Factor Xa and prothrombin
physiological function
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activated protein C is an anticoagulant serine protease with non-hemostatic functions related to inflammation, cell survival, and cell migration. Activated protein C enhances cell motility of endothelial cells and MDA-MB-231 breast cancer cells by intracellular signal transduction, mechanism by which APC promotes angiogenesis and breast cancer invasion, overview. APC activation of matrix metalloproteases 2 and/or 9 is necessary but not sufficient to increase invasion, and APC does not utilize the endogenous plasminogen activation system to increase invasion. APC activates the ERK, Akt, and NFkappaB, but not the JNK pathway to promote MDA-MB-231 cell motility. APC proteolytically inactivates factors Va and VIIIa in the presence of protein S. APC forms a stable complex with PAI-1, thereby removing a potent inhibitor of urokinase plasminogen activator, EC 3.4.21.73, from the system. APC promotes MDA-MB-231 breast cancer cell invasion through EPCR and PAR-1, and MDA-MB-231 cell chemotaxis through MAPK and PI3K/Akt activation
physiological function
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activated protein C modulates inflammation, apoptosis and tissue factor procoagulant activity by regulating endoplasmic reticulum calcium depletion in blood monocytes. Protective effects of APC treatment in severe sepsis. APC decreases phosphorylated eukaryotic translational initiation factor 2alpha and C/EBP homologous protein levels induced by thapsigargin. APC inhibits thapsigargin-induced ER Ca2+ flux and reactive oxygen species generation. Functionally, APC diminishes thapsigargin-induced caspase-3 activity and degradation of the nuclear factor kappaB inhibitor IkappaBalpha. Furthermore, APC dampens the induction of tissue factor procoagulant activity facilitated by thapsigargin, and APC dampens unfolded protein response activation
physiological function
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activated protein C promotes fibrinolysis while inhibiting coagulation and inflammation. Although aPC does not affect ET-1-dependent sinusoidal vasoconstriction, it induces hepatoprotective effects via enhanced red blood cell velocity. aPC ameliorates ET-1-dependent changes in hepatic microcirculation and improves hepatic function in the setting of sepsis in rats
physiological function
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activated protein C upregulates TF activity by endothelial cell protein C receptordependent shedding of the Kunitz 1 domain from membrane-associated TFPI. Exogenous or endogenously generated APC leads to increased TF-dependent factor Xa activity. Induction requires APC's proteolytic activity and binding to endothelial cell protein C receptor but not protease activated receptors, mechanism, overview. APC does not affect total TF antigen expression or the availability of anionic phospholipids on the apical cell membrane
physiological function
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APC inhibits activation of caspase-3, -8, and -9 by hypoxia
physiological function
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protein C is the central enzyme of the natural anticoagulant pathway, its activated form activated protein C is able to proteolyse non-active as well as active coagulation factors V and VIII in a protein S and factor V dependent manner, mechanism, overview. Proteolysis renders these cofactors inactive, resulting in an attenuation of thrombin formation and overall downregulation of coagulation. The activated enzyme also has direct cytoprotective effects on cells, since it is able to protect the endothelial barrier function and expresses anti-inflammatory and anti-apoptotic activities. Both the protease activated receptor 1 and EPCR are essential for the cytoprotective activity of APC. Also other receptors like sphingosine 1-phosphate receptor 1, Cd11b/CD18 and tyrosine kinase with immunoglobulin-like and EGFlike domains 2 are likewise important for APC signalling. The N-terminal Gla-domain, residues 1-45, confers protein C its membrane and EPCR binding capacity and contributes to the binding between APC and protein S, the C-terminus of the Gla-domain, residues 25-45, and particularly D35, D36, L38 and A39 were shown to interact with protein S
physiological function
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treatment with recombinant activated protein C reduces the activation of splenic dendritic cells as well as systemic inflammation in MRL-Fas(lpr) mice. Activated protein C attenuates systemic lupus erythematosus and lupus nephritis in autoimmune female MRL-Fas(lpr) mice injected with recombinant human activated protein C, overview. Activated protein C treatment significantly suppresses lupus nephritis as evidenced by decrease in activity index, glomerular IgG and complement C3 deposits, macrophage counts, as well as intrarenal IL-12 expression. Further, activated protein C attenuates cutaneous lupus and lung disease as compared with vehicle-treated MRL-Fas(lpr) mice. In addition, parameters of systemic autoimmunity, such as plasma cytokine levels of IL-12p40, IL-6, and CCL2/MCP-1, and numbers of B cells and plasma cells in spleen are suppressed by activated protein C
