Cell Adhesion to Phosphatidylserine Mediated by a Product of Growth Arrest-specific Gene 6

Abstract

Gas6, a product of a growth arrest-specific gene 6, potentiates proliferation of vascular smooth muscle cells and prevents cell death of vascular smooth muscle cells. It has been also demonstrated that Gas6 is a ligand of receptor tyrosine kinases Axl, Sky, and Mer. Gas6 contains ␥-carboxyglutamic acid residues, which are found in some blood coagulation factors and mediate the interaction of the coagulation factors with negatively charged phospholipid. In this study, we clarified that Gas6 specifically bound to phosphatidylserine and the binding was dependent on Ca 2؉ and ␥-carboxyglutamic acid residues. Furthermore, we found that U937 cells, which express Gas6 receptor on their surfaces, adhered to phosphatidylserine-coated enzyme-linked immunosorbent assay (ELISA) plate only in the presence of Gas6 and Ca 2؉ . U937 cells also bound to ELISA plate coated with phosphatidylinositol, but the binding was independent of Gas6 and Ca 2؉ . On the other hand, U937 cells did not adhere to phosphatidylcholine-or phosphatidylethanolamine-coated ELISA plate even in the presence of Gas6 and Ca 2؉ . These findings suggest that Gas6 may play a role in recognition of cells exposing phosphatidylserine on their surfaces by phagocytic cells, which is supposed to be one of the mechanisms for clearing dying cells.

Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells

“…43 Gas6, one of these ligands, binds to phosphatidylserine exposed at the surface of dying cells through its NH 2 -terminal Gla domain, and to its receptors on macrophages and HSC through its COOH domain. 44 This role of Gas6 was confirmed in mice invalidated for one of the Gas6 receptors, which develop an inability to clear apoptotic cells. 45 Pathways controlling HSC transformation into MFB and survival are important issues in tissue repair and fibrosis.…”

Ligand Recognition and Homophilic Interactions in Tyro3

“…Gas6, a vitamin K-dependent protein encoded by growth arrest-specific gene 6 (17), binds to Axl, Tyro3, and Mer with nanomolar affinities (0.4, 2.9, and 29 nM, respectively) (18). The interaction between Axl and Gas6 has been implicated in cell adhesion processes (19,20), prevention of apoptosis (21), and cell proliferation (22), whereas Tyro3-Gas6 signaling was reported to stimulate osteoclastic bone resorption (23). In fibroblasts, high expression of Tyro3 or Axl has been found to cause transformation even in the absence of the ligand (9,24).…”

Fonctions nouvelles de Gas-6 et de la protéine S

“…En effet, l'inhibition de l'interaction de MFG-E8 ou de Gas6 avec leurs récepteurs respectifs résulte en un défaut d'élimination de cellules apoptotiques [27]. La protéine Gas6 interagit avec les phosphatidylsérines oxydées par son domaine Gla et avec ses récepteurs TAM, présents à la surface du macrophage, par son domaine SHBG [28]. Cela favoriserait l'interaction entre la cellule apoptotique et le phagocyte [29] (Figure 3).…”