Fonctions nouvelles de Gas-6 et de la protéine S : Facteurs vitamine K-dépendants et ligands des récepteurs tyrosine kinase de la famille TAM

Abstract

Les protéines vitamine K-dépendantes sont essentiellement connues pour leur implication dans la coagulation du sang. Récemment, deux protéines vitamine K-dépendantes, le facteur anticoagulant protéine S et son homologue structural Gas-6, ont été identifiés comme ligands des récepteurs à activité tyrosine kinase TAM (Tyro-3/Axl/Mer). L’analyse des phénotypes de souris transgéniques invalidées pour les gènes codant pour Gas-6 ou pour ses récepteurs a révélé que Gas-6 et la protéine S sont impliquées dans la régulation de la phagocytose des cellules apoptotiques, processus important dans la réponse immunitaire ainsi que dans les processus de différenciation cellulaire. Les nouvelles fonctions de ces protéines vitamine K-dépendantes ainsi que leur utilisation potentielle dans l’élaboration de traitements de pathologies associées à un déficit de phagocytose font l’objet de cet article.

The γ-carboxyglutamate-containing proteins are a family of secreted vitamin K-dependent proteins in which some glutamyl residues are post-translationally modified to γ-carboxyglutamic acid residues. A vitamin K-dependent γ-glutamyl carboxylase enzyme catalyses this post-translational modification. The γ-carboxylase reaction requires vitamin K in its reduced form, vitamin K hydroquinone, and generates γ-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 γ-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 vitamine 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.