Introduction of Annexin
Annexin, a widely classified calcium-phospholipid binding protein, shares common biological characteristics in protein structure, gene structure, and sequences, participating in various cellular and molecular regulatory processes. Each annexin molecule possesses one highly homologous C-terminal core structure and one variable N-terminal domain.
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Annexin A2 (ANXA2), a vital member of the annexin family, is a calcium-dependent phospholipid-binding protein present extensively in both plants and animals. Positioned on chromosome 15, it comprises 339 amino acids with a size of 36 kDa. ANXA2 is produced by various cells, including vascular endothelial cells, monocytes, macrophages, dendritic cells, nourishing layer cells, epithelial cells, and tumor cells. ANXA2 can exist as a free monomer in the cytoplasm, bind to the internal cell membrane, or attach to the outer surface of the plasma membrane. Structurally similar to other superfamily members, it has a variable N-terminal and a conserved core region (C-terminal). The C-terminal domain contains binding sites for calcium ions, phospholipids, and actin; the N-terminal is its functional region with binding activity, featuring P11, tPA binding sites, phosphorylation sites Tyr23, Ser11, Ser25, and a nuclear export signal. The core region consists of four homologous repeat sequences, each containing five α-helical structures, forming a conserved disk with calcium-binding ability, regulating the binding of ANXA2 to phospholipids – a calcium-dependent phospholipid-binding protein. The N-terminal of ANXA2 has a nuclear export signal, indicating its capability to translocate from the cytoplasm to the cell nucleus for functional execution. Research reveals that phosphorylation of ANXA2 is conducive to its nuclear translocation.
Fig.1 Domain structure of annexin A2 (Bharadwaj A., et al., 2013).
ANXA2 primarily exists in two forms: monomer and heterotetramer. ANXA2 first forms a heterodimer with its ligand p11, and two molecules of this heterodimer further bind to each other, creating a heterotetramer. Through binding, the N-terminal of ANXA2 forms an α-helix, containing crucial hydrophilic amino acid residues. Simultaneously, one ANXA2's L2 Loop and HIV helix, along with another ANXA2's HI helix, jointly form a gap. The heterodimer is closely related to the cell proliferation process. The heterotetramer serves as a shared receptor for tissue-type plasminogen activator (t-PA) and plasminogen (PLG), mediating t-PA-dependent activation of plasminogen and the production of plasmin, dissolving fibrin to maintain vascular homeostasis and promoting the invasion of tumor cells. Research indicates that the heterotetramer is a crucial form for ANXA2 to exert its functions.
Distribution and Regulation of ANXA2 in Cells
ANXA2 protein is mainly distributed in the cell nucleus, cytoplasm, cell membrane, and extracellular fluid, exhibiting calcium-dependent phospholipid-binding characteristics. Under conditions such as thermal stimulation, thrombin stimulation and hypoxia, ANXA2 in endothelial cells can be rapidly distributed from the cytoplasm to the cell membrane, this process requires the participation of sufficient phosphorylated p11. ANXA2 is mainly distributed in the cell membrane, so it is involved in cell-cell interactions and cell adhesion. Intracellular ANXA2 has important roles in cellular endocytosis, exocytosis, and membrane trafficking. Knockdown of ANXA2 revealed that cell division and proliferation were inhibited. It plays an important role in the formation of lipid rafts and signal transduction by interacting with CD44. ANXA2 can bind to a variety of ligands, including calcium, lipids, mRNA, and many intracellular and extracellular proteins, and distinguish gene expression modifications by regulating the function after interaction with ligands. Studies have found that ANXA2 can serve as a ligand for C1q in apoptotic cells, suggesting that ANXA2 is also closely related to apoptosis. In addition, protein kinase C (PKC) can inhibit the distribution of ANXA2 from the cytoplasm to the cell membrane by phosphorylating amino acid residues S11 or S25 of ANXA2, and the two bind to each other to create a specific membrane microenvironment and regulate the downstream effector pathways at specific membrane sites.
The Relationship between ANXA2 and Cancer
Membrane-associated protein, annexin, is widely distributed in cells and closely associated with the development of malignant tumors. Its involvement includes cell adhesion, proliferation, cell surface fibrinolytic activity, regulation of cell growth, angiogenesis, and apoptosis. Different members of the annexin family play distinct roles in tumor occurrence, with ANXA2 primarily influencing angiogenesis and the invasive metastasis of tumor cells.
ANXA2 is found within the cytoplasm, cell membrane, and cellular cytoskeletal network, playing a crucial role in the mobility of cancer cells. It exhibits heightened expression across numerous cancer types, and its presence is often linked to fibrinolysis-related enzymes on the tumor surface. This association enables ANXA2 to mediate the degradation of the extracellular matrix, foster angiogenesis, and consequently promote tumor growth. Recent studies establish a significant correlation between ANXA2 and the development of diverse cancers, including but not limited to prostate cancer, hematological tumors, gastric cancer, pancreatic cancer, renal cancer, brain astrocytomas, cervical cancer, colorectal cancer, and ovarian cancer.
In tissues such as gastric, pancreatic, colorectal, liver, and brain cancer, the expression of ANXA2 shows an increasing trend, while in prostate cancer, a decreasing trend is observed. Furthermore, in metastatic breast cancer, the expression of ANXA2 is higher than in non-metastatic tissues of the same cancer type. For instance, in hepatocellular carcinoma, the expression of ANXA2 in cell membranes and cytoplasm was found to be significantly higher than in normal populations, both in tissue and serum, with peripheral blood levels notably elevated compared to normal individuals. In lung cancer, ANXA2 was found to potentially promote drug-resistant phenotypes by regulating SA100A10 and SOX2. Experimental screening of differential proteins in gastric cancer, validated by Western blotting, revealed a significant upregulation of ANXA2. Detection of ANXA2 in the serum of clinical gastric cancer patients showed markedly higher levels compared to the control group, with ineffective chemotherapy patients having higher serum ANXA2 levels than effective chemotherapy patients. Examination of fresh ovarian cancer tissue slices and formalin-fixed paraffin-embedded ovarian cancer tissue slices revealed that ANXA2 plays a crucial role in ovarian cancer cell proliferation, possibly promoting the metastasis of epithelial ovarian cancer. Overexpression of ANXA2 was also observed in breast cancer tissues. In xenograft models of breast cancer growth, the use of monoclonal antibodies against ANXA2 significantly inhibited tumor cell growth. The expression of ANXA2 in renal cell carcinoma was found to be elevated to varying degrees, and silencing the ANXA2 gene was shown to significantly inhibit cell invasion and migration. Immunohistochemical staining of ANXA2 and S100A4 expression in urothelial carcinoma tissues showed a significant upregulation, suggesting that ANXA2 and S100A4 could be used for predicting bladder cancer in the future. In addition, research on ANXA2 has been conducted in other cancers, demonstrating a close relationship between ANXA2 and cancer infiltration and metastasis.
Scientific studies on ANXA2 have been ongoing, showcasing its diverse functions that highlight the marvels of living organisms. Continued research on ANXA2, exploring and understanding its intricacies, is important for disease prevention and diagnosis.
References
- Bharadwaj A.; et al. Annexin A2 heterotetramer: structure and function. International Journal of Molecular Sciences. 2013, 14(3): 6259-6305.
- Lokman N. A.; et al. The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenvironment. 2011, 4: 199-208.
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