There are two types of enkephalins, namely methionine enkephalin and leucine enkephalin. They are all morphine-like neurotransmitters in the central nervous system. They bind to cell surface receptors like opioids. Neurons containing enkephalin are present in the brain and spinal cord gray matter. Its main function in the spinal cord is to regulate the feeling of pain, the function of the brain is unknown, but it can also calm and raise the pain threshold. The Eph receptor (which is Eph after the human hepatocyte receptor that produces erythropoietin) is a group of receptors that are activated in response to binding to Eph receptor interacting proteins (Ephrins). Eph forms the largest known subfamily of receptor tyrosine kinases (RTKs). Eph receptors and their corresponding ephrin ligands are membrane-bound proteins that require direct cell-cell interactions to activate Eph receptors. Eph/ephrin signaling is involved in the regulation of many processes critical for embryonic development, including axon guidance, tissue boundary formation, cell migration and segmentation. In addition, Eph/ephrin signaling has recently been found to play a key role in multiple processes of maintaining adulthood, including long-term potentiation, angiogenesis, and stem cell differentiation and cancer.
Figure 1. Structure of the kinase domain of human eph type-A receptor 5 (EphA5)
1. Nervous system
The correct connection of nerve fibers is a necessary prerequisite for the signal transmission of the nervous system. In most areas, the nerve fibers are mainly axons, and the axons must follow the correct path to reach the target area. In the target area, each axon must be found and identified correctly. Target cells form a specific junction. Studies in chickens and mice have shown that mice lacking EphB3 and EphB2 exhibit increased frequency of path-orientation errors in the axons of the retinal ganglion cells (RGC) to the optic disc. On the dorsal side . The decrease in adhesion caused by the Eph/R-Ras pathway can explain the repulsive effect of Eph receptors in axon path-directed, causing axonal retraction, thereby guiding axonal out of incorrect Target site; and make tumor cells susceptible to invasion and angiogenesis.
Eph receptors are highly present during angiogenesis (angiogenesis) and other early developmental processes of the circulatory system. Without it, this development will be disrupted. It is believed that it is possible to distinguish between arterial and venous endothelium (Figure 3), stimulate the production of capillary buds, and differentiate mesenchymal cells into perivascular supporting cells. The construction of blood vessels requires the coordination of endothelial cells and supporting mesenchymal cells through multiple stages to develop the complex network required for a functionally complete circulatory system. The dynamic nature and expression of Ephs make it an ideal choice for angiogenesis.
Figure 2. Diagram showing the location of endothelial cells.
Many Eph receptors are highly expressed in tumors. In several human tumors (lung cancer, breast cancer, colon cancer, liver cancer, colon cancer), Epha1 expression is higher than corresponding normal tissues, but no gene amplification, in vitro Epha1 in NiH3T3 cells High expression caused NIH3T3 to induce tumorigenesis in nude mice and cloned on soft agar, suggesting that high expression of eph may be associated with tumorigenesis. Ephb2 expression in various tumor tissues is several times higher than that of corresponding normal tissues, among which It is the most prominent in gastric cancer tissues, and about 75% is highly expressed, so it is thought that it may play a role in the occurrence of gastric embryos and tumors.
4. Embryonic development
The Eph family involves the formation of spatial boundaries that contribute to the orderly development of the developing organism. Bidirectional signaling between the EphB receptor and its ligands limits the mixing of adjacent cell populations and maintains their respective characteristics, precisely determining cells. Destiny plays an important role. Eph receptors and ephrins ligands are key regulators of cell rejection and adhesion, which in turn are the basis for establishing, maintaining and remodeling cellular tissue morphology. EphA3, ephrin-A5 interfere with zebrafish embryogenesis In early events, exogenous expression of both proteins resulted in dose-dependent somite development defects and defects in the midbrain-posterior border and hindbrain tissue. The critical role of Eph receptors and their ligands in development suggests future research. The important clinical value provides an ideological and material basis for exploring the application prospects.
The extracellular domain of the Eph receptor consists of a highly conserved globular ephrin ligand binding domain, a cysteine-rich region and two type III fibronectin domains. The cytoplasmic domain of the Eph receptor consists of a juxtamembrane region with two conserved tyrosine residues, a tyrosine kinase domain, a sterile alpha motif (Figure 2) and a PDZ binding motif. After the ephrin ligand binds to the extracellular globular domain of the Eph receptor, the tyrosine and serine residues in the Eph juxtamembrane region are phosphorylated, thereby transforming intracellular tyrosine kinases. It is its active form and subsequently activates or inhibits the downstream signaling cascade. The structure of trans autophosphorylation of the membrane proximal region of EPHA2 has been observed in the crystal of EPHA2.
Figure 3. SAM domain from fungal protein Ste50p.
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