{"gene":"EPHA1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"EphA1 activation (via ephrin-A1 stimulation) inhibits cell spreading and migration in a RhoA-ROCK-dependent manner. EphA1 interacts with integrin-linked kinase (ILK) through its C-terminal SAM domain (EphA1) and the ankyrin region of ILK; this interaction is independent of EphA1 kinase activity but dependent on ephrin-A1 stimulation. Kinase-active EphA1 reduces ILK activity, and expression of a kinase-active ILK mutant (S343D) rescues EphA1-mediated spreading defects and attenuates RhoA activation, placing EphA1 upstream of ILK-RhoA-ROCK in regulating cell morphology and motility.","method":"Co-immunoprecipitation, domain-deletion mapping, ILK activity assay, RhoA activation assay, rescue experiments with ILK S343D mutant, cell spreading/migration assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, multiple orthogonal functional assays (ILK activity, RhoA activation, morphology rescue), single lab but several converging methods","pmids":["19118217"],"is_preprint":false},{"year":2001,"finding":"Murine EphA1 preferentially binds ephrin-A1 (as does the human homologue) but also shows significant binding to other A-type ephrin ligands, consistent with class-promiscuous EphA subclass binding. mEphA1 mRNA is expressed in differentiated epithelial tissues including skin, adult thymus, kidney, and adrenal cortex.","method":"Binding assays with soluble recombinant and native mEphA1, in situ hybridization on tissue sections, chromosomal localization, genomic organization analysis","journal":"Growth factors (Chur, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus localization by in situ hybridization, single lab, two complementary methods","pmids":["11519828"],"is_preprint":false}],"current_model":"EphA1 is a receptor tyrosine kinase that, upon ephrin-A1-induced activation, inhibits cell spreading and migration by suppressing integrin-linked kinase (ILK) activity and activating the RhoA-ROCK pathway; its C-terminal SAM domain physically associates with the ankyrin region of ILK in a kinase-independent but ligand-dependent manner, placing EphA1 at the head of an ILK→RhoA→ROCK signaling axis that controls cell morphology and motility, while its ligand-binding specificity is directed preferentially toward ephrin-A class ligands and its expression is enriched in differentiated epithelial tissues."},"narrative":{"mechanistic_narrative":"EPHA1 is an ephrin-A-class receptor tyrosine kinase that controls cell morphology and motility, acting as a negative regulator of cell spreading and migration upon ligand engagement [PMID:19118217]. Ligand-binding studies establish that EPHA1 preferentially binds ephrin-A1 while retaining class-promiscuous binding to other A-type ephrin ligands, and that its expression is enriched in differentiated epithelial tissues including skin, thymus, kidney, and adrenal cortex [PMID:11519828]. Mechanistically, ephrin-A1 stimulation drives EPHA1 to associate, via its C-terminal SAM domain, with the ankyrin region of integrin-linked kinase (ILK); this interaction is independent of EPHA1 kinase activity but requires ligand stimulation [PMID:19118217]. Kinase-active EPHA1 suppresses ILK activity, and a constitutively active ILK mutant (S343D) rescues EPHA1-mediated spreading defects and attenuates RhoA activation, placing EPHA1 at the head of an ILK→RhoA→ROCK signaling axis that inhibits cell spreading and migration [PMID:19118217]. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2001,"claim":"Defining the ligand specificity and tissue distribution of EPHA1 established it as an ephrin-A-class receptor expressed in differentiated epithelia, framing where its signaling is likely relevant.","evidence":"Soluble and native receptor binding assays, in situ hybridization on tissue sections, and genomic/chromosomal analysis of murine EphA1","pmids":["11519828"],"confidence":"Medium","gaps":["Binding promiscuity across the full ephrin-A panel quantified only for murine receptor","Functional consequence of receptor expression in each tissue not addressed","No downstream signaling characterized in this study"]},{"year":2009,"claim":"Linking EPHA1 to ILK answered how the receptor controls cell shape and motility, showing it acts through a kinase-independent SAM-domain interaction that suppresses ILK and engages RhoA-ROCK.","evidence":"Co-immunoprecipitation with domain-deletion mapping, ILK activity and RhoA activation assays, and rescue with the kinase-active ILK S343D mutant in cell spreading/migration assays","pmids":["19118217"],"confidence":"High","gaps":["How kinase-active EPHA1 reduces ILK activity at the molecular level is not resolved","The downstream RhoA-ROCK effectors mediating spreading inhibition are not delineated","Findings derive from a single lab and defined cell systems"]},{"year":null,"claim":"The phosphorylation substrates of EPHA1 and the physiological contexts in which the ILK-RhoA-ROCK axis operates in vivo remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct kinase substrates identified","No structural model of the EPHA1 SAM–ILK ankyrin interaction","Physiological/developmental role in epithelial tissues not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["ILK","EFNA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21709","full_name":"Ephrin type-A receptor 1","aliases":["EPH tyrosine kinase","EPH tyrosine kinase 1","Erythropoietin-producing hepatoma receptor","Tyrosine-protein kinase receptor EPH"],"length_aa":976,"mass_kda":108.1,"function":"Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Binds with a low affinity EFNA3 and EFNA4 and with a high affinity to EFNA1 which most probably constitutes its cognate/functional ligand. Upon activation by EFNA1 induces cell attachment to the extracellular matrix inhibiting cell spreading and motility through regulation of ILK and downstream RHOA and RAC. Also plays a role in angiogenesis and regulates cell proliferation. May play a role in apoptosis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P21709/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPHA1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EPHA1","total_profiled":1310},"omim":[{"mim_id":"608907","title":"ALZHEIMER DISEASE 9, SUSCEPTIBILITY TO; AD9","url":"https://www.omim.org/entry/608907"},{"mim_id":"606242","title":"KONDOH SYNDROME","url":"https://www.omim.org/entry/606242"},{"mim_id":"605991","title":"NEURONAL GUANINE NUCLEOTIDE EXCHANGE FACTOR; NGEF","url":"https://www.omim.org/entry/605991"},{"mim_id":"605414","title":"ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 7; ABCA7","url":"https://www.omim.org/entry/605414"},{"mim_id":"601185","title":"STANNIOCALCIN 1; STC1","url":"https://www.omim.org/entry/601185"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":55.7},{"tissue":"parathyroid gland","ntpm":194.2}],"url":"https://www.proteinatlas.org/search/EPHA1"},"hgnc":{"alias_symbol":["EPH"],"prev_symbol":["EPHT","EPHT1"]},"alphafold":{"accession":"P21709","domains":[{"cath_id":"2.60.120.260","chopping":"27-204","consensus_level":"high","plddt":82.633,"start":27,"end":204},{"cath_id":"2.60.40.1770","chopping":"208-265","consensus_level":"medium","plddt":87.0466,"start":208,"end":265},{"cath_id":"2.60.40.10","chopping":"337-443","consensus_level":"medium","plddt":85.2118,"start":337,"end":443},{"cath_id":"2.60.40.10","chopping":"454-535","consensus_level":"high","plddt":80.4129,"start":454,"end":535},{"cath_id":"3.30.200.20","chopping":"603-685","consensus_level":"high","plddt":81.788,"start":603,"end":685},{"cath_id":"1.10.510.10","chopping":"709-885","consensus_level":"high","plddt":85.6883,"start":709,"end":885},{"cath_id":"1.10.150.50","chopping":"907-976","consensus_level":"high","plddt":73.8376,"start":907,"end":976}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21709","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21709-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21709-F1-predicted_aligned_error_v6.png","plddt_mean":80.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPHA1","jax_strain_url":"https://www.jax.org/strain/search?query=EPHA1"},"sequence":{"accession":"P21709","fasta_url":"https://rest.uniprot.org/uniprotkb/P21709.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21709/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21709"}},"corpus_meta":[{"pmid":"21460840","id":"PMC_21460840","title":"Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21460840","citation_count":1635,"is_preprint":false},{"pmid":"18394988","id":"PMC_18394988","title":"Eph-ephrin bidirectional signaling in physiology and disease.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18394988","citation_count":1062,"is_preprint":false},{"pmid":"20179713","id":"PMC_20179713","title":"Eph receptors and ephrins in cancer: bidirectional signalling and beyond.","date":"2010","source":"Nature reviews. 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and migration in a RhoA-ROCK-dependent manner. EphA1 interacts with integrin-linked kinase (ILK) through its C-terminal SAM domain (EphA1) and the ankyrin region of ILK; this interaction is independent of EphA1 kinase activity but dependent on ephrin-A1 stimulation. Kinase-active EphA1 reduces ILK activity, and expression of a kinase-active ILK mutant (S343D) rescues EphA1-mediated spreading defects and attenuates RhoA activation, placing EphA1 upstream of ILK-RhoA-ROCK in regulating cell morphology and motility.