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Vitamin K-dependent crosstalk
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
Many vitamin K-dependent proteins containing gamma-carboxyglutamic acid (gla)-residues are members of the coagulation cascade. However, others are not directly related to coagulation but important for endothelial cell survival and pathophysiology of vascular calcification. Thus the Gla metabolism and corresponding protein-protein interactions provides opportunity for cross-talk among different endothelial pathways.
Activated protein C (APC), a vitamin K-dependent plasma protein, plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va (FVa) and factor VIIIa (FVIIIa), and thus down regulating thrombin (f2) generation. The endothelial protein C receptor (EPCR)-dependent cleavage of protease activated receptor 1 (PAR-1) by either APC or thrombin in lipid rafts initiates protective signaling responses in endothelial cells. The lipid raft localization renders the scissile bond of the PAR-1 exodomain unavailable for interaction with coagulation proteases. The binding of either the Gla-domain of protein C to EPCR or exosite-1 of thrombin to the C-terminal hirudin-like sequence of PAR-1 changes the membrane localization and/or the conformation of the PAR-1 exodomain to facilitate its recognition and subsequent cleavage by these proteases.
The vitamin K-dependent protein matrix Gla-protein (mgp) has been identified as a potent inhibitor of the transformation of smooth muscle cells in the vessel wall to osteoblast-like cells in a process known to precede arterial calcification. Growth arrest-specific gene 6 (gas6), which is similar to the anticoagulant protein S, has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family. It has been shown to affects vascular smooth muscle cell apoptosis and movement.
Overall, the anticoagulant, cytoprotective and arterial calcification pathways are important. The pathways differ not only in terms of biologic effects but also in terms of substrates and cofactors. However, there is cross-talk between the pathways. The fact that the pathways are distinct as well as interconnected is useful for the design and interpretation of preclinical and clinical results, especially those concerning vitamin K therapy.
Activated protein C (APC), a vitamin K-dependent plasma protein, plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va (FVa) and factor VIIIa (FVIIIa), and thus down regulating thrombin (f2) generation. The endothelial protein C receptor (EPCR)-dependent cleavage of protease activated receptor 1 (PAR-1) by either APC or thrombin in lipid rafts initiates protective signaling responses in endothelial cells. The lipid raft localization renders the scissile bond of the PAR-1 exodomain unavailable for interaction with coagulation proteases. The binding of either the Gla-domain of protein C to EPCR or exosite-1 of thrombin to the C-terminal hirudin-like sequence of PAR-1 changes the membrane localization and/or the conformation of the PAR-1 exodomain to facilitate its recognition and subsequent cleavage by these proteases.
The vitamin K-dependent protein matrix Gla-protein (mgp) has been identified as a potent inhibitor of the transformation of smooth muscle cells in the vessel wall to osteoblast-like cells in a process known to precede arterial calcification. Growth arrest-specific gene 6 (gas6), which is similar to the anticoagulant protein S, has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family. It has been shown to affects vascular smooth muscle cell apoptosis and movement.
Overall, the anticoagulant, cytoprotective and arterial calcification pathways are important. The pathways differ not only in terms of biologic effects but also in terms of substrates and cofactors. However, there is cross-talk between the pathways. The fact that the pathways are distinct as well as interconnected is useful for the design and interpretation of preclinical and clinical results, especially those concerning vitamin K therapy.
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