-
Cells Dec 2022It has been four decades since protein S-glutathionylation was proposed to serve as a regulator of cell metabolism. Since then, this redox-sensitive covalent... (Review)
Review
BACKGROUND
It has been four decades since protein S-glutathionylation was proposed to serve as a regulator of cell metabolism. Since then, this redox-sensitive covalent modification has been identified as a cell-wide signaling platform required for embryonic development and regulation of many physiological functions.
SCOPE OF THE REVIEW
Mitochondria use hydrogen peroxide (HO) as a second messenger, but its availability must be controlled to prevent oxidative distress and promote changes in cell behavior in response to stimuli. Experimental data favor the function of protein S-glutathionylation as a feedback loop for the inhibition of mitochondrial HO production.
MAJOR CONCLUSIONS
The glutathione pool redox state is linked to the availability of HO, making glutathionylation an ideal mechanism for preventing oxidative distress whilst playing a part in desensitizing mitochondrial redox signals.
GENERAL SIGNIFICANCE
The biological significance of glutathionylation is rooted in redox status communication. The present review critically evaluates the experimental evidence supporting its role in negating mitochondrial HO production for cell signaling and prevention of electrophilic stress.
Topics: Hydrogen Peroxide; Protein S; Mitochondria; Glutathione; Oxidation-Reduction
PubMed: 36611901
DOI: 10.3390/cells12010107 -
Clinical and Applied... Nov 2014The increased risk of cardiovascular and cerebrovascular events in patients with migraine remains unexplained. Prothrombotic states are thought to contribute to this...
The increased risk of cardiovascular and cerebrovascular events in patients with migraine remains unexplained. Prothrombotic states are thought to contribute to this increased risk. The present study aimed to compare the prevalence of prothrombotic states in patients with migraine and headache-free controls. We conducted a case-control study to screen for prothrombotic states protein C, protein S (PS), antithrombin III, factor V Leiden, lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein 1 antibodies in 101 consecutive patients with migraine and 148 controls. An underlying prothrombotic state was encountered in 11.8% of the patients with migraine, PS deficiency being the most common (4.0%). There was no significant difference in the prevalence of prothrombotic states in patients with migraine compared to controls. Traditional prothrombotic states do not seem to have a higher prevalence in patients with migraine compared to controls.
Topics: Adolescent; Adult; Antibodies, Anticardiolipin; Antithrombin III; Blood Coagulation Disorders; Case-Control Studies; Factor V; Female; Humans; Male; Middle Aged; Migraine Disorders; Protein C; Protein S; beta 2-Glycoprotein I
PubMed: 23637003
DOI: 10.1177/1076029613486538 -
Proceedings of the National Academy of... Mar 1994Although human protein S binds to human factor Va and inhibits prothrombinase activity, this inhibition is not totally dependent on factor Va. Hence, we investigated...
Although human protein S binds to human factor Va and inhibits prothrombinase activity, this inhibition is not totally dependent on factor Va. Hence, we investigated possible interaction of protein S with human factor Xa. Factor Xa, diisopropylphospho-factor Xa and their biotin derivatives ligand blotted specifically to protein S and protein S ligand blotted specifically to factor X and factor Xa. Biotinylated factors X and Xa bound to immobilized protein S and, reciprocally, protein S bound to immobilized factor Xa with a Kd of approximately 19 nM. In fluid phase, protein S bound to factor Xa with a Kd of approximately 18 nM. Protein S at 33 nM reversibly inhibited 50% of factor Xa amidolytic activity. Protein S inhibition of prothrombin conversion to thrombin by factor Xa was phospholipid-independent and was 1.6 times stimulated by Ca2+ ions. Inhibition of prothrombinase activity by protein S was 2.3-fold more potent in the presence of factor Va, with 50% inhibition at approximately 8 nM protein S. Protein S prolonged the factor Xa one-stage clotting time of protein S-depleted plasma in a dose-dependent manner. These data demonstrate mechanisms of anticoagulant action for protein S that are independent of activated protein C and that involve direct binding to factors Xa and Va and direct inhibition of factor Xa.
Topics: Biotin; Blood Coagulation Tests; Calcium; Factor Xa; Factor Xa Inhibitors; Humans; Protein C; Protein S; Prothrombin; Thrombin; Thromboplastin
PubMed: 8146182
DOI: 10.1073/pnas.91.7.2728 -
The Journal of Biological Chemistry Jul 2003The procoagulant function of activated factor V (FVa) is inhibited by activated protein C (APC) through proteolytic cleavages at Arg306, Arg506, and Arg679. The effect...
