Eph Receptor Tyrosine Kinase Signaling in Cancer Biology

Eph receptors constitute the largest family of receptor tyrosine kinases and interact with membrane-bound ephrin ligands to regulate cell positioning, adhesion, migration and proliferation. In cancer, dysregulated Eph–ephrin signalling can exert paradoxical effects: ligand-bound receptors often suppress tumour growth and invasion, whereas unliganded or aberrantly phosphorylated receptors may promote metastasis, angiogenesis and chemoresistance. EphA2, the most intensively studied member, exemplifies this duality through ligand-independent phosphorylation at serine-897, which drives cell motility and survival, and through ligand-dependent oligomerisation, which recruits opposing antitumour cascades. Beyond intrinsic tumour cell functions, Eph signalling shapes the tumour microenvironment by modulating vascular remodelling and immune cell trafficking. Recent structural and mechanistic insights into receptor clustering, pseudokinase regulation and non-catalytic interfaces have begun to resolve the complexity of Eph-dependent networks. As clinical efforts advance small-molecule modulators, biologics and imaging agents that selectively engage Eph receptors, a nuanced understanding of kinase-dependent and kinase-independent mechanisms will be crucial to harnessing their therapeutic potential.

Research from Nature Portfolio

Recent studies have revealed that inhibition of EphA2 serine-897 phosphorylation by multikinase inhibitors can underlie unexpected organ toxicity, identifying chemical activation of this site as a strategy to mitigate off-target effects. Parallel structural analyses of full-length EphA2 in the plasma membrane demonstrated that distinct ligands stabilise diverse oligomeric assemblies, each supporting specific tyrosine-phosphorylation patterns and downstream outputs. Additionally, foundational work has shown that inflammatory cues activate a ribosomal S6 kinase-dependent pathway to phosphorylate EphA2 at serine-897, thereby driving breast cancer cell motility and correlating with poor patient survival in certain lung cancers. Together, these studies illuminate how ligand context, kinase cross-talk and oligomer geometry converge to influence EphA2’s protumorigenic versus tumour-suppressive roles.

Eph Receptor Tyrosine Kinase Signaling in Cancer Biology publication trend

The graph below shows the total number of articles in eph receptor tyrosine kinase signaling in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Eph receptor: A member of the receptor tyrosine kinase family that binds ephrin ligands to mediate cell–cell communication.

Ephrin ligand: A membrane-anchored protein that engages Eph receptors to trigger bidirectional signalling.

Serine-897 phosphorylation: A modification of EphA2 that promotes ligand-independent pro-migratory and survival signals.

Oligomerisation: Assembly of multiple receptor molecules into clusters that influence kinase activation and downstream pathways.

Radiotheranostic agent: A molecule combining diagnostic imaging and therapeutic radionuclide delivery functions.

References

1. Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis. Nature Communications (2023).
2. Development and preclinical characterization of a novel radiotheranostic EphA2-targeting bicyclic peptide. Theranostics (2024).
3. Targeting EphA2 in cancer. Journal of Hematology & Oncology (2020).
4. Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity. Frontiers in Immunology (2019).
5. Crucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2. Nature Communications (2015).
6. The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures. Communications Biology (2018).
7. Eph receptor signalling: from catalytic to non-catalytic functions. Oncogene (2019).