{"gene":"YPEL4","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2010,"finding":"YPEL4 interacts with the major vault protein (MVP) as identified by yeast two-hybrid screen and confirmed by mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, and immunocytochemistry. MVP inhibits YPEL4's ability to activate Elk-1 in the MAPK/ERK signaling pathway, as demonstrated by a reporter system.","method":"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, mammalian two-hybrid assay, immunocytochemistry, Elk-1 reporter assay","journal":"Biochemistry and cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods confirming interaction and functional consequence","pmids":["20555386"],"is_preprint":false},{"year":2016,"finding":"YPEL4 overexpression in human adrenocortical HAC15 cells stimulates cell proliferation (measured by XTT assay and crystal violet staining) and increases basal aldosterone production, indicating a pro-proliferative role in adrenal cortical cells.","method":"Overexpression in HAC15 cells, XTT assay, crystal violet staining, aldosterone measurement","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — clean overexpression with defined cellular phenotype, single lab","pmids":["27333825"],"is_preprint":false},{"year":2021,"finding":"Ypel4-null mice exhibit red blood cell membrane integrity defects including ovalocytic morphology, reduced deformability, increased RBC clearance, and reduced Band 3 protein levels in RBC membranes, demonstrating an intrinsic role for Ypel4 in maintaining normal RBC membrane structure. No direct physical interaction between YPEL4 and Band 3 was detected.","method":"Ypel4-null mouse model, scanning electron microscopy, RBC deformability assay, membrane protein analysis, in vivo clearance assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse with multiple orthogonal phenotypic readouts establishing intrinsic RBC defect","pmids":["34354145"],"is_preprint":false},{"year":2023,"finding":"YPEL4 was identified as an anticancer gene in a gain-of-function forward genetic screen in mammalian cells, where its ectopic overexpression selectively induced cell death in transformed cells.","method":"Gain-of-function forward genetic screen in mammalian cells","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 — single screen result with no mechanistic follow-up for YPEL4 specifically","pmids":["37864183"],"is_preprint":false}],"current_model":"YPEL4 is a nuclear, Yippee-domain (zinc-finger-like) protein that promotes ERK/MAPK signaling (Elk-1 activation) in a manner inhibited by its binding partner MVP, stimulates adrenal cortical cell proliferation and aldosterone production, and is required for red blood cell membrane integrity, with loss of Ypel4 causing ovalocytosis, reduced deformability, and decreased Band 3 levels in mouse RBCs."},"narrative":{"teleology":[{"year":2010,"claim":"The discovery that YPEL4 physically interacts with MVP and that MVP suppresses YPEL4-mediated Elk-1 activation established YPEL4 as a signaling-active protein regulated by vault-associated mechanisms, placing it within the MAPK/ERK pathway.","evidence":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, mammalian two-hybrid, and Elk-1 reporter assays in mammalian cells","pmids":["20555386"],"confidence":"High","gaps":["Whether YPEL4 directly activates upstream kinases or acts at the level of Elk-1 itself is unknown","The structural basis of the YPEL4–MVP interaction has not been resolved","Whether endogenous MVP regulation of YPEL4 occurs in physiological contexts is untested"]},{"year":2016,"claim":"Demonstrating that YPEL4 overexpression promotes adrenocortical cell proliferation and aldosterone secretion linked its signaling activity to a specific endocrine cellular context.","evidence":"Overexpression in HAC15 adrenocortical cells with XTT assay, crystal violet staining, and aldosterone measurement","pmids":["27333825"],"confidence":"Medium","gaps":["Loss-of-function experiments in adrenal cells have not been performed","Whether the proliferative effect depends on the MAPK/ERK–Elk-1 axis identified earlier is untested","The mechanism by which YPEL4 enhances aldosterone production is unknown"]},{"year":2021,"claim":"Knockout mouse studies revealed an unanticipated, cell-intrinsic requirement for YPEL4 in erythrocyte membrane integrity, showing that its loss causes ovalocytosis, reduced deformability, and diminished Band 3 levels — broadening its known biology beyond signaling.","evidence":"Ypel4-null mouse model analyzed by scanning electron microscopy, RBC deformability assays, membrane protein quantification, and in vivo clearance assays","pmids":["34354145"],"confidence":"High","gaps":["No direct physical interaction between YPEL4 and Band 3 was detected; the mechanism by which YPEL4 maintains Band 3 levels is unknown","Whether YPEL4 acts during erythropoiesis or in mature RBCs has not been determined","Human genetic evidence linking YPEL4 mutations to hereditary ovalocytosis is lacking"]},{"year":null,"claim":"How YPEL4's Yippee/zinc-finger-like domain contributes to its molecular activity — whether enzymatic, scaffolding, or otherwise — remains unresolved, and the relationship between its MAPK signaling role and its erythrocyte membrane function is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic activity or substrate has been identified for YPEL4","No structural model of YPEL4 exists","The connection between MAPK/ERK signaling activity and RBC membrane maintenance has not been investigated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["MVP"],"other_free_text":[]},"mechanistic_narrative":"YPEL4 is a Yippee-domain protein that functions in ERK/MAPK signaling, cell proliferation, and red blood cell membrane integrity. It activates Elk-1 in the MAPK/ERK pathway, an activity inhibited by its physical interaction with the major vault protein (MVP), as demonstrated by multiple orthogonal biochemical assays [PMID:20555386]. Overexpression of YPEL4 in adrenocortical cells stimulates proliferation and basal aldosterone production [PMID:27333825]. Loss of Ypel4 in mice causes ovalocytic red blood cell morphology, reduced deformability, increased RBC clearance, and decreased Band 3 membrane protein levels, establishing an intrinsic role in maintaining erythrocyte membrane structure [PMID:34354145]."