Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

Abstract

Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

EPHA2 Interacts with DNA-PKcs in Cell Nucleus and Controls Ionizing Radiation Responses in Non-Small Cell Lung Cancer Cells

“…Given these findings and the results presented in this study, it is relevant to think of therapeutic approaches towards EphA2 for RT sensitizing purposes. Thus far, no EphA2 interference strategies are used in the clinical setting of NSCLC, yet multiple ways to intrude with EphA2 signaling have been described for anti-tumor purposes, including antibodies, blocking peptides, kinase inhibitors and small molecules that act as antagonists or agonists towards EphA2 (reviewed in Baudet et al [ 59 ] and Hughes and Virag [ 60 ]). These approaches may act by interfering with EFN ligand binding or by targeting the EphA2 kinase domain, thereby influencing the EphA2 oncogenic signaling.…”

EphA4 Obstructs Spinal Cord Neuron Regeneration by Promoting Excessive Activation of Astrocytes

“…After SCI, Eph family members and their ligands (ephrins) accumulate in the proximal axon stump, and reactive astrocytes play an important role in the formation of glial scars and neurite regeneration (Elgebaly 2020 ). EphA4 reduces the expression of glutamate transporters and the glutamate absorption capacity of astrocytes by activating the reverse signal transduction of ephrin-A3, which indicates that EphA4-mediated ephrin-A3 reverse signal transduction is an important mechanism by which astrocytes control glial glutamate transporters and prevent glutamate excitotoxicity under pathological conditions (Baudet et al 2020 ). In epha4 −/− mice, the number of astrocytes and the area of glial scars were significantly reduced after lateral spinal cord hemisection (Dixon et al 2012 ; Fiore et al 2019 ), and neurons cocultured with wild-type astrocytes exhibited shorter neurites than those cocultured with epha4 −/− astrocytes (Goldshmit et al 2011 ).…”

Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment

“…The Eph receptors of both subclasses and the ephrin-B ligands can signal through both tyrosine phosphorylation and ensuing protein-protein interactions, as well as protein-protein interactions through the PDZ motif and SAM domain (Binns et al, 2000 ; Cowan and Henkemeyer, 2001 ; Lu et al, 2001 ; Palmer et al, 2002 ; Leone et al, 2008 ; Wang et al, 2018 ; Liang et al, 2019 ; Baudet et al, 2020 ). Importantly the ephrin-A molecules localize to lipid rafts/micro-compartments within the plasma membrane and engage transmembrane proteins, such as caveolins, neurotrophin receptor p75 and intracellular Src family kinase dependent signaling (Davy et al, 1999 ; Davy and Robbins, 2000 ; Lim et al, 2008 ).…”