Zn2+‐containing protein S inhibits extrinsic factor X‐activating complex independently of tissue factor pathway inhibitor

Fernandes, Nikita; Mosnier, Laurent O.; Tonnu, L.; Heeb, Mary J.

doi:10.1111/j.1538-7836.2010.03919.x

Cited by 20 publications

(34 citation statements)

References 19 publications

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“…In recent decades, evidence has been presented that suggests that ProS can act specifically as a cofactor for tissue factor pathway inhibitor (TFPI) to inhibit tissue factor (TF) activity by facilitating the interaction between full-length TFPI and FXa [9]. More recently, studies have shown that ProS also inhibits extrinsic and intrinsic FXase complexes independently of TFPI and APC [10,11]. In addition to anticoagulant properties, several findings suggest that ProS may have other important roles in cellular processes and anti-inflammatory actions [12].…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of protein S deficiency in China

et al. 2013

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Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the downregulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation. Am. J.

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Section: Introductionmentioning

confidence: 99%

Molecular basis of protein S deficiency in China

et al. 2013

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“…Analyses of aPC and fV variants indicated that this mechanism involved direct aPC-pS interaction and required the same or similar structural features of fV that govern its anticoagulant cofactor activity (reviewed in Cramer and Gale 12 ). Potential candidate mechanisms that do not involve the degradation of fVa or fVIIIa but are consistent with known functions of pS and fV include (1) the destabilization of the signaling-competent conformation of the TF complex secondary to physical interactions of B domain-containing fVa with fXa 49 and of pS with TF and fXa 50 , and/or (2) the recruitment of TF pathway inhibitor a (TFPIa) to the TF-fVIIa-fXa complex via interaction of pS with the TFPIa K3 domain or of the fV B domain with the carboxyterminal fragment of TFPIa (reviewed in Wood et al 51 ). It also remains to be clarified whether other naturally occurring fV variants such as fV Liverpool (I359T), 52 fV Nara (W1920R), 53 fV released from platelets, 54 or fV present in homozygous carriers of the fV R2 haplotype 11,[55][56][57] would exhibit similarly defective cofactor function for the inhibition of TF signaling by aPC as does fV Leiden.…”

Section: Discussionmentioning

confidence: 99%

“…Log-phase cultures of S aureus (American Type Culture Collection 25923) were injected intraperitoneally at a predetermined median lethal dose (LD 50 ) inoculum of ;10 8 bacteria. LPS was injected intraperitoneally.…”

Section: Endotoxemia and Sepsis Modelsmentioning

confidence: 99%

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

Liang

Kerschen

Basu

et al. 2015

Blood

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Key Points• Factor V and protein S are required for sepsis mortality reduction and suppression of inflammatory gene expression by activated protein C.• The R506Q mutation (Leiden mutation) abrogates the antiinflammatory cofactor function of factor V for activated protein C.The key effector molecule of the natural protein C pathway, activated protein C (aPC), exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation. 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. In this study, using a mouse model of Staphylococcus aureus sepsis, we demonstrate marked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC. aPC resistance of factor (f)V due to the R506Q Leiden mutation protected against detrimental anticoagulant effects of aPC therapy but also abrogated the anti-inflammatory and mortalityreducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function. We found that procofactor V (cleaved by aPC at R506) and protein S were necessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The antiinflammatory cofactor function of fV involved the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities did not involve proteolysis of activated coagulation factors Va and VIIIa. These findings reveal a novel biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of fV are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection. (Blood. 2015;126(21):2415-2423 Introduction Natural aPC exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation (for review, see Esmon, 1 Mosnier and Griffin,2 and Dahlbäck and Villoutreix 3 ) that are predominantly mediated by 2 mechanistically discernable pathways: (1) aPC degrades activated coagulation factor (f)Va and fVIIIa to curtail the formation of thrombin by the plasma coagulation system and (2) when bound to the endothelial protein C receptor (EPCR, ProcR) or the integrin aMb2 (Mac1)(CD11b/CD18), aPC becomes competent for activating the G protein-coupled protease activated receptor (PAR) 1, 2, or 3. PAR activation and crosstalk with other receptors mediate anti-inflammatory and cytoprotective effects of aPC in innate immune cells, vascular endothelium, and other cells (for review, see Weiler,4 Mosnier et al, 5 and Dahlbäck and Villoutreix 6). In animal models of endotoxemia and sepsis, the cell signaling activity of aPC on vascular endothelium and innate immune cells is the predominant therapeutic mechanism of action, and recombinant variants of aPC that are largely devoid of anticoagulant activity but retain signaling function confer vasoprotection, inhibit inflammation, and reduce mortality. 7-9 Although the incidence of microvascular coagulopathies in p...

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“…PS also regulates blood coagulation independently of APC and TFPI. It directly inhibits the prothrombinase and extrinsic FXase complexes, functions which our group showed to be dependent on incorporation of Zn 2ϩ in PS (6,7). Forty percent of PS present in plasma circulates in its free form, whereas 60% is in a highaffinity complex with C4b-binding protein (C4BP; ref.…”

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confidence: 99%

Phosphorylation of protein S by platelet kinases enhances its activated protein C cofactor activity

2013

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Protein S (PS) is a multifunctional plasma protein of the hemostatic and inflammatory pathways, although mechanisms for its regulation are poorly understood. Since certain plasma proteins are regulated through extracellular phosphorylation, we investigated whether the anticoagulant activity of PS is regulated through phosphorylation by platelet-secreted kinases. PS was phosphorylated on exposure to activated platelets or their releasates, as judged by immunoblotting for phospho-amino acids and PS. PS phosphorylation was reduced by specific inhibitors of casein kinase 1 (CK1) and casein kinase 2 (CK2) (10 μM D4476, 100 μM CK2-inhibitory peptide YNLKSKSSEDIDESS). Involvement of CKs in PS phosphorylation was confirmed using purified CK1/CK2. Phosphorylation of PS by purified CK1 did not affect its activated protein C (APC) cofactor activity in activated partial thromboplastin time assays in PS-depleted plasma. However, phosphorylation of PS by CK2 or by CK1/CK2 increased PS cofactor activity ∼1.5-fold (158.7±4.8%, P<0.01) or ∼2-fold (191.5±6.4%, P<0.0001), respectively. The APC cofactor activity of PS in PS-depleted plasma exposed to platelet-secreted kinases was enhanced, while CK2 but not CK1 inhibitors reduced APC cofactor activity. Mass spectrometry revealed a phosphorylated CK2 site at Thr37 within the N-terminal Gla-domain. Thus, platelet-mediated extracellular phosphorylation of PS is a potential mechanism by which its activity is regulated.

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Zn2+‐containing protein S inhibits extrinsic factor X‐activating complex independently of tissue factor pathway inhibitor

Abstract: 2+-containing protein S inhibits extrinsic factor X-activating complex independently of tissue factor pathway inhibitor. J Thromb Haemost 2010; 8: 1976-85. Summary. Background: Protein S (PS) has direct anticoagulant activity, independently of activated protein C (APC

Cited by 20 publications

References 19 publications

Molecular basis of protein S deficiency in China

Molecular basis of protein S deficiency in China

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

Phosphorylation of protein S by platelet kinases enhances its activated protein C cofactor activity

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