EPHA6

EPHA6 is an Eph-family receptor tyrosine kinase that mediates repellent ephrin-A signaling to pattern neural and vascular tissue and that is co-opted in cancer progression (PMID:20011078, PMID:26041887). During development its transcription is set by dedicated regulators: HOXA13 binds conserved cis-elements in the EphA6 promoter and activates its expression in genital tubercle vascular endothelium (PMID:17304517), dimerized HMX1 represses EPHA6 to control retinal development (PMID:24945320), and Mef2c downregulates EphA6 postnatally in layer 2/3 callosal projection neurons so that axons are desensitized to EphrinA5-mediated repulsion and target the contralateral cortex correctly. Consistent with a role in neuronal architecture, combined deletion of EphA6 and EphA5 disrupts dendritic spine morphology (PMID:27489614). In prostate cancer, full-length EphA6 promotes invasion, metastasis, and angiogenesis, acting upstream of a PIK3IPA/AKT1/EIF5A2 pathway (PMID:26041887), while NONO/p54nrb-driven aberrant splicing produces a truncated EPHA6-001 variant that sustains proliferation and invasion under androgen deprivation (PMID:29535823). The catalytic and signaling biochemistry of the EphA6 kinase itself, and its ephrin-binding interface, have not been characterized in the available corpus beyond expression-level ligand assignment.

1. 2007 High

   Established a direct transcriptional input to EphA6, answering how the receptor is positioned in developing vasculature rather than what it signals.

   Evidence In vivo ChIP from genital tubercle, promoter-reporter assays, and expression analysis in Hoxa13 mutant mice

   PMID:17304517

   Open questions at the time

   • Does not address EphA6 downstream signaling or kinase output
   • Restricted to genital tubercle endothelium
2. 2009 Low

   Identified ephrin-A1 and ephrin-A4 as candidate EphA6 ligands and proposed repellent signaling in retinal patterning, framing EphA6 within axon guidance and vascular patterning.

   Evidence RT-PCR, in situ hybridization, and immunohistochemistry on fetal macaque retina

   PMID:20011078

   Open questions at the time

   • Localization and ligand assignment by expression correlation only, no functional perturbation
   • No biochemical demonstration of receptor-ligand binding
   • Repellent signaling role inferred, not tested
3. 2014 Medium

   Showed that HMX1 must dimerize to enter the nucleus and repress EPHA6, defining a repressive transcriptional control distinct from HOXA13 activation.

   Evidence Co-IP with domain-deletion mutants, nuclear localization assays, and reporter/expression assays in mouse and zebrafish retina

   PMID:24945320

   Open questions at the time

   • Does not establish direct HMX1 binding at the EPHA6 promoter
   • Functional consequence of EPHA6 repression for retinal cells not resolved
4. 2015 Medium

   Placed full-length EphA6 as a driver of prostate cancer invasion, metastasis, and angiogenesis upstream of a defined gene-expression pathway, extending EphA6 beyond development into oncogenesis.

   Evidence RNAi knockdown in a spontaneous metastasis mouse model with invasion and tube-formation assays and genome-wide expression profiling

   PMID:26041887

   Open questions at the time

   • PIK3IPA/AKT1/EIF5A2 link is correlative from expression analysis, not mechanistically reconstituted
   • Whether kinase activity is required is untested
5. 2016 Medium

   Demonstrated a structural role for EphA6 in neuronal architecture via spine morphology, linking the receptor to dendritic organization.

   Evidence EphA5/EphA6 double knockout with Golgi staining and morphological analysis of brain sections

   PMID:27489614

   Open questions at the time

   • EphA5 and EphA6 deleted together, so EphA6-specific contribution is unresolved
   • No molecular mechanism for spine regulation
6. 2018 Medium

   Revealed that aberrant splicing produces a truncated EPHA6-001 variant driving castration-resistant growth, distinguishing the oncogenic splice isoform from full-length receptor function.

   Evidence RNA-seq and siRNA knockdown of NONO with in vitro proliferation/invasion assays and xenografts in castrated mice

   PMID:29535823

   Open questions at the time

   • Signaling output of the truncated EPHA6-001 protein not defined
   • Direct NONO action on EPHA6 pre-mRNA not shown biochemically
7. 2022 Low

   Mapped the EphA6 intracellular residues engaging Odin, addressing how the receptor couples to a regulator of EphA endocytosis and degradation.

   Evidence Molecular dynamics, steered MD, umbrella sampling, and binding free-energy calculation validated against an experimental affinity value

   PMID:35732074

   Open questions at the time

   • Computational prediction without mutagenesis or in-cell verification of the key residues
   • Functional consequence of the EphA6-Odin complex for receptor trafficking not directly tested
8. 2025 Medium

   Identified Mef2c as a postnatal repressor of EphA6 that tunes axonal sensitivity to EphrinA5, explaining how callosal neurons achieve correct contralateral targeting.

   Evidence Conditional Mef2c knockout in L2/3 neurons with EphA-EphrinA epistasis rescue and axon targeting assays in postnatal mouse cortex (preprint)

   Open questions at the time

   • Preprint, single lab
   • Whether Mef2c regulates EphA6 directly or indirectly is not established

• The intrinsic kinase activity, autophosphorylation, and direct ephrin-binding biochemistry of EphA6 remain uncharacterized, leaving the signal-transduction step between ligand engagement and downstream pathways undefined.
• No demonstration of EphA6 tyrosine kinase activity or substrates
• No structural model of the ephrin-binding interface
• Downstream effectors linking receptor to AKT1 axis not mechanistically connected