[Gas-6 and protein S: vitamin K-dependent factors and ligands for the TAM tyrosine kinase receptors family].
The gamma-carboxyglutamate-containing proteins are a family of secreted vitamin K-dependent proteins in which some glutamyl residues are post-translationally modified to gamma-carboxyglutamic acid residues. A vitamin K-dependent gamma-glutamyl carboxylase enzyme catalyses this post-translational modification. The gamma-carboxylase reaction requires vitamin K in its reduced form, vitamin K hydroquinone, and generates gamma-carboxyglutamate and vitamin K 2,3,-epoxide which is then recycled back to the hydroquinone form by a vitamin K reductase system. Warfarin blocks the vitamin K cycle and hence inhibits the gamma-carboxylase reaction, and this property of Warfarin has led to its wide use in anticoagulant therapy. Until recently, interest in vitamin K-dependent proteins was mostly restricted to the field of hematology. However, the discovery that the anti-coagulant factor protein S and its structural homologue Gas6 (growth arrest-specific gene 6), two vitamin K-dependent proteins, are ligands for the Tyro3/Axl/Mer family of related tyrosine kinase receptors has opened up a new area of research. Moreover, the phenotypes associated with the invalidation of genes encoding vitamin K-dependent proteins or their receptors revealed their implication in regulating phagocytosis during many cell differentiation phenomena such as retinogenesis, neurogenesis, osteogenesis, and spermatogenesis. Additionally, protein S was identified as the major factor responsible for serum-stimulated phagocytosis of apoptotic cells. Therefore, the elucidation of the molecular mechanisms underlying the role of vitamin K-dependent proteins in regulating apoptotic cell phagocytosis may lead to a better understanding of the physiopathology of cell differentiation and could form the framework of new therapeutic strategies aiming at a selective targeting of cell phagocytosis associated pathologies.
Benzakour
Omar
O
Institut de Physiologie et Biologie Cellulaires, France. Omar.Benzakour@univ-poitiers.fr
Gely
Aurore
A
Lara
Romain
R
Coronas
Valérie
V
D015055:1-Carboxyglutamic Acid / Q000378:metabolism; D000215:Acylation; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000502:physiology; D019735:Carbon-Carbon Ligases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008322:Mammals / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D005810:Multigene Family; D010587:Phagocytosis / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017293:Protein S; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000502:physiology*; D014859:Warfarin / Q000494:pharmacology
D000925:Anticoagulants; D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D014812:Vitamin K; D015055:1-Carboxyglutamic Acid; D014859:Warfarin; D020794:Receptor Protein-Tyrosine Kinases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase