Therapeutic potential of targeting the Eph/ephrin signaling complex

Abstract

The Eph-ephrin signaling pathway mediates developmental processes and the proper functioning of the adult human body. This distinctive bidirectional signaling pathway includes a canonical downstream signal cascade inside the Eph-bearing cells, as well as a reverse signaling in the ephrin-bearing cells. The signaling is terminated by ADAM metalloproteinase cleavage, internalization, and degradation of the Eph/ephrin complexes. Consequently, the Eph-ephrin-ADAM signaling cascade has emerged as a key target with immense therapeutic potential particularly in the context of cancer. An interesting twist was brought forth by the emergence of ephrins as the entry receptors for the pathological Henipaviruses, which has spurred new studies to target the viral entry. The availability of high-resolution structures of the multi-modular Eph receptors in complexes with ephrins and other binding partners, such as peptides, small molecule inhibitors and antibodies, offers a wealth of information for the structure-guided development of therapeutic intervention. Furthermore, genomic data mining of Eph mutants involved in cancer provides information for targeted drug development. In this review we summarize the distinct avenues for targeting the Eph-ephrin signaling pathway, including its termination by ADAM proteinases. We highlight the latest developments in Eph-related pharmacology in the context of Eph-ephrin-ADAM-based antibodies and small molecules. Finally, the future prospects of genomics- and proteomics-based medicine are discussed.

Pathophysiologic Role of Molecules Determining Arteriovenous Differentiation in Adult Life

“…Although early Notch activation can bestow positional determination, this does not irrevocably commit cells to an arterial fate. Lineage-tracing studies reveal that Notch-activated cells initially and positionally committed to the dorsal aorta can later become venous tissue by de-or transdifferentiation [17].…”

p28 Bacterial Peptide, as an Anticancer Agent

“…It has been reported that the G-H loop region in the C-terminal domain of azurin (aa 96-113) has structural similarity to ephrinB2 at the G-H loop region, which has a role in receptor binding. Additionally, azurin could interfere in autophosphorylation of the tyrosine residue in the kinase domain of EphB2 resulting in the prevention of tumor progression and in cancer growth inhibition (30,31). One previous study reported that azurin is also able to decrease the signaling of the FAK/Src complex, which mediates the decrease in the expression of P-cadherin at the cellular membrane and represses the growth of breast cancer cells with highly invasive P-cadherin overexpression.…”

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

“…Antibodies, interfering RNAs (iRNAs), peptides, soluble fragments of Eph/ephrin, and small molecules -including protein-protein interaction inhibitor (PPIs) and kinase inhibitors -have been used. Since reviews summarizing therapeutic-oriented strategies are available in the literature [6,[80][81][82], we will here focus on recently developed tools targeting EphA receptors.…”

“…Like peptides, recent efforts have been focused on optimizing existing PPI inhibitors since most of them exhibit lack of specificity and stability, as well as weak bioavailability [131]. PPI inhibitors targeting EphAs have been reviewed recently [82]. Recent improvements are summarized here.…”