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Annexin A2 (ANXA2) is an important member of the annexin family and is a calcium ion-dependent phospholipid-binding protein. ANXA2 exists mainly in two forms: monomeric and heterotetramers. ANXA2 and its ligand p11 first form a heterodimer, and the two heterodimers combine to form a heterotetramer. By binding, the N-terminus of ANXA2 forms an α-helix containing many important hydrophilic amino acid residues, and one of the ANXA2 L2 Loop and the HIV helix can form a gap with the other ANXA2 HI helix. Heterodimers are closely related to the cell proliferation process. Heterotetramers are co-receptors of tissue plasminogen activator (t-PA) and plasminogen (PLG). It mediates t-PA-dependent plasmin activation and plasmin production, solubilizes fibrin and maintains vascular homeostasis. It also promotes the invasion of tumor cells. Studies have shown that heterotetramers are an important form of ANXA2 functioning.
Figure 1. Experimental model of inflammatory pathway regulation by the annexin A2-S100A10 heterotetramer. (Bharadwaj, et al. 2013).
ANXA2 protein molecules are mainly distributed in the nucleus, cytoplasm, cell membrane and extracellular fluid, and have calcium-dependent phospholipid binding properties. ANXA2 can exist as a free monomer in the cytoplasm, bind to the inner membrane of the cell, or attach to the outer surface of the plasma membrane. Annexin has a variety of biological functions that regulate cell function, including angiogenesis, cell proliferation, apoptosis, cell migration, invasion, and adhesion. Therefore, annexin also plays an important role in the development of many human tumors.
Distribution and Regulation of ANXA2 in Cells
Under conditions of thermal stimulation, thrombin stimulation, and hypoxia, ANXA2 in endothelial cells can be rapidly distributed from the cytoplasm to the cell membrane, a process that requires sufficient phosphorylation of p11 to participate. ANXA2 is mainly distributed on the cell membrane, so it is also involved in cell-cell interactions and cell adhesion.
Intracellular ANXA2 plays an important role in endocytosis, efflux, and membrane transport of cells. Wang et al. knocked out ANXA2 and found that cell division and proliferation were inhibited. It plays an important role in the production of lipid rafts and signal transduction through interaction with CD44. ANXA2 binds to a variety of ligands, including calcium, lipids, mRNA, and many intracellular and extracellular proteins, and differentiates gene expression modifications by regulating interactions with ligands. The study found that ANXA2 acts as a ligand for C1q in apoptotic cells, suggesting that ANXA2 is also closely related to apoptosis.
Relationship Between ANXA2 and Plasmin Activity
The fibrinolysis process mainly refers to the process of modification and degradation of fibrin-rich thrombus, and ANXA2 also plays an important role in the fibrinolysis process. tPA is synthesized by vascular endothelial cells and macrophages, which promote the conversion of plasminogen to active plasmin in the thrombus. ANXA2 is a calcium-binding protein that binds to acidic phospholipids and plays an important role in many cell regulation processes. Yamanaka et al. found that ANXA2 is an important thrombolytic receptor for tissue plasminogen activator tPA and is involved in the plasmin system.
Cell surface-expressed ANXA2 plays an important role in regulating the activity of plasminogen activator. Studies have shown that ANXA2 can shorten the distance between plasminogen and t-PA space so that tPA activates plasmin, which significantly improves the thrombolytic effect. Dai et al. found that ANXA2 dysfunction leads to loss of plasmin activity on the surface of human endothelial cells caused by hyperglycemia, and the addition of recombinant ANXA2 can restore the cell surface plasmin activity. Therefore, the decrease in plasmin activity caused by diabetes is related to the glycosylation of ANXA2, and ANXA2 can restore plasmin activity, suggesting that ANXA2 can be used for the treatment of impaired fibrinolytic activity caused by diabetes.
ANXA2 and Tumor
Different members of the annexin family have different effects on tumorigenesis. The main role of ANXA2 is in angiogenesis and infiltration and metastasis of tumor cells. ANXA2 is located in the cytoplasm, cell membrane, and cytoskeleton network and is involved in the movement of tumor cells.
ANXA2 is overexpressed in many cancers and can be associated with plasmin on the surface of tumors. It then mediates the degradation of the extracellular matrix and promotes angiogenesis, thereby promoting tumor growth. In gastric cancer, pancreatic cancer, colon cancer, liver cancer and brain cancer tissues, the expression of ANXA2 is on the rise. In prostate cancer, ANXA2 showed a decreasing trend. In addition, in metastatic breast cancer, the expression level of ANXA2 is higher than that of non-metastatic cancer tissues.
Sharma et al. also found ANXA2 overexpression in breast cancer tissues. In a xenograft model of breast cancer growth, the use of monoclonal antibodies against ANXA2 significantly inhibited the growth of tumor cells. Yang et al. found that ANXA2 has different degrees of improvement in renal cell carcinoma expression. Silencing ANXA2 gene revealed significant inhibition of cell invasion and metastasis. Zhang et al. used immunohistochemical staining to examine the expression of ANXA2 and S100A4 in urothelial carcinoma tissues, and the results showed that their expression was significantly up-regulated. It is suggested that bladder cancer can be predicted by detecting ANXA2 and S100A4 in the future. In addition, there are studies on ANXA2 in other cancers, and studies have shown that ANXA2 is closely related to the invasion and metastasis of cancer.