VITAMIN K-DEPENDENT PROTEINS IN BLOOD AND DEVELOPMENT

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In what is the only known biological process dependent on vitamin K, the vitamin K-dependent lambda-glutamyl carboxylase catalyzes the posttranslational modification of glutamate to lambda-carboxyglutamate in the vitamin K-dependent proteins during their synthesis. This modification is essential for the biological activities of all known vitamin K-dependent proteins. Substrates of the carboxylase include several proteins involved in blood coagulation as well as bone matrix proteins and Gas6. Gas6, a cell cycle regulated protein is a ligand for receptor tyrosine kinases and has been implicated in the prevention of apoptosis of growth arrested cells. While we have previously focused our studies on the role of vitamin K-dependent carboxylation in hemostasis, we have recently demonstrated extrahepatic expression of the vitamin K-dependent carboxylase gene in adult and embryonic rat tissues, supporting the hypothesis that vitamin K has an important physiological role outside of blood coagulation. Warfarin, a potent vitamin K antagonist, is a widely used anticoagulant which indirectly inhibits the activity of the vitamin K-dependent carboxylase. Warfarin is also a teratogen. Human maternal exposure to warfarin during pregnancy is associated with developmental abnormalities in the fetus, the warfarin embryopathy, suggesting critical developmental functions for the carboxylase enzyme and its substrates. New data from our laboratory demonstrates temporal variations in tissue specific expression of vitamin K-dependent carboxylase mRNA in developing rat embryonic tissues, supporting the hypothesis that vitamin K-dependent carboxylation is a developmentally regulated posttranslational modification important for normal embryogenesis. In the current application, studies are proposed to clarify the role of vitamin K in development by examining the developmental and tissue specific expression of the vitamin K-dependent carboxylase in rat embryos. The regulation of vitamin K-dependent carboxylase gene transcription will be evaluated in vitro to study the factors that regulate vitamin K- dependent protein activity during development. An animal model of warfarin embryopathy will be developed, to direct future in vivo studies for testing the functions of carboxylase substrates in development of the normal embryo. Vitamin K-dependent carboxylation will serve as a model for other developmentally regulated posttranslational modifications of proteins important in fetal development.