Novel vitamin K-dependent pathways regulating cell survival

Historically, the vitamin K-1-dependent proteins have been associated primarily with blood coagulation and secondarily with bone formation. Recent identification of K-1-dependent proteins as specific ligands for the receptor tyrosine kinases (RTKs) that can stimulate cell replication and transformation and participate in cell survival highlighted a previously unrecognized and potentially important role for vitamin K-1 in cell signaling. Growing evidence suggests that most normal and tumor cells possess an active K-1-dependent gamma -carboxylation mechanism necessary for the production of gamma -carboxyglutamic acid (Gla)-containing proteins. Gla residues in proteins facilitate calcium-dependent protein/phospholipid interaction. Recent studies demonstrating the potentially positive effects of a vitamin K-dependent receptor:ligand system on cell growth and survival in general and the effects of the overexpression of these RTKs on malignant cell survival provide a new perspective on the role of vitamin K-1, its dependent protein ligands, and their receptors. These cumulative observations also provide an explanation for the rigidly controlled K-1 levels in the mammalian fetus and the minimal hepatic stores in the adult.