},"prefetch_data":{"uniprot":{"accession":"Q96NS1","full_name":"Protein yippee-like 4","aliases":[],"length_aa":127,"mass_kda":14.3,"function":"","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q96NS1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YPEL4","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/YPEL4","total_profiled":1310},"omim":[{"mim_id":"609726","title":"YIPPEE-LIKE 5; YPEL5","url":"https://www.omim.org/entry/609726"},{"mim_id":"609725","title":"YIPPEE-LIKE 4; YPEL4","url":"https://www.omim.org/entry/609725"},{"mim_id":"609724","title":"YIPPEE-LIKE 3; YPEL3","url":"https://www.omim.org/entry/609724"},{"mim_id":"609723","title":"YIPPEE-LIKE 2; YPEL2","url":"https://www.omim.org/entry/609723"},{"mim_id":"608082","title":"YIPPEE-LIKE 1; YPEL1","url":"https://www.omim.org/entry/608082"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":38.8}],"url":"https://www.proteinatlas.org/search/YPEL4"},"hgnc":{"alias_symbol":["FLJ30213"],"prev_symbol":[]},"alphafold":{"accession":"Q96NS1","domains":[{"cath_id":"-","chopping":"45-122","consensus_level":"high","plddt":96.8827,"start":45,"end":122}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NS1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NS1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NS1-F1-predicted_aligned_error_v6.png","plddt_mean":86.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YPEL4","jax_strain_url":"https://www.jax.org/strain/search?query=YPEL4"},"sequence":{"accession":"Q96NS1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96NS1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96NS1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NS1"}},"corpus_meta":[{"pmid":"20555386","id":"PMC_20555386","title":"MVP interacts with YPEL4 and inhibits YPEL4-mediated activities of the ERK signal pathway.","date":"2010","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/20555386","citation_count":33,"is_preprint":false},{"pmid":"34668383","id":"PMC_34668383","title":"Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke.","date":"2021","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/34668383","citation_count":19,"is_preprint":false},{"pmid":"29892964","id":"PMC_29892964","title":"Potential important roles and signaling mechanisms of YPEL4 in pulmonary diseases.","date":"2018","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29892964","citation_count":11,"is_preprint":false},{"pmid":"27333825","id":"PMC_27333825","title":"YPEL4 modulates HAC15 adrenal cell proliferation and is associated with tumor diameter.","date":"2016","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27333825","citation_count":9,"is_preprint":false},{"pmid":"34354145","id":"PMC_34354145","title":"Yippee like 4 (Ypel4) is essential for normal mouse red blood cell membrane integrity.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34354145","citation_count":9,"is_preprint":false},{"pmid":"39333211","id":"PMC_39333211","title":"Identification of common biomarkers in diabetic kidney disease and cognitive dysfunction using machine learning algorithms.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39333211","citation_count":4,"is_preprint":false},{"pmid":"38432499","id":"PMC_38432499","title":"Differential mRNA profiles reveal the potential roles of genes involved in lactate stimulation in mouse macrophages.","date":"2024","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38432499","citation_count":2,"is_preprint":false},{"pmid":"39858200","id":"PMC_39858200","title":"Investigation of the Molecular Mechanism of Asthma in Meishan Pigs Using Multi-Omics Analysis.","date":"2025","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/39858200","citation_count":2,"is_preprint":false},{"pmid":"37864183","id":"PMC_37864183","title":"Genetic screening for anticancer genes highlights FBLN5 as a synthetic lethal partner of MYC.","date":"2023","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/37864183","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5788,"output_tokens":953,"usd":0.015829},"stage2":{"model":"claude-opus-4-6","input_tokens":4153,"output_tokens":1233,"usd":0.077385},"total_usd":0.093214,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"YPEL4 interacts with the major vault protein (MVP) as identified by yeast two-hybrid screen and confirmed by mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, and immunocytochemistry. MVP inhibits YPEL4's ability to activate Elk-1 in the MAPK/ERK signaling pathway, as demonstrated by a reporter system.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, mammalian two-hybrid assay, immunocytochemistry, Elk-1 reporter assay\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods confirming interaction and functional consequence\",\n      \"pmids\": [\"20555386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YPEL4 overexpression in human adrenocortical HAC15 cells stimulates cell proliferation (measured by XTT assay and crystal violet staining) and increases basal aldosterone production, indicating a pro-proliferative role in adrenal cortical cells.