Annexin A5 Down-regulates Surface Expression of Tissue Factor

Abstract

Phosphatidylserine (PtdSer) is exposed on the external leaflet of the plasma membrane during apoptosis. The protein annexin A5 (anxA5) shows high affinity for PtdSer. When anxA5 binds to the PtdSer-expressing membranes during apoptosis, it crystallizes as an extended two-dimensional network and activates thereby a novel portal of cell entry that results in the internalization of the PtdSer-expressing membrane patches. This novel pathway of cell entry is potentially involved in the regulation of the surface expression of membrane receptors. In this study we report the regulation of surface expression of the initiator of blood coagulation tissue factor (TF) by this novel pathway of cell entry. AnxA5 induces the internalization of tissue factor expressed on the surface of apoptotic THP-1 macrophages. This down-regulation depends on the abilities of anxA5 to bind to PtdSer and to form a two-dimensional crystal at the membrane. We furthermore show that THP-1 cells produce and externalize anxA5 that cause the internalization of TF in an autocrine type of mechanism. We extended our in vitro work to the in vivo situation and show in a mouse model that anxA5 causes the downregulation of TF expression by smooth muscle cells of the media of the carotid artery that was mechanically injured. In conclusion, anxA5 down-regulates surfaceexpressed TF by activating the novel portal of cell entry. This mechanism may be part of a more general autocrine function of anxA5 to regulate the plasma membrane receptor repertoir under stress conditions associated with the surface expression of PtdSer.

Involvement of phosphatidylserine externalization in the down-regulation of c-myb expression in differentiating C2C12 cells

“…It has been shown that annexin V associates with PScontaining membranes, bends its, and finally causes the internalization of PS-expressing membrane patches (Kenis et al, 2004;Ravassa et al, 2005). Therefore, we can speculate that because of the ability of annexin V to influence membrane conformation as soon as PS is exposed, cells treated with annexin V for different times could differ (90 min with annexin-V-Fluos vs. 30 hr with annexin V).…”

Phospholipids: Key Players in Apoptosis and Immune Regulation

“…Furthermore, it has been shown that after PS binding, AnxA5 crystallizes as an extended two-dimensional network resulting in the internalization of the PS-expressing membrane patches. This additionally reduces the availability of PS on apoptotic cells for phagocytes [ 129 ].…”

Annexin A5 Binds to Lipopolysaccharide and Reduces Its Endotoxin Activity

“…There is significant evidence that the protein serves an antithrombotic function on vascular endothelial cells and placental trophoblasts since autoantibody-mediated deficiencies are associated with vascular atherothrombosis (8, 9) and with recurrent pregnancy losses (10–12). In addition, AnxA5 has been shown to modulate tissue factor expression (13), to promote endocytosis (14), and to participate in cell protection from engulfment by phagocytosis (15). However, the fact that the protein is highly expressed by cells that have a barrier function but do not play any role in blood coagulation—such as biliary, pancreatic, salivary, and renal ductular epithelial cells (16) and mammary epithelium cells (17)—suggests that it may serve other functions.…”