physiological function
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activated protein C has a protective efficacy against ischemia-reperfusion injury in several organs, e.g. in myocardium, possible mechanism, overview. The enzyme improves ischemia-reperfusion injury in spinal cord as neuroprotective effect through insulin like growth factor and AKT1 cascade. AKT1 is one of signals that prevent from heart failure
physiological function
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activated protein C induces endoplasmic reticulum stress and attenuates lipopolysaccharide-induced apoptosis both mediated by glycogen synthase kinase-3beta. Activated protein C elicits a rise in glucose-regulated protein 78 and glycogen synthase kinase-3beta and inhibits apoptosis in human umbilical vein endothelial cells induced by lipopolysaccharide. Calcium inhibition does not alter the antiapoptotic effect of activated protein C
physiological function
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activated protein C is a natural anticoagulant that exerts anti-inflammatory and cytoprotective effects in various diseases via endothelial protein C receptor and proteinase-activated receptor-mediated pathways. Activated protein C inhibits proliferation and tumor necrosis factor alpha-stimulated activation of p38, c-Jun NH2-terminal kinase, and Akt in rheumatoid synovial fibroblasts. The enzyme induces the phosphorylation of extracellular signal-regulated protein kinase and enhances expression of p21 and p27 in a dose-dependent manner in rheumatoid synovial fibroblasts. The enzyme stimulates proliferation of normal human dermal fibroblasts by up to 60%, but robustly downregulates proliferation of rheumatoid synovial fibroblasts
physiological function
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activated protein C is a natural anticoagulant with strong cyto-protective and anti-inflammatory properties and inhibits pancreatic islet inflammation, stimulates T regulatory cells, and prevents diabetes when regularly injected into non-obese diabetic BALB/c mice, islets of which exhibit markedly increased expression of insulin, aPC/protein C, endothelial protein C receptor, and matrix metalloproteinase-2. Culture of non-obese diabetic mouse spleen cells with the recombinant human enzyme reduces the secretion of inflammatory cytokines interleukin-1beta and interferon-beta1 but increases interleukin-2 and transforming growth factor-beta1, two cytokines required for Treg differentiation, overview
physiological function
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activated protein C is an important factor in the anticoagulant system. It also regulates amyloid beta secretion by shifting amyloid beta precursor protein processing from the amyloidogenic pathway toward the nonamyloidogenic pathway. ADAM-10 expression is increased by the enzyme and inhibits amyloid beta secretion by stimulating activity of alpha-secretase, expression of presenilin-1 is not influenced by the enzyme in SH-SY5Ycells
physiological function
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direct cytoprotective activities of activated protein C on cells convey therapeutic, relevant, beneficial effects in injury and require the endothelial protein C receptor and protease activated receptor 3, PAR3. In vivo, the enzyme-derived PAR3 tethered-ligand peptide, but not the thrombin-derived PAR3 peptide, blunts vascular endothelial growth factor-induced vascular permeability
physiological function
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microvascular thrombosis occurs in severe acute pancreatitis, injection of recombinnat activated protein C in a rat model does not modify coagulation parameters or lead to hemorrhage but ameliorates pancreatic injury with preservation of IkappaB and reduction of NF-kappaB p65 and modulation of apoptosis, overview
physiological function
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the activated protein C plays a central role in physiological anticoagulation, and has potent anti-inflammatory mediator and cytoprotective properties. Activated protein C is a cytoprotective anticoagulant that can promote cutaneous healing. The enzyme favorably regulates MG63 viability and differentiation toward bone growth. Bisphosphonates alendronate, zoledronate or pamidronate induce MG-63 cell death in a dose- and time-dependent manner. Pamidronate- and zoledronate-related cell death is prevented by the enzyme treatment, but cell death induced by alendronate is accelerated by the enzyme. The enzyme induces MG-63 cell differentiation that is enhanced by alendronate, but inhibited by pamidronate or zoledronate. Endothelial protein C receptor is expressed by MG-63 cells and mediates the protective effect of the enzyme on zoledronate-induced viability. Expression of type 1 collagen and endothelial protein C receptor is induced by activated protein C treatment in MG-63 cells
