|CDCB157180||Mouse EPHA2 ORF clone (NM_010139.2)||Inquiry|
|CDCB159538||Human EPHA2 ORF clone (NM_004431.2)||Inquiry|
|CDCB191608||Rabbit EPHA2 ORF clone (XM_002722324.2)||Inquiry|
|CDCR248339||Mouse Epha2 ORF Clone(NM_010139.3)||Inquiry|
|CDCR375616||Rat Epha2 ORF Clone(NM_001108977.1)||Inquiry|
|CDFR008541||Rat Epha2 cDNA Clone(NM_001108977.1)||Inquiry|
EphA2 receptor is a member of the Eph receptor tyrosine kinase family and is highly expressed in many tumors. It is a promising new target for tumor therapy through signal transduction leading to tumorigenesis, invasion and metastasis and angiogenesis. The EphA2 receptor has two states of phosphorylation and non-phosphorylation on the cell membrane. In normal epithelial cells, when the extracellular domain of the receptor binds to the ligand, the conformation changes, resulting in autophosphorylation and degradation. At the same time, tyrosine phosphorylation of a large number of downstream intracellular substrate protein molecules initiates different signaling pathways to transmit and amplify signals step by step, regulate cell growth, proliferation, differentiation, and participate in physiological processes such as embryonic development, cell migration, and angiogenesis. The EphA2 receptor of tumor cells is mainly present in a non-phosphorylated state and has an increased expression. Because most malignant tumors are unstable between cells, EphA2 is difficult to effectively bind to membrane anchoring ligands and phosphorylate to degrade.
Possible Mechanism of High Expression of EphA2 Receptor in Malignant Tumors
It is currently believed that the main cause of high expression of the EphA2 receptor is its increased protein stability. EphA2 protein is highly expressed in transformed breast cancer cells, but its mRNA levels are not different between transformed and non-transformed mammary epithelial cells. It is speculated that the regulatory mechanism of EphA2 may be at the translational level. On the one hand, the EphA2 receptor has a reduced probability of binding to the ligand and reduced degradation. Receptors on the cell surface are endocytosed by binding to their ligands. Because malignant tumor cells lose the regulation of E-cadherin, the cell adhesion is decreased, the structure is loose or detached, and the adjacent cells expressing EphA2 receptor and its ligand are not connected, and the probability of receptor-ligand binding is decreased. This results in a decrease in EphA2 receptor degradation and accumulation on the cell surface, resulting in high expression. On the other hand, the EphA2 receptor cannot be effectively degraded in cancer tissues. The epha2 receptor is highly expressed in many malignant tumors and exists in the tumor cell membrane in a non-phosphorylated state. It does not react well with downstream signal transduction proteins, probably because of the lack of a tyrosine "activation ring" in the intracellular enzyme domain of EphA2.
Hamaoka et al. found that overexpressed EphA2 induces ERK activation through its tyrosine kinase activity, resulting in phosphorylation of serine 897 (S897) and promotion of glioblastoma cell proliferation. This group induced EGFA2 S897 phosphorylation by EGF-inducing cells and was found to be inhibited by MEK and RSK inhibitors but not by PI3K/AKT inhibitors. In addition, RSK inhibitors or RSK2-targeted shRNA also inhibit EGF-induced cell proliferation. These results indicate that EphA2 is a key downstream target for the regulation of MEK / ERK / RSK signaling pathway in glioblastoma cell proliferation.
EphA2 Receptor Enhances Tumor Invasion and Metastasis
Busch et al. found that EphA2 plays an important role in tumor invasion and metastasis. The EphA2 receptor interacts with cell adhesion molecules and affects cell adhesion. The most common adhesion molecule that interacts with EphA2 is E-cadherin. The decrease in E-cadherin and loss of function reduce intercellular adhesion. The EphA2 receptor does not bind well to the ligand, resulting in a decrease in receptor phosphorylation and degradation, and an abnormality in downstream signal transduction. E-cadherin regulates tumor cell adhesion and biological behavior may play a role through EphA2. In colon cancer EphA2 and E-cadherin are co-expressed at the cell contact site. As the degree of malignancy of the tumor increased, the expression of EphA2 increased significantly, but the expression decreased significantly, and the two were negatively correlated. It has also been found in esophageal cancer, cervical cancer, bladder cancer, melanoma, and the like. Phosphorylation of Tyr932, which is conserved in the sterile alpha motif (SAM) of EphA2, binds to SH2 of the Src family kinase and regulates cell morphology, adhesion and movement. Phosphorylation of tyrosine residues in the proximal transmembrane region of EphA2 activates Ras, regulates the activity of P13K/AKT, regulates cell adhesion and movement, and maintains the normal skeleton of cells. EphA2 can amplify the ErbB2 signal, activate the Ras-MAPK pathway and RhoA kinase to reduce the stability of the cell junction and promote tumor cell invasion and metastasis.
Figure 1. EphA2 is a key downstream target of the MEK/ERK/RSK signaling pathway in the regulation of glioblastoma cell proliferation. (Hamaoka, et al. 2016)
EphA2 Receptor Is Involved in the Formation of Malignant Tumor Blood vessels
EphA2 expression was positively correlated with microvascular density (MVD), an important indicator of angiogenesis, suggesting that EphA2 is involved in tumor angiogenesis. However, the mechanism by which EphA2 promotes tumor angiogenesis remains unclear. EphA2 promotes tumor vascular endothelial cell migration and promotes capillary-like structure formation by affecting cytoskeleton, matrix adhesion, and/or cell adhesion. Ventrella et al. found that the EphA2 receptor tyrosine kinase is activated by the ephrin-A1 ligand. Ephrin-A1 acts as a chemoattractant during vascular remodeling, and both interact with tumor cells and vascular endothelial cells to participate in angiogenesis. Blocking EphA2 receptor signaling can inhibit endothelial cell growth, migration, sprouting and corneal angiogenesis induced by VEGF in vitro, suggesting that EphA2 expression is mainly involved in tumor vascularization. Ephrin-A1 does not cause endothelial cell proliferation and acts as a chemical adhesion to endothelial cells. Brantley-Sieders et al. used RNAi technology to inhibit Ephrin-A1 expression in breast cancer cells, and then subcutaneously injected into nude mice to form xenografts. Studies have found that EphA2, VEGF expression decreased and MVD decreased. In turn, overexpression of Ephrin-A1 expression increased EphA2, VEGF, and MVD, suggesting that Ephrin-A1 and receptor EphA2 bind to a cascade effect, including stimulation of VEGF production and reticular formation. It can be seen that the EphA2 receptor and its ligands have the different division of labor in tumor angiogenesis.
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