Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S–C4b binding protein complex

Rezende, Suely Meireles; Simmonds, Rachel E.; Lane, David A.

doi:10.1182/blood-2003-05-1551

Cited by 190 publications

(182 citation statements)

References 170 publications

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“…In addition to its role as a TAM ligand, for example, protein S has an important, TAM-independent activity as a blood anticoagulant -an activity that is not exhibited by GAS6. Protein S, which is present at relatively high levels (~300 nM) in the serum, serves as an essential cofactor for activated protein C, a protease that degrades factor Va and factor VIIIa, and thereby inhibits blood coagulation 12 .…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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“…Only free protein S has the ability to function as a cofactor to APC. [15][16][17] Although protease inhibitors such as the protein C inhibitor, ␣1-antitrypsin, and ␣2-macroglobulin inhibit APC, the halflife of APC in the circulation is relatively long (Ϸ20 minutes). 15 …”

Section: Components Of the Protein C Pathwaymentioning

confidence: 99%

Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway

Dahlbäck

Villoutreix

2005

ATVB

276

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Abstract-The protein C system provides important control of blood coagulation by regulating the activities of factor VIIIa (FVIIIa) and factor Va (FVa), cofactors in the activation of factor X and prothrombin, respectively. The system comprises membrane-bound and circulating proteins that assemble into multi-molecular complexes on cell surfaces. Vitamin K-dependent protein C, the key component of the system, circulates in blood as zymogen to an anticoagulant serine protease. It is efficiently activated on the surface of endothelial cells by thrombin bound to the membrane protein thrombomodulin. The endothelial protein C receptor (EPCR) further stimulates the protein C activation. Activated protein C (APC) together with its cofactor protein S inhibits coagulation by degrading FVIIIa and FVa on the surface of negatively charged phospholipid membranes. Efficient FVIIIa degradation by APC requires not only protein S but also intact FV, which like thrombin is a Janus-faced protein with both procoagulant and anticoagulant potential. In addition to its anticoagulant properties, APC has antiinflammatory and antiapoptotic functions, which are exerted when APC binds to EPCR and proteolytic cleaves protease-activated receptor 1 (PAR-1). The protein C system is physiologically important, and genetic defects affecting the system are the most common risk factors of venous thrombosis. The proteins of the protein C system are composed of multiple domains and the 3-dimensional structures of several of the proteins are known. The molecular recognition of the protein C system is progressively being unraveled, giving us new insights into this fascinating and intricate molecular scenario at the atomic level. Key Words: factor V Ⅲ protein C Ⅲ protein S Ⅲ thrombomodulin P latelet-dependent primary hemostasis and blood coagulation have evolved as important defense mechanisms against bleeding. The initial occlusion of a vascular lesion is provided by the formation of the platelet plug. 1 This is temporally coordinated with the initiation of the coagulation system by the exposure of tissue factor (TF) to blood and the subsequent binding to TF of circulating factor VIIa (FVIIa). 2 The FVIIa-TF complex efficiently converts factor IX (FIX) and factor X (FX) to active enzymes FIXa and FXa, which together with factor VIIIa (FVIIIa) and factor Va (FVa), respectively, propagate the coagulation process (Figure 1). Factor VIII (FVIII) and factor V (FV) circulate in blood as high-molecular-weight inactive procofactors, which are converted into their active forms, FVIIIa and FVa, early during the coagulation process by thrombin or FXa. FVIIIa and FVa bind to negatively charged phospholipid membranes, eg, on activated platelets, and form complexes with FIXa and FXa, respectively. 3-5 The FIXa-FVIIIa complex (tenase) activates FX, whereas the FXa-FVa complex (prothrombinase) converts prothrombin to thrombin. In both the tenase and the prothrombinase complexes, the cofactors increase the catalytic efficiency of the respective enzyme by several orders ...

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“…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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Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S–C4b binding protein complex

Cited by 190 publications

References 170 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway

Molecular basis of protein S deficiency in China

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