physiological function
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the enzyme has anticoagulant function in the coagulation system counteracting apoptosis and inflammation in cells. the antiseptic activity of the enzyme is mediated by its binding to leukkocyte integrins, the integrin-binding motif of the enzyme locates at the N-terminus of the catalytic chain
physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
physiological function
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the enzyme significantly reduced thrombin-induced cell monolayer permeability, cell stiffening, and cell contraction. The enzyme reduces the disruption of barrier integrity induced by thrombin, thus contributing to alveolar epithelial barrier protection, overview
physiological function
activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by activation of protease-activated receptors 1 and 3 (PAR1, PAR3) via non-canonical cleavage1. Recombinant APC and/or its analogues with reduced by over 90% anticoagulant activity such as mutant 3K3A-APC (K191A/K192A/K193A), engineered to reduce APC-associated bleeding risk while retaining normal cell signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic/reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes, and lethal body radiation. Enzyme mutant 3K3A-APC stimulates neuronal production by human neural stem/progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate receptor 1-Akt pathway. Effects of late post-ischemic 3K3A-APC treatment on the in vivo production of neurons from transplanted NSCs in C57BL/6J mice, and the effects of this combination therapy on long-term neurological recovery and restoration of disrupted neural circuitry in the post-ischemic murine brain, functional integration of NSCs into the host neuronal circuitry, overview
physiological function
Activated protein C (APC) is a vitamin K-dependent serine protease that plays a key role in the regulation of blood coagulation but also exerts a broad range of cytoprotective actions on endothelium including suppression of inflammation and stabilization of endothelial barrier function. Activated protein C (APC) is a natural anticoagulant with strong anti-inflammatory, anti-apoptotic, and barrier stabilizing properties. These cytoprotective properties of APC are thought to be exerted through its pathway involving the binding of APC to endothelial protein C receptor and cleavage of protease-activated receptors. APC enhances endothelial barrier integrity via a novel pathway, by binding directly to and activating Tie2, a transmembrane endothelial tyrosine kinase receptor. After binding, APC rapidly activates Tie2 to enhance endothelial barrier function. APC-mediated cytoprotective signaling requires endothelial protein C receptor (EPCR) and cleavage of protease-activated receptor (PAR)1 at Arg46, which may occur in caveolin-1-enriched lipid rafts. In addition, other receptors, such as sphingosine-1-phosphate receptor 1 (S1P1), epidermal growth factor receptor (EGFR), PAR3, and Tie2, may independently or co-operatively contribute to APC-mediated protective effects on endothelium. For example, APC protects against endothelial barrier disruption by cross-activating S1P1 or by stimulating Ang1 whilst inhibiting Ang2 to activateTie2, both these mechanisms require signaling through EPCR and PAR1. APC rapidly suppresses endothelial permeability via Tie2. APC signals through Tie2 to reverse vascular leakage in vivo. Tie2-I alone does not affect EBA leakage into the kidneys or lungs. The protective effect of APC is significantly reversed by Tie2-I in all experiments
physiological function
activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. Importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC
physiological function
activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. Importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC. Analysis of APC inhibition of cytokine secretion from RAW-264.7 cells. APC-beta exhibits superior inhibition of cerebral injury in murine ischemic stroke
physiological function
coagulation-independent cell signaling by aPC appears to be the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. Using a mouse model of Staphylococcus aureus sepsis,marked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC are demonstrated. Factor V and protein S are required for sepsis mortality reduction and suppression of inflammatory gene expression by activated protein C. Procofactor V (cleaved by aPC at R506) and protein S are necessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The antiinflammatory cofactor function of fV involves the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities do not involve proteolysis of activated coagulation factors Va and VIIIa. Sepsis stage-related response to infusion of aPC variants, overview. Inhibition of tissue factor-EPCR-PAR2 signaling by enzyme aPC requires protein S and the factor V B domain. aPC inhibits PAR2 activation by the ternary tissue factor-factor VIIa-factor Xa complex