The procoagulant function of activated factor V (FVa) is inhibited by activated protein C (APC) through proteolytic cleavages at Arg306, Arg506, and Arg679. The effect of APC is potentiated by negatively charged phospholipid membranes and the APC cofactor protein S. Protein S has been reported to selectively stimulate cleavage at Arg306, an effect hypothesized to be related to reorientation of the active site of APC closer to the phospholipid membrane. To investigate the importance of protein S and phospholipid in the APC-mediated cleavages of individual sites, recombinant FV variants FV(R306Q/R679Q) and FV(R506Q/R679Q) (can be cleaved only at Arg506 and Arg306, respectively) were created. The cleavage rate was determined for each cleavage site in the presence of varied protein S concentrations and phospholipid compositions. In contrast to results on record, we found that protein S stimulated both APC cleavages in a phospholipid composition-dependent manner. Thus, on vesicles containing both phosphatidylserine and phosphatidylethanolamine, protein S increased the rate of Arg306 cleavage 27-fold and that of Arg506 cleavage 5-fold. Half-maximal stimulation was obtained at approximately 30 nm protein S for both cleavages. In conclusion, we demonstrate that APC-mediated cleavages at both Arg306 and Arg506 in FVa are stimulated by protein S in a phospholipid composition-dependent manner. These results provide new insights into the mechanism of APC cofactor activity of protein S and the importance of phospholipid composition.
Topics: Animals; Blood Coagulation; COS Cells; Factor Va; Humans; Phospholipids; Protein C; Protein S; Recombinant Proteins
PubMed: 12707283
DOI: 10.1074/jbc.M303829200 -
Cells Sep 2020The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, AXL, and MERTK, the TAM subfamily... (Review)
Review
The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, AXL, and MERTK, the TAM subfamily of receptor tyrosine kinases (RTK), are key regulators of inflammation and vascular response to damage. TAM signaling, which has largely studied in the immune system and in cancer, has been involved in coagulation-related pathologies. Because of these established biological functions, the GAS6-PROS1/TAM system is postulated to play an important role in SARS-CoV-2 infection and progression complications. The participation of the TAM system in vascular function and pathology has been previously reported. However, in the context of COVID-19, the role of TAMs could provide new clues in virus-host interplay with important consequences in the way that we understand this pathology. From the viral mimicry used by SARS-CoV-2 to infect cells, to the immunothrombosis that is associated with respiratory failure in COVID-19 patients, TAM signaling seems to be involved at different stages of the disease. TAM targeting is becoming an interesting biomedical strategy, which is useful for COVID-19 treatment now, but also for other viral and inflammatory diseases in the future.
Topics: Adaptive Immunity; Animals; COVID-19; Coronavirus Infections; Hemostasis; Humans; Intercellular Signaling Peptides and Proteins; Pandemics; Pneumonia, Viral; Protein S; Thrombosis; c-Mer Tyrosine Kinase
PubMed: 32998369
DOI: 10.3390/cells9102186 -
Arteriosclerosis, Thrombosis, and... Jan 2014Tissue factor pathway inhibitor (TFPI) is produced in 2 isoforms: TFPIα, a soluble protein in plasma, platelets, and endothelial cells, and TFPIβ, a...
OBJECTIVE
Tissue factor pathway inhibitor (TFPI) is produced in 2 isoforms: TFPIα, a soluble protein in plasma, platelets, and endothelial cells, and TFPIβ, a glycosylphosphatidylinositol-anchored protein on endothelium. Protein S (PS) functions as a cofactor for TFPIα, enhancing the inhibition of factor Xa. However, PS does not alter the inhibition of prothrombinase by TFPIα, and PS interactions with TFPIβ are undescribed. Thus, the physiological role and scope of the PS-TFPI system remain unclear.
APPROACH AND RESULTS
Here, the cofactor activity of PS toward platelet and endothelial TFPIα and endothelial TFPIβ was quantified. PS enhanced the inhibition of factor Xa by TFPIα from platelets and endothelial cells and stabilized the TFPIα/factor Xa inhibitory complex, delaying thrombin generation by prothrombinase. By contrast, PS did not enhance the inhibitory activity of TFPIβ or a membrane-anchored form of TFPI containing the PS-binding third Kunitz domain (K1K2K3) although PS did function as a cofactor for K1K2K3 enzymatically released from the cell surface.
