Poster Presentation 50th Lorne Proteins Conference 2025

Understanding the molecular structure and signalling functions of Eph receptor pseudokinase EphA10 (#121)

Emily C Park 1 2 3 , Andrew P Thompson 1 2 3 , Joshua M Hardy 1 2 3 , Lurlene Trepout 1 2 , Isabelle S Lucet 1 2 3
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
  3. Australian Research Council Center for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmacological Sciences, Parkville, VIC, Australia

The erythropoietin-producing human hepatocellular (Eph) family of receptor tyrosine kinases are regulators of cell proliferation, differentiation, and migration through contact-dependent cell-cell communication [1]. The 14 members of the Eph receptor family form the largest class of receptor tyrosine kinases and are classified as EphA (EphA1–A8, EphA10) or EphB (EphB1–B4, EphB6) receptors by sequence homology and preferential binding to ephrin-A (ephrin-A1–A5) or ephrin-B (ephrin-B1–B3) ligands. Unlike other receptor tyrosine kinases, whose soluble ligands are released into the extracellular environment, the Eph receptors and their ligands are both membrane-bound, allowing for transmission of cellular signals in both the receptor- and ligand-presenting cells. Mechanistically, activation of Eph receptors upon ligand binding results in receptor dimerisation, oligomerisation, and the assembly of dynamic receptor clusters along the cell membrane [2]. Cluster assembly amplifies localised autophosphorylation of the intracellular domains, creating multiple binding sites for adaptor and effector proteins in signalling hubs that initiate diverse downstream pathways [3]. Whilst the catalytic kinase activity of Eph receptors plays an essential role in signal transduction, the presence of two pseudokinase members within the Eph family, EphA10 and EphB6, suggests a key role for non-catalytic functions in regulating signal transduction events that is not well understood [4]. Critically, dysregulation of Eph receptor pseudokinase expression is proven to drive progression of many types of cancer, inflammation, and infectious diseases [5, 6, 7], emphasising the significance of non-catalytic signalling functions and relevance as potential therapeutic targets. By drawing from structural characterisation and biological validation of the key molecular interfaces which underpin signalling properties of Eph receptor pseudokinase EphA10, this work aims to facilitate structure-guided drug design towards previously untargeted non-catalytic signalling functions.

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  2. Liang, L.Y., Geoghegan, N.D., Mlodzianoski, M. et al. 2024. Co-clustering of EphB6 and ephrinB1 in trans restrains cancer cell invasion. Commun Biol 7(1) 461.
  3. Liang, L.Y., Roy, M., Horne, C.R. et al. 2021. The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs. Biochem J 478(17) 3351-3371.
  4. Liang, L.Y., Patel, O., Janes, P. et al. 2019. Eph receptor signalling: from catalytic to non-catalytic functions. Oncogene 38(39) 6567-6584.
  5. Pasquale, E.B. 2024. Eph receptors and ephrins in cancer progression. Nat Rev Cancer 24(1) 5-27.
  6. Darling, T.K. and Lamb, T.J. 2019. Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity. Front. Immunol 10(1) 1473.
  7. Wang, J., Zheng, X., Peng, Q. et al. 2020. Eph receptors: the bridge linking host and virus. Cell Mol Life Sci 77(12) 2355-2365.