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mapping, ILK activity assay, RhoA activation assay, rescue experiments with ILK S343D mutant, cell spreading/migration assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, multiple orthogonal functional assays (ILK activity, RhoA activation, morphology rescue), single lab but several converging methods\",\n      \"pmids\": [\"19118217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Murine EphA1 preferentially binds ephrin-A1 (as does the human homologue) but also shows significant binding to other A-type ephrin ligands, consistent with class-promiscuous EphA subclass binding. mEphA1 mRNA is expressed in differentiated epithelial tissues including skin, adult thymus, kidney, and adrenal cortex.\",\n      \"method\": \"Binding assays with soluble recombinant and native mEphA1, in situ hybridization on tissue sections, chromosomal localization, genomic organization analysis\",\n      \"journal\": \"Growth factors (Chur, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus localization by in situ hybridization, single lab, two complementary methods\",\n      \"pmids\": [\"11519828\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EphA1 is a receptor tyrosine kinase that, upon ephrin-A1-induced activation, inhibits cell spreading and migration by suppressing integrin-linked kinase (ILK) activity and activating the RhoA-ROCK pathway; its C-terminal SAM domain physically associates with the ankyrin region of ILK in a kinase-independent but ligand-dependent manner, placing EphA1 at the head of an ILK→RhoA→ROCK signaling axis that controls cell morphology and motility, while its ligand-binding specificity is directed preferentially toward ephrin-A class ligands and its expression is enriched in differentiated epithelial tissues.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPHA1 is an ephrin-A-class receptor tyrosine kinase that controls cell morphology and motility, acting as a negative regulator of cell spreading and migration upon ligand engagement [#0]. Ligand-binding studies establish that EPHA1 preferentially binds ephrin-A1 while retaining class-promiscuous binding to other A-type ephrin ligands, and that its expression is enriched in differentiated epithelial tissues including skin, thymus, kidney, and adrenal cortex [#1]. Mechanistically, ephrin-A1 stimulation drives EPHA1 to associate, via its C-terminal SAM domain, with the ankyrin region of integrin-linked kinase (ILK); this interaction is independent of EPHA1 kinase activity but requires ligand stimulation [#0]. Kinase-active EPHA1 suppresses ILK activity, and a constitutively active ILK mutant (S343D) rescues EPHA1-mediated spreading defects and attenuates RhoA activation, placing EPHA1 at the head of an ILK\\u2192RhoA\\u2192ROCK signaling axis that inhibits cell spreading and migration [#0]. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining the ligand specificity and tissue distribution of EPHA1 established it as an ephrin-A-class receptor expressed in differentiated epithelia, framing where its signaling is likely relevant.\",\n      \"evidence\": \"Soluble and native receptor binding assays, in situ hybridization on tissue sections, and genomic/chromosomal analysis of murine EphA1\",\n      \"pmids\": [\n        \"11519828\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding promiscuity across the full ephrin-A panel quantified only for murine receptor\",\n        \"Functional consequence of receptor expression in each tissue not addressed\",\n        \"No downstream signaling characterized in this study\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking EPHA1 to ILK answered how the receptor controls cell shape and motility, showing it acts through a kinase-independent SAM-domain interaction that suppresses ILK and engages RhoA-ROCK.\",\n      \"evidence\": \"Co-immunoprecipitation with domain-deletion mapping, ILK activity and RhoA activation assays, and rescue with the kinase-active ILK S343D mutant in cell spreading/migration assays\",\n      \"pmids\": [\n        \"19118217\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How kinase-active EPHA1 reduces ILK activity at the molecular level is not resolved\",\n        \"The downstream RhoA-ROCK effectors mediating spreading inhibition are not delineated\",\n        \"Findings derive from a single lab and defined cell systems\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The phosphorylation substrates of EPHA1 and the physiological contexts in which the ILK-RhoA-ROCK axis operates in vivo remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct kinase substrates identified\",\n        \"No structural model of the EPHA1 SAM\\u2013ILK ankyrin interaction\",\n        \"Physiological/developmental role in epithelial tissues not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ILK\",\n      \"EFNA1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}