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Eph receptor signalling: from catalytic to non-catalytic functions
Lung-Yu Liang1,2, Onisha Patel1,2, Peter W Janes3
1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
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.
Insights
Eph receptors, crucial in cell proliferation and cancer, have complex regulatory mechanisms hindering therapeutic development. This review explores their structural dynamics and non-catalytic functions, particularly pseudokinases EphA10 and EphB6, for better understanding.
Area of Science:
- Molecular biology
- Cell signaling
- Structural biology
Background:
- Eph receptors, a large receptor tyrosine kinase subfamily, are implicated in proliferative diseases like cancer due to altered expression or mutations.
- Targeting Eph receptors for cancer therapy is challenging due to limited understanding of their molecular regulation.
- Complexity arises from 14 members (including pseudokinases EphA10/EphB6), diverse oligomerization states, and overlooked non-catalytic functions.
Purpose of the Study:
- To provide a structural perspective on Eph receptor signaling mechanisms.
- To investigate intra- and inter-molecular interactions within Eph receptor intracellular domains and with binding partners.
- To focus on the non-catalytic functions of Eph receptors relevant to cancer, including pseudokinases EphA10 and EphB6.
Main Methods:
- Structural analysis of Eph receptor interactions.
- Review and reconciliation of existing literature on Eph receptor signaling.
- Focus on intracellular domain interactions and pseudokinase functions.
Main Results:
- Eph receptor signaling complexity stems from multiple members, dimerization/oligomerization, and signaling clusters.
- Non-catalytic functions, especially of pseudokinases EphA10 and EphB6, play a significant role.
- Intra- and inter-molecular interactions are critical drivers of diverse downstream signaling outputs.
Conclusions:
- A deeper understanding of Eph receptor structural mechanisms and non-catalytic roles is essential for therapeutic advancement.
- Reconciling conflicting data and focusing on pseudokinases like EphA10 and EphB6 can clarify signaling pathways.
- This review offers insights to guide future research in Eph receptor biology and cancer therapy.
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