Vitamin K|1-dependent growth regulatory pathways during embryogenesis

Abstract

The normal embryonic development requires a well coordinated repertoire of cellular activities including cell division, differentiation, and migration. Protein tyrosine kinases (PTKs) are involved in regulating these events during embryonic development. Recently, vitamin K-dependent $\gamma$-carboxylated proteins and Gas6 have been identified as ligands for a unique family (Tyro 3, 7 and 12) of receptor tyrosine kinases (RTKs). Since Tyro 7 and 12 RTKs show wide spatial and temporal expression during embryonic development, and overexpression of Axl (Tyro 7) in transgenic mice appears to cause prenatal lethality, the developmental signals from vitamin K-dependent receptor-ligand system are required for orderly embryogenesis. Furthermore, the involvement of vitamin K metabolism and functions in two well characterized birth defects, warfarin embryopathy and vitamin K epoxide reductase deficiency, also supports this hypothesis. Using a chick model of embryogenesis, we demonstrated the existence of a vitamin K$\sb1$-dependent protein-tyrosine phosphorylation cascade during embryogenesis. This cascade is sensitive to alteration in levels and metabolism of vitamin K$\sb1$ and involves c-Eyk, a member of the Tyro 12 family, and a group of key intracellular proteins, including focal adhesion kinase (pp125$\sp{\rm FAK}$), paxillin, and pp60$\sp{\rm c-src}$ The precise regulation of vitamin K$\sb1$-dependent regulatory pathways appears to be critical for orderly embryogenesis. These findings explain partly why, in the mammalian fetus, the vitamin K-dependent proteins are maintained in an undercarboxylated state, even to the point of placing the newborn at hemorrhagic risk.