Expression of the vitamin K-dependent proteins GAS6 and protein S and the TAM receptor tyrosine kinases in human atherosclerotic carotid plaques

2011 ◽  
Vol 105 (05) ◽  
pp. 873-882 ◽  
Author(s):  
Begoña Hurtado ◽  
Xavier Muñoz ◽  
Pedro Recarte-Pelz ◽  
Nadia Garcia ◽  
Anna Luque ◽  
...  
Keyword(s):  
Vitamin K ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Carotid Arteries ◽  
Protein S ◽  
Tam Receptors ◽  
Atherosclerotic Plaque Formation ◽  
Mrna And Protein Expression ◽  
Advanced Stages ◽  
Human Carotid

SummaryThe GAS6/ProS-TAM system is composed of two vitamin K-dependent ligands (GAS6 and protein S) and their three protein tyrosine kinase receptors TYRO3, AXL and MERTK, known as the TAM receptors. The system plays a prominent role in conditions of injury, inflammation and repair. In murine models of atherosclerotic plaque formation, mutations in its components affect atherosclerosis severity. Here we used Taqman low-density arrays and immunoblotting to study mRNA and protein expression of GAS6, ProS and the TAM receptors in human carotid arteries with different degrees of atherosclerosis. The results show a clear down-regulation of the expression of AXL in atheroma plaques with respect to normal carotids that is matched by decreased abundance of AXL in protein extracts detected by immunoblotting. A similar decrease was observed in PROS1 mRNA expression in atherosclerotic carotids compared to the normal ones, but in this case protein S (ProS) was clearly increased in protein extracts of carotid arteries with increasing grade of atherosclerosis, suggesting that ProS is carried into the plaque. MERTK was also increased in atherosclerotic carotid arteries with respect to the normal ones, suggesting that the ProS-MERTK axis is functional in advanced human atherosclerotic plaques. MERTK was expressed in macrophages, frequently in association with ProS, while ProS was abundant also in the necrotic core. Our data suggest that the ProS-MERTK ligand-receptor pair was active in advanced stages of atherosclerosis, while AXL signalling is probably down-regulated.

scholarly journals Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2186
Author(s):  
Anna Tutusaus ◽  
Montserrat Marí ◽  
José T. Ortiz-Pérez ◽  
Gerry A. F. Nicolaes ◽  
Albert Morales ◽  
...  
Keyword(s):  
Vitamin K ◽  
Tyrosine Kinases ◽  
Vascular Function ◽  
Inflammatory Diseases ◽  
Protein S ◽  
Specific Gene ◽  
Biological Functions ◽  
Tam Receptors ◽  
Viral Mimicry

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.

Growth arrest-specific gene 6 (GAS6)

2008 ◽  
Vol 100 (10) ◽  
pp. 604-610 ◽  
Author(s):  
Laura Fernández-Fernández ◽  
Lola Bellido-Martín ◽  
Pablo García de Frutos
Keyword(s):  
Vitamin K ◽  
Tyrosine Kinases ◽  
Growth Arrest ◽  
Protein S ◽  
Membrane Receptors ◽  
Coagulation Cascade ◽  
Specific Gene ◽  
Plasma Vitamin ◽  
Tam Receptors ◽  
Mediators Of Inflammation

SummaryGAS6 (growth arrest-specific 6) belongs structurally to the family of plasma vitamin K-dependent proteins. GAS6 has a high structural homology with the natural anticoagulant protein S, sharing the same modular composition and having 40% sequence identity. Despite this, the low concentration of GAS6 in plasma and the pattern of tissue expression of GAS6 suggest a distinct function among vitamin-K dependent proteins. Indeed, GAS6 has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family; Tyro3, Axl and MerTK. GAS6 employs a unique mechanism of action, interacting through its vitamin K-dependent GLA (γ-carboxyglutamic acid) module with phosphatidylserine-containing membranes and through its carboxy-terminal LamG domains with the TAM membrane receptors. During the last years there has been a considerable expansion of our knowledge of the biology of TAM receptors that has lead to a clear picture of their importance in inflammation, haemostasis and cancer, making this system an interesting target in biomedicine. The innate immune response and the coagulation cascade have been shown to be interconnected. Mediators of inflammation are essential in the initiation and propagation of the coagulation cascade, while natural anticoagulants have important anti-inflammatory functions. GAS6 represents a new player in this context, while protein S seems to have new functions beyond its anticoagulant role through its interaction with TAM receptors.