\",\n      \"method\": \"Overexpression in HAC15 cells, XTT assay, crystal violet staining, aldosterone measurement\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean overexpression with defined cellular phenotype, single lab\",\n      \"pmids\": [\"27333825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ypel4-null mice exhibit red blood cell membrane integrity defects including ovalocytic morphology, reduced deformability, increased RBC clearance, and reduced Band 3 protein levels in RBC membranes, demonstrating an intrinsic role for Ypel4 in maintaining normal RBC membrane structure. No direct physical interaction between YPEL4 and Band 3 was detected.\",\n      \"method\": \"Ypel4-null mouse model, scanning electron microscopy, RBC deformability assay, membrane protein analysis, in vivo clearance assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse with multiple orthogonal phenotypic readouts establishing intrinsic RBC defect\",\n      \"pmids\": [\"34354145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YPEL4 was identified as an anticancer gene in a gain-of-function forward genetic screen in mammalian cells, where its ectopic overexpression selectively induced cell death in transformed cells.\",\n      \"method\": \"Gain-of-function forward genetic screen in mammalian cells\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single screen result with no mechanistic follow-up for YPEL4 specifically\",\n      \"pmids\": [\"37864183\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YPEL4 is a nuclear, Yippee-domain (zinc-finger-like) protein that promotes ERK/MAPK signaling (Elk-1 activation) in a manner inhibited by its binding partner MVP, stimulates adrenal cortical cell proliferation and aldosterone production, and is required for red blood cell membrane integrity, with loss of Ypel4 causing ovalocytosis, reduced deformability, and decreased Band 3 levels in mouse RBCs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YPEL4 is a Yippee-domain protein that functions in ERK/MAPK signaling, cell proliferation, and red blood cell membrane integrity. It activates Elk-1 in the MAPK/ERK pathway, an activity inhibited by its physical interaction with the major vault protein (MVP), as demonstrated by multiple orthogonal biochemical assays [PMID:20555386]. Overexpression of YPEL4 in adrenocortical cells stimulates proliferation and basal aldosterone production [PMID:27333825]. Loss of Ypel4 in mice causes ovalocytic red blood cell morphology, reduced deformability, increased RBC clearance, and decreased Band 3 membrane protein levels, establishing an intrinsic role in maintaining erythrocyte membrane structure [PMID:34354145].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"The discovery that YPEL4 physically interacts with MVP and that MVP suppresses YPEL4-mediated Elk-1 activation established YPEL4 as a signaling-active protein regulated by vault-associated mechanisms, placing it within the MAPK/ERK pathway.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, mammalian two-hybrid, and Elk-1 reporter assays in mammalian cells\",\n      \"pmids\": [\"20555386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether YPEL4 directly activates upstream kinases or acts at the level of Elk-1 itself is unknown\",\n        \"The structural basis of the YPEL4–MVP interaction has not been resolved\",\n        \"Whether endogenous MVP regulation of YPEL4 occurs in physiological contexts is untested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that YPEL4 overexpression promotes adrenocortical cell proliferation and aldosterone secretion linked its signaling activity to a specific endocrine cellular context.\",\n      \"evidence\": \"Overexpression in HAC15 adrenocortical cells with XTT assay, crystal violet staining, and aldosterone measurement\",\n      \"pmids\": [\"27333825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Loss-of-function experiments in adrenal cells have not been performed\",\n        \"Whether the proliferative effect depends on the MAPK/ERK–Elk-1 axis identified earlier is untested\",\n        \"The mechanism by which YPEL4 enhances aldosterone production is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Knockout mouse studies revealed an unanticipated, cell-intrinsic requirement for YPEL4 in erythrocyte membrane integrity, showing that its loss causes ovalocytosis, reduced deformability, and diminished Band 3 levels — broadening its known biology beyond signaling.\",\n      \"evidence\": \"Ypel4-null mouse model analyzed by scanning electron microscopy, RBC deformability assays, membrane protein quantification, and in vivo clearance assays\",\n      \"pmids\": [\"34354145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct physical interaction between YPEL4 and Band 3 was detected; the mechanism by which YPEL4 maintains Band 3 levels is unknown\",\n        \"Whether YPEL4 acts during erythropoiesis or in mature RBCs has not been determined\",\n        \"Human genetic evidence linking YPEL4 mutations to hereditary ovalocytosis is lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How YPEL4's Yippee/zinc-finger-like domain contributes to its molecular activity — whether enzymatic, scaffolding, or otherwise — remains unresolved, and the relationship between its MAPK signaling role and its erythrocyte membrane function is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No enzymatic activity or substrate has been identified for YPEL4\",\n        \"No structural model of YPEL4 exists\",\n        \"The connection between MAPK/ERK signaling activity and RBC membrane maintenance has not been investigated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MVP\"],\n    \"other_free_text\": []\n  }\n}\n```"}