CONCLUSIONS
The PS-TFPI anticoagulant system is limited to plasma TFPIα and TFPIα released from platelets and endothelial cells. PS likely functions to localize solution-phase TFPIα to the cell surface, where factor Xa is bound. PS does not alter the activity of membrane-associated TFPI. Because activated platelets release TFPIα and PS, the PS-TFPIα anticoagulant system may act physiologically to dampen thrombin generation at the platelet surface.
Topics: Animals; Blood Coagulation; Blood Platelets; CHO Cells; Cell Membrane; Cricetinae; Cricetulus; Factor Xa; Human Umbilical Vein Endothelial Cells; Humans; Kinetics; Lipoproteins; Platelet Activation; Protein Binding; Protein Interaction Domains and Motifs; Protein S; Thrombin; Thromboplastin; Transfection
PubMed: 24233490
DOI: 10.1161/ATVBAHA.113.302655 -
Blood Oct 1995Previous studies showed that infusion of C4b-binding protein with sublethal Escherichia coli (E. coli) in the primate produced a consumptive coagulopathy followed by... (Comparative Study)
Comparative Study
Previous studies showed that infusion of C4b-binding protein with sublethal Escherichia coli (E. coli) in the primate produced a consumptive coagulopathy followed by microvascular thrombosis and renal failure. The first objective of this study was to characterize the pathophysiology and mechanism of this phenomena following infusion of both these agents with emphasis on defining the role of free protein S. The second objective was to examine the relevance of this model to the hemolytic uremic syndrome. Infusion of C4b-binding protein alone reduced free protein S and decreased platelet concentration to 20% of baseline, whereas infusion of the C4b-binding protein/protein S complex did not. There was no activation of other inflammatory or coagulant factors. Infusion of sublethal E coli alone produced a transient inflammatory response with no reduction of free protein S. However, coinfusion of C4b-binding protein with sublethal E coli reduced free protein S and produced a thrombocytopenia, anemia, and a microvascular thrombotic response, whereas infusion of the C4b-binding protein/protein S complex with sublethal E coli did not. Studies comparing the effects of neutralizing (S-163) and nonneutralizing (S-145) antibodies with protein S coinfused with sublethal E coli produced similar contrasting results. Therefore, we concluded that neutralization of free protein S, and not some other property of C4b-binding protein influenced by protein S, accounted for this microvascular thrombotic response. This response is similar to the hemolytic uremic syndrome characterized by thrombocytopenia, anemia, shistocytosis, and renal glomerular thrombosis with uremia. Comparison of the respective renal histopathologic appearance supports this conclusion. This raises the possibility that inhibition of protein S activity (possibly by one of the forms of C4b-binding proteins) might be one of the factors contributing to microvascular thrombotic disorder, such as the hemolytic uremic syndrome.
Topics: Animals; Blood Coagulation; Blood Platelets; Carrier Proteins; Complement Inactivator Proteins; Escherichia coli; Fibrinogen; Glycoproteins; Hematocrit; Hemolytic-Uremic Syndrome; Humans; Kidney Glomerulus; Mice; Mice, Inbred BALB C; Papio; Platelet Count; Protein S
PubMed: 7670107
DOI: No ID Found -
Journal of Thrombosis and Haemostasis :... Feb 2006Plasma protein S (PS) is an essential anticoagulant that has activated protein C-independent, direct anticoagulant activity (PS-direct). It was reported that monomeric... (Comparative Study)
Comparative Study
BACKGROUND AND OBJECTIVES
Plasma protein S (PS) is an essential anticoagulant that has activated protein C-independent, direct anticoagulant activity (PS-direct). It was reported that monomeric purified PS has poor PS-direct and that a subpopulation of multimeric purified PS has high PS-direct and high affinity for phospholipids. We independently examined the relative PS-direct and affinity for phospholipids of monomeric and multimeric PS and we obtained contrasting results.
METHODS AND RESULTS
Unpurified recombinant protein S (rPS) was monomeric and had PS-direct potency similar to that of both PS in plasma and multimeric affinity-purified PS, as measured in plasma assays for PS-direct and in thrombin-generation assays. Multimers of unpurified rPS were not induced by ethylenediaminetetraacetic acid (EDTA), pH 2.5, NaSCN, or barium adsorption/elution. Multimers were induced by chromatography in the presence of EDTA and thus may be concentration-dependent. In contrast to a different report, monomers, dimers, trimers, and higher-order PS forms were clearly separated in sedimentation velocity experiments and multimers were not dissociated by adding Ca(2+). Active plasma-derived and recombinant immunoaffinity-purified PS were fractionated into monomers and multimers. On a mass basis, monomers and multimers had similar specific PS-direct and ability to compete with prothrombinase components (factors Xa/Va) for limiting phospholipids. FXa ligand blotted to both monomers and multimers.