Gas6 and TAM Receptors in Mouse Platelets

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5199-5199
Author(s):  
Bahadir Kucuk ◽  
Ozlem Bingol-Ozakpinar ◽  
Muzaffer Demir ◽  
Fikriye Uras
Keyword(s):  
Vitamin K ◽  
Conflicts Of Interest ◽  
Anticoagulant Activity ◽  
Detection Limits ◽  
Protein S ◽  
Coagulation Cascade ◽  
Immunological Methods ◽  
Rt Pcr ◽  
Ether Anesthesia ◽  
Tam Receptors

Abstract Abstract 5199 Objective: Growth Arrest Specific-6 (Gas6) is a new vitamin K-dependent protein and is a ligand for TAM receptors, three receptors (Tyro, Axl and Mer) belonging to the receptor tyrosine kinase subfamily. The number of publications concerning the physiological importance of the new vitamin-K dependent proteins, which are not members of the coagulation cascade, is growing. Gas6 has a structural homology to natural anticoagulant of protein S, but has no anticoagulant activity. Some research groups have reported contradictory results concerning the presence of Gas6 and its receptors in mouse platelets. The purpose of this study is to investigate the presence of Gas6 and its receptors in mouse platelets as mRNA and protein levels. Material and Methods: 25 specific pathogen-free, 8–10 week old, 25–30 g in weight, race of Balb-C male/female mice were anesthetized under light ether anesthesia and blood samples were taken from their hearts. Total RNAs were isolated from platelets, then mRNAs encoding Gas6 and TAM receptors were detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Protein concentrations of Gas6 and TAM receptors in platelets were measured by ELISA. We were unable to measure the Mer protein level because of the absence of any commercial ELISA kit for mouse Mer. Results: RT-PCR results indicated the presence of mRNAs encoding to Gas6 and Mer in mouse platelets. However, although RT-PCR reactions were performed at various temperatures and cycles, we could not detect the presence of mRNAs encoding Axl and Tyro. Receptor levels of Axl and Tyro were below the detection limits of the ELISA method. Plasma Gas6 concentration was found to be 26 ng/ml. Conclusion: We found the presence of mRNAs encoding Gas6 and only receptor Mer in mouse platelets but not Axl and Tyro. Protein Gas6, Axl and Tyro levels were below the detection limits of the ELISA methods. The presence of mRNA is not evidence of protein expression in platelets because they have no DNA. Further studies are required to clarify the presence of Gas6 and TAM receptors in platelets using Real Time PCR, and more sensitive immunological methods, and then, as studies of their effects on mechanisms. Original results from these further studies will provide reliable information as to whether Gas6 and its TAM receptors may be a pharmacological target in thrombosis, hemostasis, restenosis and atherosclerosis. Disclosures: No relevant conflicts of interest to declare.

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Blood ◽  
2014 ◽  
Vol 123 (16) ◽  
pp. 2460-2469 ◽  
Author(s):  
Jonathan H. M. van der Meer ◽  
Tom van der Poll ◽  
Cornelis van ‘t Veer
Keyword(s):  
Tyrosine Kinases ◽  
Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Receptor Activation ◽  
Cell Type ◽  
Primary Hemostasis ◽  
Tam Receptors ◽  
And Migration ◽  
Receptor Family

