Abstract
Eph receptors, the largest subfamily of receptor tyrosine kinases, are linked with proliferative disease, such as cancer, as a result of their deregulated expression or mutation. Unlike other tyrosine kinases that have been clinically targeted, the development of therapeutics against Eph receptors remains at a relatively early stage. The major reason is the limited understanding on the Eph receptor regulatory mechanisms at a molecular level. The complexity in understanding Eph signalling in cells arises due to following reasons: (1) Eph receptors comprise 14 members, two of which are pseudokinases, EphA10 and EphB6, with relatively uncharacterised function; (2) activation of Eph receptors results in dimerisation, oligomerisation and formation of clustered signalling centres at the plasma membrane, which can comprise different combinations of Eph receptors, leading to diverse downstream signalling outputs; (3) the non-catalytic functions of Eph receptors have been overlooked. This review provides a structural perspective of the intricate molecular mechanisms that drive Eph receptor signalling, and investigates the contribution of intra- and inter-molecular interactions between Eph receptors intracellular domains and their major binding partners. We focus on the non-catalytic functions of Eph receptors with relevance to cancer, which are further substantiated by exploring the role of the two pseudokinase Eph receptors, EphA10 and EphB6. Throughout this review, we carefully analyse and reconcile the existing/conflicting data in the field, to allow researchers to further the current understanding of Eph receptor signalling.
Highlights
Receptor tyrosine kinases (RTKs) are a major type of membrane receptors, which govern cell proliferation, differentiation and mobility [1]
In contrast to other RTKs, the uniqueness of the erythropoietin-producing hepatoma (Eph) receptor-mediated signalling pathways includes: [1] ephrin ligand-dependent or -independent Eph receptor activation; [2] Eph receptor oligomerisation, a mechanism allowing the amplification of the downstream signal transduction; [3] the presence of the two kinase-dead members, EphA10 and EphB6, whose roles remain to be determined
The emerging state-of-the-art cryo-electron microscopy may provide a feasible solution to examine how ephrin binding to the ectodomains of the Eph receptor can convey extracellular cues to intracellular effectors
Summary
Receptor tyrosine kinases (RTKs) are a major type of membrane receptors, which govern cell proliferation, differentiation and mobility [1]. We focus on the importance of the non-catalytic functions of the kinase-active Eph receptors, and the roles of EphA10 and EphB6 pseudokinases in cancers. Both EphA10 and EphB6 likely harbour non-catalytic regulatory functions (Fig. 2a), the exact role they play in regulating Eph receptor signalling is unknown.
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