The role of the annexin A2 heterotetramer in vascular fibrinolysis

Abstract

The vascular endothelial cells line the inner surface of blood vessels and function to maintain blood fluidity by producing the protease plasmin that removes blood clots from the vasculature, a process called fibrinolysis. Plasminogen receptors play a central role in the regulation of plasmin activity. The protein complex annexin A2 heterotetramer (AIIt) is an important plasminogen receptor at the surface of the endothelial cell. AIIt is composed of 2 molecules of annexin A2 (ANXA2) bound together by a dimer of the protein S100A10. Recent work performed by our laboratory allowed us to clarify the specific roles played by ANXA2 and S100A10 subunits within the AIIt complex, which has been the subject of debate for many years. The ANXA2 subunit of AIIt functions to stabilize and anchor S100A10 to the plasma membrane, whereas the S100A10 subunit initiates the fibrinolytic cascade by colocalizing with the urokinase type plasminogen activator and receptor complex and also providing a common binding site for both tissue-type plasminogen activator and plasminogen via its C-terminal lysine residue. The AIIt mediated colocalization of the plasminogen activators with plasminogen results in the rapid and localized generation of plasmin to the endothelial cell surface, thereby regulating fibrinolysis. (Blood. 2011;118(18):4789-4797) IntroductionThe vascular endothelium consists of a single cell layer lining all vessels that separates the blood from the tissues. It is estimated to be composed of ϳ 10 13 cells, representing a weight of 1.5 kg and an area of 4000 to 7000 m 2 . 1 Endothelial cells play a role in primary hemostasis, coagulation, fibrinolysis, and regulation of vasomotor tone. In addition to regulating the flow of nutrients, the vascular endothelium regulates many diverse biologically active molecules. These functions of the endothelium are achieved through the presence of membrane-bound receptors for various proteins, lipidtransporting complexes, hormones, and metabolites, as well as through specific extracellular proteins and receptors that regulate cell-cell and cell-matrix interactions. 2 Whereas exposure to inflammatory and/or septic stimuli rapidly leads to procoagulant behavior, unperturbed endothelial cells provide an anticoagulant environment. After vascular insult, endothelial cells express tissue factor and initiate the coagulation cascade that results in thrombin activation and fibrin clot deposition. At the same time, anticoagulant pathways and fibrinolysis are activated to avoid disseminated coagulation and to also limit fibrin accumulation. [3][4][5] Fibrinogen is a large glycoprotein that constitutes the main component of a fibrin clot. Each fibrinogen molecule is composed of 2 sets of A␣-, B␤-, and ␥-polypeptide chains that form a protein containing 2 distal D regions connected to a central E region by a coiled-coil segment. 6 Fibrin is produced on cleavage of the fibrinopeptides by thrombin, which results in the formation of double-stranded half-staggered oligomers that lengthen into protofibrils...

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“…Binding sites of the S100A10 proteins and t-PA have been identified in the N-terminal domain of annexin A2 at the amino acids residues 1-14 and 8-13, respectively (Kube et al 1992, Cesarman et al 1994. Recent data suggest that annexin A2 does not bind plasminogen directly but rather acts to transport S100A10 to the cell surface (Madureira et al 2011, Bydoun & Waisman 2014. Our findings suggest that the extracellular form of annexin A2 found in the cancer-associated stroma in the ovarian cancer tissues may represent a cleaved and secreted form of annexin A2, which may assist in ovarian cancer progression and metastasis.…”

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

“…These interactions are optimised by binding of the key proteins to relevant surfaces, either the surface of a fibrin clot or the surface of endothelial cells lining the blood vessel [26]. Recent research has identified the annexin A2 heterotetramer (AIIt), comprising two molecules of annexin A2 and two of the protein S100A10, as the key endothelial receptor bringing together both plasminogen and tPA to optimise plasmin generation at the surface of the vascular wall [27]. Annexin A2 binds to anionic phospholipids, chiefly phosphatidylserine (PS) [28], and thus anchors the S100A10 subunits to the membrane, where they act to co-localise plasminogen and tPA.…”

SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression

“…AXIIR gene encodes a protein with 193 amino acids which is only detected in primate species up to now [4]. As a member of the Annexins family, Annexin II involves in many cell functions such as endocytic and exocytotic vesicular transport, interaction with cell adhesion molecules, regulation of ion channels, and being receptor for tenascin-C and plasminogen [5,6,7]. Since AXIIR is originally identified as a receptor for Annexin II, several studies have investigated the role of AXIIR in mediating Annexin II signal.…”