Eph Receptors and Ephrins: Therapeutic Opportunities

Abstract

The Eph receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis and various diseases. Interaction with ephrin ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other, through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as 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. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

“…Interestingly, TCGA data analysis revealed that EphA2 and EfnA1 alterations occur independently, and it is intriguing to hypothesize that tumors with EphA2 and EfnA1 coexpression might be negatively selected in the early stages of tumor development. However, the overexpressed EphA2, in the absence of cognate ligands (23,24,30,41), can function to promote tumorigenesis in a ligand-independent manner. Overexpressed EPHA2 can be phosphorylated at S897 by activated AKT and can function in a ligand-independent manner to promote cell growth, xenograft tumor development, anoikos resistance (42), and migration of tumor cells (43)(44)(45)(46).…”

“…Binding of Ephrin A1 (EFNA1) to EPHA2 results in phosphorylation of EPHA2 and activation of a downstream signaling cascade that regulates various cellular processes, including cell shape, movement, angiogenesis, survival, and proliferation (23,24). In cancer, EphA2 has been reported to be both tumor-promoting and tumor-inhibiting although a large amount of evidence points to its tumor suppressor activity (23,24). EphA2 knockout mice were shown to be very susceptible to DMBA/ TPA-induced skin carcinogenesis (25).…”

Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability

“…1−3 However, increased EphA4 expression and aberrant kinase activity following nervous system injury or disease can contribute to pathological processes. 1,3 EphA4 was identified as a gene promoting disease pathogenesis in amyotrophic lateral sclerosis (ALS), and studies in ALS animal models and patients have shown that reduced EphA4 activity delays disease onset and slows disease progression. 4 Evidence in cultured neurons and mouse models has also implicated EphA4 activity in the synaptic dysfunction induced by the pathogenic amyloid-β oligomers in Alzheimer's disease.…”

“…1−3 The two main strategies that could be used to inhibit the detrimental effects of EphA4 activity involve blocking either its kinase activity or its interaction with ephrin ligands. 1,2 To our knowledge, high affinity, selective EphA4 kinase inhibitors remain to be identified. 1,3 In contrast, selective and high affinity peptide antagonists targeting the ephrin-binding pocket in the extracellular ligand-binding domain (LBD) of EphA4 are available.…”

“…1,2 To our knowledge, high affinity, selective EphA4 kinase inhibitors remain to be identified. 1,3 In contrast, selective and high affinity peptide antagonists targeting the ephrin-binding pocket in the extracellular ligand-binding domain (LBD) of EphA4 are available. 2 Peptides appear to have greater potential than small molecules (such as rhynchophylline and bile acid derivatives) for high affinity, selective binding to the ephrinbinding pocket of EphA4 due to its broad surface and conformational flexibility.…”