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
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
physiological function
the anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease
physiological function
the anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease. Distinct from its crucial role in regulating blood coagulation, APC initiates cell signalling via engagement with multiple cell surface receptors. Although APC triggers an array of signalling pathways via distinct receptor interactions on different cell types, APC signalling is invariably cytoprotective, conferring protection against exposure to pro-inflammatory and/or pro-apoptotic agents. Prototypical APC signalling on endothelial cells involves initial binding to EPCR that in turn facilitates proteolysis and activation of protease-activated receptor 1 (PAR1). APC binding to EPCR is a pre-requisite for PAR3 activation by APC, which mediates similar protective signalling outputs as PAR1 activation. The role of EPCR as an APC co-receptor for PAR1 signalling can also be assumed by the integrin alphaMbeta2 (macrophage-1 antigen, Mac-1)
physiological function
the anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease. The proteolytic inactivation of FVa/FVIIIa by APC with protein S slows further thrombin generation and thus acts as a negative feedback loop to inhibit thrombus growth. Distinct from its crucial role in regulating blood coagulation, APC initiates cell signalling via engagement with multiple cell surface receptors. Although APC triggers an array of signalling pathways via distinct receptor interactions on different cell types, APC signalling is invariably cytoprotective, conferring protection against exposure to pro-inflammatory and/or pro-apoptotic agents. Prototypical APC signalling on endothelial cells involves initial binding to EPCR that in turn facilitates proteolysis and activation of protease-activated receptor 1 (PAR1). APC binding to EPCR is a pre-requisite for PAR3 activation by APC, which mediates similar protective signalling outputs as PAR1 activation. APC can also promote anti-inflammatory signalling on myeloid cells in a PAR-independent manner. APC binds apolipoprotein E receptor 2 (ApoER2) to trigger Dab1 phosphorylation and activate phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase 3beta (GSK3beta)-dependent signalling in monocytic U-937 cells. APC might interact concurrently with other APC receptors on monocytes
physiological function
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activated protein C has a protective efficacy against ischemia-reperfusion injury in several organs, e.g. in myocardium, possible mechanism, overview. The enzyme improves ischemia-reperfusion injury in spinal cord as neuroprotective effect through insulin like growth factor and AKT1 cascade. AKT1 is one of signals that prevent from heart failure
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physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
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a TFPI Lys86Ala mutation between the Kunitz 1 and 2 domains eliminates both cleavage and the enhanced TF activity in response to APC in overexpression studies
additional information
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APC generation is dependent on protein C binding to endothelial cell protein C receptor, EPCR, and thrombin binding to thrombomodulin
additional information
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function relationships of APC, overview. Presence of the APC cofactor, protein S, thrombomodulin, endothelial protein C receptor and a phospholipid surface are important for the expression of anticoagulant APC activity. Two or three cation binding-sites in the Gla-domain are occupied, resulting in a conformational change of the Gla-domain. Second, a group of four or five divalent cation binding sites with a high specificity for Ca2+ become occupied, enabling binding of the protein to acidic phosphalipid vesicles. Ca2+ interactions are essential for the anticoagulant functions of APC and are influenced by mutations in different regions of the Gla-domain. Residues R15, C22 and Gla-residues 6, 7, 16, 20, 25, 26 and 29 are thus absolutely required for APCs anticoagulant function
additional information
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residues Arg336 and Arg562 are involved in the catalytic mechanism
additional information
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molecular model of the complex of APC with alphaVbeta3 integrin obtained by protein-protein docking approach, molecular dynamics and docking simulation of natural mutant G216D of activated protein C with impaired protease activity, implications for integrin-mediated antiseptic function, overview