Abstract TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell proliferation, survival, adhesion, and migration. TAM receptors can be activated by the vitamin K–dependent proteins Gas6 and protein S. Protein S is more commonly known as an important cofactor for protein C as well as a direct inhibitor of multiple coagulation factors. To our knowledge, the functions of Gas6 are limited to TAM receptor activation. When activated, the TAM receptors have effects on primary hemostasis and coagulation and display an anti-inflammatory or a proinflammatory effect, depending on cell type. To comprehend the effects that the TAM receptors and their ligands have on hemostasis and inflammation, we compare studies that report the different phenotypes displayed by mice with deficiencies in the genes of this receptor family and its ligands (protein S+/−, Gas6−/−, TAM−/−, and variations of these). In this manner, we aim to display which features are attributable to the different ligands. Because of the effects TAM receptors have on hemostasis, inflammation, and cancer growth, their modulation could make interesting therapeutic targets in thromboembolic disease, atherosclerosis, sepsis, autoimmune disease, and cancer.

scholarly journals Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5448
Author(s):  
Viola Hedrich ◽  
Kristina Breitenecker ◽  
Leila Djerlek ◽  
Gregor Ortmayr ◽  
Wolfgang Mikulits
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinases ◽  
Cancer Biology ◽  
Kinase Inhibitors ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Protein S ◽  
Immune Checkpoint Blockade ◽  
Tam Receptors ◽  
Novel Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, showing high mortality of patients due to limited therapeutic options at advanced stages of disease. The receptor tyrosine kinases Tyro3, Axl and MerTK—belonging to the TAM family—exert a large impact on various aspects of cancer biology. Binding of the ligands Gas6 or Protein S activates TAM receptors causing homophilic dimerization and heterophilic interactions with other receptors to modulate effector functions. In this context, TAM receptors are major regulators of anti-inflammatory responses and vessel integrity, including platelet aggregation as well as resistance to chemotherapy. In this review, we discuss the relevance of TAM receptors in the intrinsic control of HCC progression by modulating epithelial cell plasticity and by promoting metastatic traits of neoplastic hepatocytes. Depending on different etiologies of HCC, we further describe the overt role of TAM receptors in the extrinsic control of HCC progression by focusing on immune cell infiltration and fibrogenesis. Additionally, we assess TAM receptor functions in the chemoresistance against clinically used tyrosine kinase inhibitors and immune checkpoint blockade in HCC progression. We finally address the question of whether inhibition of TAM receptors can be envisaged for novel therapeutic strategies in HCC.

Correlation Between Plaque Composition and Shear Stress Using Three-Dimensional Reconstructed Histology and Computational Fluid Dynamics of Diseased Human Carotid Arteries

2011 ◽  
Author(s):  
Kim van der Heiden ◽  
Harald C. Groen ◽  
Lambert Speelman ◽  
Aad van der Lugt ◽  
Anton F. W. van der Steen ◽  
...  
Keyword(s):  
Fluid Dynamics ◽  
Shear Stress ◽  
Carotid Arteries ◽  
Three Dimensional ◽  
Plaque Formation ◽  
Plaque Composition ◽  
Atherosclerotic Plaque Formation ◽  
Plaque Destabilization ◽  
The Relationship ◽  
Human Carotid

Wall shear stress (WSS) has been shown to play a crucial role in atherosclerotic plaque formation and progression. Moreover, some recent studies suggest that WSS is also involved in determining plaque composition (Cheng et al., 2006) and plaque destabilization in advanced atherosclerosis (Groen et al., 2007). More detailed studies on the relationship between WSS and plaque composition are needed to confirm those relationships.

scholarly journals TAM receptors, Phosphatidylserine, inflammation, and Cancer

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Tal Burstyn-Cohen ◽  
Avi Maimon
Keyword(s):  
Tyrosine Kinases ◽  
Cell Biology ◽  
Receptor Tyrosine Kinases ◽  
Growth Arrest ◽  
Protein S ◽  
Special Issue ◽  
Ligand Complex ◽  
Tam Receptors ◽  
Tumor Cell Biology ◽  
The Impact

