Saxena S P, Fan T, Li M, Israels E D, Israels L G
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.
J Clin Invest. 1997 Feb 15;99(4):602-7. doi: 10.1172/JCI119202.
The development of the embryo is dependent upon a highly coordinated repertoire of cell division, differentiation, and migration. Protein-tyrosine 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 tyrosine kinases (RTKs) with transforming ability. The involvement of vitamin K metabolism and function in two well characterized birth defects, warfarin embryopathy and vitamin K epoxide reductase deficiency, suggests that developmental signals from K-dependent pathways may be required for normal embryogenesis. Using a chick embryogenesis model, we now demonstrate the existence of a vitamin K1-dependent protein-tyrosine phosphorylation cascade involving c-Eyk, a member of the Tyro 12 family, and key intracellular proteins, including focal adhesion kinase (pp125FAK), paxillin, and pp60src. This cascade is sensitive to alteration in levels or metabolism of vitamin K1. These findings provide 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 regulation of vitamin K1-dependent regulatory pathways would appear to be critical for orderly embryogenesis.
胚胎的发育依赖于细胞分裂、分化和迁移的高度协调过程。蛋白质酪氨酸磷酸化在这些过程的调节中起着关键作用。维生素K依赖的γ-羧化蛋白已被鉴定为具有转化能力的独特受体酪氨酸激酶（RTK）家族（Tyro 3和7）的配体。维生素K代谢和功能与两种特征明确的出生缺陷——华法林胚胎病和维生素K环氧化物还原酶缺乏症——有关，这表明K依赖途径的发育信号可能是正常胚胎发生所必需的。利用鸡胚胎发育模型，我们现在证明了存在一种维生素K1依赖的蛋白质酪氨酸磷酸化级联反应，涉及Tyro 12家族成员c-Eyk以及关键的细胞内蛋白，包括粘着斑激酶（pp125FAK）、桩蛋白和pp60src。这种级联反应对维生素K1水平或代谢的改变敏感。这些发现为哺乳动物（和人类）胎儿中K依赖蛋白为何保持羧化不足状态，甚至使新生儿面临出血风险这一问题提供了重要线索。维生素K1依赖调节途径的精确调控对于有序的胚胎发生似乎至关重要。
