Promotion of the Uptake of PS Liposomes and Apoptotic Cells by a Product of Growth Arrest-Specific Gene, gas6

Abstract

Gas6, a ligand of receptor tyrosine kinases Axl, Sky, and Mer, potentiates cell proliferation and prevents cell death. It also contains g-carboxylglutamic acid residues that mediate the interaction of some blood coagulation factors with negatively charged phospholipids. In our previous study, we demonstrated that Gas6 specifically binds to phosphatidylserine (PS) and links Axl-expressing cells to the PS-coated surface. In this study, to further understand the biological role of the interaction of Gas6 with PS, we examined the effect of Gas6 on the uptake of PS liposomes by macrophages. In vitro phagocytosis studies showed that Gas6 enhanced the uptake of PS liposomes approximately threefold and that the interaction of Gas6 with the surface of macrophages was essential for this enhancement. Analyses of the mechanism of the uptake of PS liposome suggested that Gas6 interacts with PS liposome via its N-terminal Gla domain and with macrophages via its C-terminal domain. Like that of PS liposomes, the uptake of apoptotic cells by macrophages was also enhanced, approximately twofold, in the presence of Gas6. These findings suggest that Gas6 may help phagocytic cells recognize cells with PS exposed on their surfaces, which is considered to be one of the mechanisms for clearing away dying cells. Thus, Gas6 may play a critical role in homeostasis by facilitating the clearance of PS-expressing cells.

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…Direct recognition can occur via brainspecific angiogenesis inhibitor 1 (BAI1), 12 Stabilin-2, 13 and members of the T-cell immunoglobulin mucin domain; [14][15][16] alternatively, bridging molecules such as GAS6/Protein S and milk-fat globule EGF factor 8 can bind to the PtdSer exposed on the apoptotic cells, and in turn be recognized by members of the Tyro-Axl-Mer family and α v β 3 integrin, respectively, on the phagocyte. 17,18 Although some of these receptors only serve to tether the apoptotic cells, others can initiate intracellular signaling to induce phagocytosis. Receptors such as BAI1 can signal intracellularly through the ELMO1-DOCK180-Rac signaling module to stimulate cytoskeletal rearrangement and engulfment.…”

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…For example, PS can be recognized by cell surface receptors including TIM-4 (Kobayashi et al 13 and Miyanishi et al 14 ) and BAI-1. 15 PS can also be recognized by soluble opsonins such as MFG-E8 and Gas6, that are in turn detected by cell surface molecules α V β 3 and TAM receptors, respectively [16][17][18] (Figure 2a). The recognition of PS by phagocytes through various phospholipid detectors is an important molecular step to trigger the engulfment of apoptotic cells, 3 and exemplifies how modification of the phospholipid code on the surface of apoptotic cells can promote their clearance.…”

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

“…Stabilin-2, a large multi-functional scavenger receptor has also been identified as a PS receptor which can mediate engulfment of apoptotic cells and aged red blood cells [17]. Other PS-dependent receptors for apoptotic cells include Mer receptor tyrosine kinase [18] and αVβ5 integrin both of which bind PS through soluble bridging molecules [19,20] while a PS independent pathway, the calreticulin/LDL-receptor-related protein (LRP)-dependent pathway has been reported for the removal of tumor targets by dendritic cells [21]. Since redundancy is a prominent feature of apoptotic cell clearance in the body, other pathways are likely to exist.…”