Abstract The numerous and diverse biological roles of Phosphatidylserine (PtdSer) are featured in this special issue. This review will focus on PtdSer as a cofactor required for stimulating TYRO3, AXL and MERTK – comprising the TAM family of receptor tyrosine kinases by their ligands Protein S (PROS1) and growth-arrest-specific 6 (GAS6) in inflammation and cancer. As PtdSer binding to TAMs is a requirement for their activation, the biological repertoire of PtdSer is now recognized to be broadened to include functions performed by TAMs. These include key homeostatic roles necessary for preserving a healthy steady state in different tissues, controlling inflammation and further additional roles in diseased states and cancer. The impact of PtdSer on inflammation and cancer through TAM signaling is a highly dynamic field of research. This review will focus on PtdSer as a necessary component of the TAM receptor-ligand complex, and for maximal TAM signaling. In particular, interactions between tumor cells and their immediate environment - the tumor microenvironment (TME) are highlighted, as both cancer cells and TME express TAMs and secrete their ligands, providing a nexus for a multifold of cross-signaling pathways which affects both immune cells and inflammation as well as tumor cell biology and growth. Here, we will highlight the current and emerging knowledge on the implications of PtdSer on TAM signaling, inflammation and cancer. Graphical Abstract

Protein S and C4b-Binding Protein: Components Involved in the Regulation of the Protein C Anticoagulant System

1991 ◽  
Vol 66 (01) ◽  
pp. 049-061 ◽  
Author(s):  
Björn Dahlbäck
Keyword(s):  
Vitamin K ◽  
Complement System ◽  
Protein C ◽  
Protein S ◽  
High Affinity ◽  
Anticoagulant System ◽  
Dependent Protein ◽  
The Complement System ◽  
Β Chain ◽  
Dependent Domain

SummaryThe protein C anticoagulant system provides important control of the blood coagulation cascade. The key protein is protein C, a vitamin K-dependent zymogen which is activated to a serine protease by the thrombin-thrombomodulin complex on endothelial cells. Activated protein C functions by degrading the phospholipid-bound coagulation factors Va and VIIIa. Protein S is a cofactor in these reactions. It is a vitamin K-dependent protein with multiple domains. From the N-terminal it contains a vitamin K-dependent domain, a thrombin-sensitive region, four EGF)epidermal growth factor (EGF)-like domains and a C-terminal region homologous to the androgen binding proteins. Three different types of post-translationally modified amino acid residues are found in protein S, 11 γ-carboxy glutamic acid residues in the vitamin K-dependent domain, a β-hydroxylated aspartic acid in the first EGF-like domain and a β-hydroxylated asparagine in each of the other three EGF-like domains. The EGF-like domains contain very high affinity calcium binding sites, and calcium plays a structural and stabilising role. The importance of the anticoagulant properties of protein S is illustrated by the high incidence of thrombo-embolic events in individuals with heterozygous deficiency. Anticoagulation may not be the sole function of protein S, since both in vivo and in vitro, it forms a high affinity non-covalent complex with one of the regulatory proteins in the complement system, the C4b-binding protein (C4BP). The complexed form of protein S has no APC cofactor function. C4BP is a high molecular weight multimeric protein with a unique octopus-like structure. It is composed of seven identical α-chains and one β-chain. The α-and β-chains are linked by disulphide bridges. The cDNA cloning of the β-chain showed the α- and β-chains to be homologous and of common evolutionary origin. Both subunits are composed of multiple 60 amino acid long repeats (short complement or consensus repeats, SCR) and their genes are located in close proximity on chromosome 1, band 1q32. Available experimental data suggest the β-chain to contain the single protein S binding site on C4BP, whereas each of the α-chains contains a binding site for the complement protein, C4b. As C4BP lacking the β-chain is unable to bind protein S, the β-chain is required for protein S binding, but not for the assembly of the α-chains during biosynthesis. Protein S has a high affinity for negatively charged phospholipid membranes, and is instrumental in binding C4BP to negatively charged phospholipid. This constitutes a novel mechanism for control of the complement system on phospholipid surfaces. Recent findings have shown circulating C4BP to be involved in yet another calcium-dependent protein-protein interaction with a protein known as the serum amyloid P-component (SAP). The binding sites on C4BP for protein S and SAP are independent. SAP, which is a normal constituent in plasma and in tissue, is a so-called pentraxin being composed of 5 non-covalently bound 25 kDa subunits. It is homologous to C reactive protein (CRP) but its function is not yet known. The specific high affinity interactions between protein S, C4BP and SAP suggest the regulation of blood coagulation and that of the complement system to be closely linked.

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