Annexin A2 (ANXA2) orchestrates multiple biologic processes and clinical associations, especially in cancer progression. The structure of ANXA2 affects its cellular localization and function. However, posttranslational modification and protease-mediated N-terminal cleavage also play critical roles in regulating ANXA2. ANXA2 expression levels vary among different types of cancers. With some cancers, ANXA2 can be used for the detection and diagnosis of cancer and for monitoring cancer progression. ANXA2 is also required for drug-resistance. This review discusses the feasibility of ANXA2 which is active in cancer development and can be a therapeutic target in cancer management. 1. Introduction Annexin A2 (also called p36, annexin II, ANXA2, calpactin I, lipocortin II, chromobindin VIII, or placental anticoagulant protein IV), a 36？kDa protein [1], is located on chromosome 15q22.2 [2]. ANXA2 is expressed in some tumor cells, endothelial cells, macrophages, and mononuclear cells. ANXA2 contains three distinct functional regions: the N-terminal region, the C-terminal region, and the core region. The N-terminal region contains the tissue plasminogen activator (tPA)- [3] and S100/A10 (also called p11)-binding site [4]. The core region of ANXA2 contains the calcium and phospholipid-binding site [1, 5]. The C-terminal region contains the F-actin- [6], heparin- [7] and plasminogen-binding sites [8]. The core domain contains four repeats, and each repeat features five alpha-helices. In ANXA2, the core domain possesses two annexin-type calcium-binding sites with the sequence GxGT-[38 residues]-D/E [1, 5]. ANXA2 is activated in a calcium-dependent manner and undergoes a conformational change that exposes a hydrophobic amino acid to form a heterotetramer with p11. This complex shows a high affinity for phospholipids [9]. ANXA2 exists as a monomer or heterotetramer composed of two ANXA2 molecules and two p11 molecules and has four forms, including secrete, membrane-bound, cytoplasmic, and nuclear form. ANXA2 heterotetramer would translocate from the cytoplasm to the extracellular plasma membrane [10]. In general, ANXA2 expressed in the nucleus is cell-cycle-dependent. 2. Physiological Function of ANXA2 Intracellular ANXA2 has been reported to play roles in exocytosis [11], endocytosis [12, 13], and membrane trafficking [14]. Knockdown of ANXA2 inhibits cell division and proliferation [15]. Protein kinase C-dependent phosphorylation of ANXA2 blocks the ability of the protein to aggregate phospholipid vesicles but does not affect its lipid vesicle binding properties
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