A NOVEL ROLE FOR VITAMIN-K-1 IN A TYROSINE PHOSPHORYLATION CASCADE DURING CHICK EMBRYOGENESIS

The development of the embryo is dependent upon a highly coordinated r epertoire of cell division, differentiation, and migration. Protein-ty rosine phosphorylation plays a pivotal role in the regulation of these processes. Vitamin K-dependent gamma-carboxylated proteins have been identified as ligands for a unique family (Tyro 3 and 7) of receptor t yrosine kinases (RTKs) with transforming ability. The involvement of v itamin K metabolism and function in two well characterized birth defec ts, warfarin embryopathy and vitamin K epoxide reductase deficiency, s uggests that developmental signals from K-dependent pathways may be re quired for normal embryogenesis. Using a chick embryogenesis model, we now demonstrate the existence of a vitamin K-1-dependent protein-tyro sine phosphorylation cascade involving c-Eyk, a member of the Tyro 12 family, and key intracellular proteins, including focal adhesion kinas e (pp125(FAK)), paxillin, and pp60(src). This cascade is sensitive to alteration in levels or metabolism of vitamin K-1. These findings prov ide a major clue as to why, in the mammalian (and human) fetus, the K- dependent proteins are maintained in an undercarboxylated state, even to the point of placing the newborn at hemorrhagic risk. The precise r egulation of vitamin K-1-dependent regulatory pathways would appear to be critical for orderly embryogenesis.