EPHA10

EPHA10 is a catalytically defective (pseudokinase) EphA-subclass receptor that preferentially binds ephrin-A ligands and contributes to epithelial adhesion and tumor cell behavior through non-catalytic signaling (PMID:15777695, PMID:32644283). Although its intracellular region lacks catalytic activity, the juxtamembrane–pseudokinase–SAM module is conformationally flexible and retains the ability to bind ATP and ATP-competitive small molecules, making the pseudokinase domain pharmacologically tractable (PMID:34431498). EphA10 physically associates with the kinase-competent receptor EPHA7, co-localizing at the cell surface and, for soluble isoforms, forming complexes in the cytoplasm and nucleus (PMID:27566654). Functionally, EphA10 isoforms differentially control the E-cadherin/β-catenin membrane complex: the secreted EphA10s isoform stabilizes membrane β-catenin via ephrin-A5 interaction, while the cytoplasmic full-length isoform maintains E-cadherin phosphorylation, and restoring the normal isoform balance suppresses invasion and metastasis (PMID:28427223). In multiple cancers EphA10 acts as a scaffold driving pro-tumorigenic signaling — increasing phosphorylation of ERK, JNK, AKT, FAK, and NF-κB and enhancing MMP-9 secretion in pancreatic cells (PMID:32644283), acting upstream of MEK/ERK and promoting PD-L1 expression in lung adenocarcinoma (PMID:35839564). EphA10 expression is post-transcriptionally controlled by RBM15B-written m6A modification read by YTHDF1, which stabilizes its mRNA and activates ERK/AKT signaling in prostate cancer (PMID:41296142). A 5′-UTR variant that upregulates EPHA10 co-segregates with autosomal dominant non-syndromic hearing loss, linking EPHA10 dosage to auditory function (PMID:36048850).

1. 2005 Medium

   Establishing EPHA10 as a receptor with ligand-binding identity answered whether this orphan-like gene was a functional Eph receptor and to which subclass it belonged.

   Evidence Molecular cloning of three isoforms and ephrin ligand-binding assays in testis-derived material

   PMID:15777695

   Open questions at the time

   • No mutagenesis or structural validation of the ligand-binding interface
   • Catalytic status not yet established at this stage
   • Functional consequence of ephrin binding not defined
2. 2016 Medium

   Identifying a physical interaction with the kinase-competent EPHA7 addressed how a catalytically defective receptor could signal, pointing to heteromeric receptor coupling.

   Evidence Reciprocal co-immunoprecipitation and confocal immunocytochemistry in breast carcinoma cells

   PMID:27566654

   Open questions at the time

   • Single-lab study without structural mapping of the interaction
   • Proposed nuclear gene-regulatory function not mechanistically defined
   • No demonstration that EPHA7 transphosphorylates or activates EphA10
3. 2017 Medium

   Dissecting isoform-specific roles answered how EphA10 controls epithelial integrity, showing secreted versus cytoplasmic isoforms oppositely regulate the E-cadherin/β-catenin complex and invasiveness.

   Evidence Isoform-specific overexpression/knockdown, Co-IP of EphA10s–ephrin-A5, E-cadherin phosphorylation Westerns, invasion assays, and an in vivo metastasis model

   PMID:28427223

   Open questions at the time

   • No structural or in vitro reconstitution of the EphA10s–ephrin-A5 complex
   • Mechanism by which the cytoplasmic isoform maintains E-cadherin phosphorylation unresolved
   • Confined to breast cancer context
4. 2020 Medium

   Defining downstream signaling answered how EphA10 promotes tumorigenesis non-catalytically, linking it to multiple kinase cascades and matrix remodeling.

   Evidence siRNA knockdown and overexpression with phospho-Westerns (ERK/JNK/AKT/FAK/NF-κB), gelatin degradation assays, and MIA PaCa-2 xenografts

   PMID:32644283

   Open questions at the time

   • Direct molecular link between EphA10 and each phosphorylated effector not established
   • Scaffolding mechanism vs indirect effect not distinguished
   • Single lineage (pancreatic cells)
5. 2021 High

   Biophysical characterization answered whether the pseudokinase domain is a viable drug target despite catalytic inactivity, revealing a flexible ATP-binding module.

   Evidence SAXS, cross-linking mass spectrometry, and direct ATP / ATP-competitive small-molecule binding assays of the intracellular region

   PMID:34431498

   Open questions at the time

   • No high-resolution crystal/cryo-EM structure
   • Functional role of ATP binding in signaling not determined
   • Interdomain interactions not linked to cellular activity
6. 2022 Medium

   Epistasis testing placed EphA10 upstream of MEK/ERK and connected it to immune evasion, clarifying its position in the signaling hierarchy.

   Evidence Lentiviral knockdown/overexpression with U0126 MEK-inhibitor epistasis, NK-cell co-culture cytotoxicity, and xenografts in lung adenocarcinoma

   PMID:35839564

   Open questions at the time

   • Mechanism linking EphA10 to PD-L1 expression undefined
   • Direct effector between EphA10 and MEK not identified
   • Single tumor type
7. 2023 Medium

   Demonstrating cochlear expression and a dosage-sensitive variant answered whether EPHA10 has a physiological role beyond cancer, implicating it in hearing.

   Evidence Mouse cochlear RT-PCR/immunostaining, Drosophila Eph overexpression chordotonal-organ assay, promoter-activity assay of a 5′-UTR variant, and family co-segregation

   PMID:36048850

   Open questions at the time

   • Mechanism connecting EPHA10 overexpression to auditory dysfunction unknown
   • Reliance on a Drosophila homolog rather than the mammalian gene for functional readout
   • Single family/study
8. 2025 Medium

   Identifying m6A regulation answered how EphA10 expression is controlled post-transcriptionally, defining an RBM15B/YTHDF1 axis that stabilizes its mRNA.

   Evidence Dot blot and MeRIP-qPCR for m6A, RBM15B/YTHDF1 knockdown, and proliferation/invasion/migration assays in prostate cancer cells

   PMID:41296142

   Open questions at the time

   • Specific m6A sites on EphA10 mRNA not mapped
   • Direct binding of YTHDF1 to EphA10 transcript not shown
   • Single lab, single study

• Whether the EphA10 pseudokinase actively transmits signal through EPHA7 heterodimers in a defined biochemical pathway, and how this couples to the diverse downstream cascades, remains unresolved.
• No reconstituted signaling complex linking EPHA7 binding to ERK/AKT/JNK/FAK/NF-κB activation
• No structure of the receptor in complex with ligand or EPHA7
• Physiological (non-cancer) signaling mechanism in testis and cochlea undefined