Eph receptors (Ephs, after erythropoietin-producing human hepatocellular receptors) are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of receptor tyrosine kinases (RTKs).
Introduction of Ephrin receptor
Erythropoietin-producing hepatocellular (Eph) receptors comprise a large family, with 16 members cloned, classified as EphA and EphB on the basis of amino acid sequence homology and relative binding affinities to glycosylphosphatidylinositol (GPI)-linked ephrin-A or transmembrane ephrin-B ligands. Both EphA and EphB receptors contain a single transmembrane-spanning domain. The extracellular region of Eph receptors is glycosylated, consisting of a ligand-binding domain, a cysteine-rich domain and two fibronectin type III repeats. The intracellular region contains a juxtamembrane region with several conserved tyrosine residues, a tyrosine kinase domain, a sterile α motif (SAM) domain and a PDZ-binding motif within the non-catalytic region of the COOH-terminus. The Eph receptor tyrosine kinase family plays a vital role in developmental processes, adult tissue homeostasis and varieties of diseases. Eph receptors bind ephrins on neighboring cells, generating cell contact-dependent bidirectional signals that regulate cell shape, movement, survival and proliferation. Except for interaction with other, Eph receptors and ephrins can function independently, through interplay with other signaling systems. Eph receptors distribute widely in the developing nervous system, responsible for regulating the spatial organization of cell populations, tissue patterning, axon guidance and the formation of synaptic connections. Some family members remain substantially distributing in the adult nervous system to control the structure and function of synapses and various aspects of neural stem/progenitor cell biology. Eph receptors can also function via ‘non-classical’ signaling modalities, including interplay with secreted major sperm protein (MSP) domain-containing proteins, the extracellular protein reelin, other receptor tyrosine kinases, the lipoprotein receptor LRP1, and several intracellular proteins. Importantly, Eph receptors represent key players in many physiological and pathological conditions ranging from neurological disorders to cancer and viral infections, together with their ligands, the ephrins (Eph receptor interacting proteins). Increasing experimental evidence has demonstrated that both Eph receptor and ephrins are overexpressed in a number of human tumours, closely related to tumour growth, invasiveness and metastasis. Eph receptors and ephrins are increasingly thought to be attractive therapeutic targets and a variety of strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offers opportunities for Eph/ephrin-based targeted drug delivery and imaging.
Small molecule antagonists that target Eph receptors so far display weak binding affinities in the micromolar range, probably due to the large size and flexibility of the ephrin-binding pocket. Efforts to elevate affinity have contributed to more potential but larger (>500 kDa) compounds. Small molecules match the ATP-binding pocket better in the Eph kinase domain. Advantages of small molecule kinase inhibitors are their extensive track record as drugs, potential for oral bioavailability, and in many cases ease of synthesis. However, most kinase inhibitors exhibit poor selectivity and target multiple kinases. Indeed, several small molecules identified as inhibitors of other kinase families, taking dasatinib as an example, can also strongly inhibit Eph receptors. Accidentally, recently dasatinib was reported to also inhibit kinase-independent EphA2 oncogenic signaling in cells through an indirect mechanism. Various types of screens to identify Eph kinase inhibitors have also produced several potential compounds.
1. Hong-Qing Xi, Xiao-Song Wu , Bo Wei, Lin Chen. Eph receptors and ephrins as targets for cancer therapy. J Cell Mol Med. 2012,16(2):2894-2909.
2. Bethany E Perez White, Spiro Getsios. Eph receptor and ephrin function in breast, gut, and skin epithelia. Cell Adhesion & Migration. 2014, 8(4): 327-338.
3. Antonio Barquilla, Elena B. Pasquale. Eph Receptors and Ephrins: Therapeutic Opportunities. Annu Rev Pharmacol Toxico. 2015,55:465-487.
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