Eph receptors: the bridge linking host and virus

Abstract

Eph (erythropoietin-producing hepatoma) receptors and Ephrin ligands constitute the largest subfamily of receptor tyrosine kinase (RTK), which were first discovered in tumors. Heretofore, Eph protein has been shown to be involved in various tumor biological behaviors including proliferation and progression. The occurrence of specific types of tumor is closely related to the virus infection. Virus entry is a complex process characterized by a series of events. The entry into target cells is an essential step for virus to cause diseases, which requires the fusion of the viral envelope and host cellular membrane mediated by viral glycoproteins and cellular receptors. Integrin molecules are well known as entry receptors for most herpes viruses. However, in recent years, Eph receptors and their Ephrin ligands have been reported to be involved in virus infections. The main mechanism may be the interaction between Eph receptors and conserved viral surface glycoprotein, such as the gH/gL or gB protein of the herpesviridae. This review focuses on the relationship between Eph receptor family and virus infection that summarize the processes of viruses such as EBV, KSHV, HCV, RRV, etc., infecting target cells through Eph receptors and activating its downstream signaling pathways resulting in malignancies. Finally, we discussed the perspectives to block virus infection, prevention, and treatment of viral-related tumors via Eph receptor family.

Keywords: EBV; Eph receptor; KSHV; Virus infection; Virus-associated cancer.

Fig. 1

Members of Eph family. In the human genome, there are totally nine EphA and five EphB receptors. The EphA receptors promiscuously bind five glycosylphosphatidylinositol (GPI) linked Ephrin-A ligands, and the EphB receptors promiscuously bind three transmembrane Ephrin-B ligands

Fig. 2

Domain structure and signaling concepts of Ephs and Ephrins. a Eph receptors (Ephs) consist of a ligand-binding domain (LBD), cysteine-rich region (Cys), two fibronectin III repeat (FNIII), a transmembrane region (TM), a juxtamembrane region (JM), a tyrosine kinase domain (TK), a sterile alpha motif (SAM) a PSD-95/Dlg/ZO-1. GPI and glycosylphosphatidylinositol binding motif (PDZ). b Ephrin-As are linked to the membrane via a glycosylphosphatidylinositol (GPI) moiety, Ephrin-Bs are anchored by a transmembrane domain and contain a cytoplasmic tail. c Ephrin-A signaling promotes activation of FYN, and Erk. d EphA receptors directly activate Src and RHOA through focal adhesion kinase (FAK). EphA receptors activate JAK2 by STAT3 (signal transducer and activator of transcription 3). EphA2 activates Akt in pancreatic cancer cells. e Ephrin-Bs promote EMT and invasion by activating Src, STAT3, MMP8 (matrix metalloproteinase 8), and RAC1. f EphBs activate RHOA, RAC1, and CDC42 which promote cancer cell migration and invasion

Fig. 3

Interaction of virus and Ephs is crucial for viral entry. A generic virus is shown binding to Ephs entry receptors and co-receptors (integrins). The virion interaction with entry receptors triggers specific entry pathways, two examples are shown. Fusion at the plasma membrane mediated by entry receptors (e.g., Epstein–Barr virus infection of epithelial cells). Endocytosis mediated by entry receptors (e.g., Kaposi’s sarcoma-associated herpesvirus infection of multiple cell types)