CONCLUSIONS
Plasma PS-direct is similar to that of affinity-purified PS and unpurified rPS. Under our conditions, monomeric and multimeric PS have similar PS-direct and ability to compete for phospholipids. Discordant earlier findings are likely due to loss of PS-direct during conventional purification procedures.
Topics: Anticoagulants; Binding, Competitive; Complement C4b-Binding Protein; Dimerization; Factor Xa; Histocompatibility Antigens; Humans; In Vitro Techniques; Ligands; Phospholipids; Protein S; Protein Structure, Quaternary; Recombinant Proteins; Ultracentrifugation
PubMed: 16420570
DOI: 10.1111/j.1538-7836.2006.01743.x -
Haematologica Dec 2009The protein C pathway down-regulates thrombin generation and promotes cytoprotection during inflammation and stress. In preclinical studies using models of murine injury...
BACKGROUND
The protein C pathway down-regulates thrombin generation and promotes cytoprotection during inflammation and stress. In preclinical studies using models of murine injury (e.g., sepsis and ischemic stroke), murine protein S may be required because of restrictive species specificity.
DESIGN AND METHODS
We prepared and characterized recombinant murine protein S using novel coagulation assays, immunoassays, and cell proliferation assays.
RESULTS
Purified murine protein S had good anticoagulant co-factor activity for murine activated protein C, but not for human activated protein C, in mouse or rat plasma. In human plasma, murine protein S was a poor co-factor for murine activated protein C and had no anticoagulant effect with human activated protein C, suggesting protein S species specificity for factor V in addition to activated protein C. We estimated that mouse plasma contains 22+/-1 microg/mL protein S and developed assays to measure activated protein C co-factor activity of the protein S in murine plasma. Activated protein C-independent anticoagulant activity of murine protein S was demonstrable and quantifiable in mouse plasma, and this activity was enhanced by exogenous murine protein S. Murine protein S promoted the proliferation of mouse and human smooth muscle cells. The potency of murine protein S was higher for mouse cells than for human cells and similarly, human protein S was more potent for human cells than for mouse cells.
CONCLUSIONS
The spectrum of bioactivities of recombinant murine protein S with mouse plasma and smooth muscle cells is similar to that of human protein S. However, in vitro and in vivo studies of the protein C pathway in murine disease models are more appropriately performed using murine protein S. This study extends previous observations regarding the remarkable species specificity of protein S to the mouse.
Topics: Animals; Anticoagulants; Blood Coagulation; Cattle; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Half-Life; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mitogens; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Partial Thromboplastin Time; Protein C; Protein S; Rats; Recombinant Proteins; Species Specificity
PubMed: 19815836
DOI: 10.3324/haematol.2009.009233 -
Vitamins and Hormones 2008Gas6 (growth arrest-specific gene 6) is the last addition to the family of plasma vitamin K-dependent proteins. Gas6 was cloned and characterized in 1993 and found to be... (Review)
Review
Gas6 (growth arrest-specific gene 6) is the last addition to the family of plasma vitamin K-dependent proteins. Gas6 was cloned and characterized in 1993 and found to be similar to the plasma anticoagulant protein S. Soon after it was recognized as a growth factor-like molecule, as it interacted with receptor tyrosine kinases (RTKs) of the TAM family; Tyro3, Axl, and MerTK. Since then, the role of Gas6, protein S, and the TAM receptors has been found to be important in inflammation, hemostasis, and cancer, making this system an interesting target in biomedicine. Gas6 employs a unique mechanism of action, interacting through its vitamin K-dependent Gla module with phosphatidylserine-containing membranes and through its carboxy-terminal LG domains with the TAM membrane receptors. The fact that these proteins are affected by anti-vitamin K therapy is discussed in detail.
Topics: Cell Physiological Phenomena; Homeostasis; Humans; Immunity; Inflammation; Intercellular Signaling Peptides and Proteins; Protein S; Receptor Protein-Tyrosine Kinases; Signal Transduction; Vitamin K
PubMed: 18374195
DOI: 10.1016/S0083-6729(07)00009-X