Eph Receptors in Cancer

Abstract

Eph receptor tyrosine kinases play critical functions during development, in the formation of tissue and organ borders, and the vascular and neural systems. Uniquely among tyrosine kinases, their activities are controlled by binding to membrane-bound ligands, called ephrins. Ephs and ephrins generally have a low expression in adults, functioning mainly in tissue homeostasis and plasticity, but are often overexpressed in cancers, where they are especially associated with undifferentiated or progenitor cells, and with tumour development, vasculature, and invasion. Mutations in Eph receptors also occur in various tumour types and are suspected to promote tumourigenesis. Ephs and ephrins have the capacity to operate as both tumour promoters and tumour suppressors, depending on the circumstances. They have been demonstrated to impact tumour cell proliferation, migration, and invasion in vitro, as well as tumour development, angiogenesis, and metastases in vivo, making them potential therapeutic targets. However, successful development of therapies will require detailed understanding of the opposing roles of Ephs in various cancers. In this review, we discuss the variations in Eph expression and functions in a variety of malignancies. We also describe the multiple strategies that are currently available to target them in tumours, including preclinical and clinical development.

Keywords: Eph receptor; cancer biology; ephrin; receptor tyrosine kinase; targeted therapy.

Figure 2

Tumour-suppressing and tumour-promoting functions of Eph receptors. (A) Interaction of Eph receptor and ephrin on neighbouring cells causes clustering of Eph–ephrin complexes and the beginning of canonical signalling. The activation of Eph kinase function involves tyrosine phosphorylation and recruitment of adaptor proteins, including SH2-domain-containing signalling proteins. In reaction to ephrin-A, ephexin stimulates RhoA, which induces cytoskeletal remodelling, cell retraction and segregation, and membrane blebbing. (B) In the absence of ephrin, Eph receptor expression can lead to noncanonical signalling, whereby crosstalk between Eph receptors and other RTK activity induces phosphorylation of Akt by the lipid kinase PI3K. Akt then phosphorylates EphA2 at S897 to enhance cellular proliferation, cell migration, and reduce apoptosis through several downstream effectors, including mTOR complex 1.

Figure 1

Structure of Eph receptors. Eph receptors are multidomain transmembrane proteins. The extracellular region consists of a ligand-binding domain (LBD) that binds to ephrin ligands on adjacent cells, a cysteine-rich domain (CRD) composed of a sushi and EGF domain, and two fibronectin III domains located C-terminally to the LBD. A juxtamembrane (JM) region, a kinase domain (KD), a SAM domain, and a C-terminal PDZ-domain-binding motif make up the Eph receptor cytoplasmic domain.

Figure 3

Eph receptors expressed on different cell types in the tumour microenvironment.

Figure 4

Illustration of potential therapeutic approaches targeting sites of Eph receptors.