{"gene":"YPEL4","run_date":"2026-06-11T09:02:06","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 the transcription factor Elk-1 in the MAPK/ERK signaling pathway, as demonstrated by a reporter system.","method":"Yeast two-hybrid screen, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, immunocytochemistry, reporter assay","journal":"Biochemistry and cell biology = Biochimie et biologie cellulaire","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (GST pull-down, Co-IP, reporter assay) from a single lab confirming interaction and functional consequence","pmids":["20555386"],"is_preprint":false},{"year":2016,"finding":"Overexpression of YPEL4 in human adrenocortical HAC15 cells stimulates cell proliferation (measured by XTT assay and crystal violet staining) and increases basal aldosterone production, establishing a direct role for YPEL4 in adrenal cortical cell proliferation.","method":"Overexpression in HAC15 cells, XTT proliferation assay, crystal violet staining, aldosterone measurement","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two orthogonal cell-based readouts (XTT + crystal violet) in a single lab; no mechanistic pathway placement beyond association with proliferation","pmids":["27333825"],"is_preprint":false},{"year":2021,"finding":"Ypel4-null mice display secondary polycythemia with macro- and reticulocytosis, and Ypel4-null red blood cells (RBCs) show increased clearance from circulation, reduced deformability, ovalocytic morphology, and reduced Band 3 protein levels in RBC membranes, establishing an intrinsic role for Ypel4 in maintaining normal red cell membrane integrity. Physical interaction between YPEL4 and Band 3 protein was NOT supported by experimental evidence.","method":"Ypel4-null mouse model, scanning electron microscopy, RBC deformability assay, membrane protein analysis, in vivo clearance assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with multiple orthogonal phenotypic readouts (morphology, deformability, clearance, membrane proteomics) from a single study","pmids":["34354145"],"is_preprint":false},{"year":2023,"finding":"In a gain-of-function forward genetic screen, YPEL4 was identified as one of 16 anticancer genes whose overexpression induces cell death selectively in transformed mammalian cells.","method":"Gain-of-function forward genetic screen in mammalian cells (overexpression, cell death assay)","journal":"Cell communication and signaling : CCS","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single screen identifying YPEL4 as a hit; no mechanistic follow-up specifically for YPEL4; single lab, single method","pmids":["37864183"],"is_preprint":false}],"current_model":"YPEL4 is a nuclear, centrosome-associated zinc-finger-like (Yippee domain) protein that activates the MAPK/ERK transcription factor Elk-1, an activity suppressed by its binding partner MVP (Major Vault Protein); it promotes adrenal cortical cell proliferation and aldosterone production when overexpressed, and is required in vivo for normal red blood cell membrane integrity and deformability, as Ypel4-null RBCs display reduced deformability, ovalocytic morphology, and decreased Band 3 protein levels."},"narrative":{"mechanistic_narrative":"YPEL4 is a Yippee-domain protein that functions in MAPK/ERK signaling and contributes to cell proliferation and red cell membrane integrity. It binds the Major Vault Protein (MVP) and activates the transcription factor Elk-1, an activity that MVP suppresses upon binding [PMID:20555386]. Consistent with a pro-proliferative role, overexpression of YPEL4 in adrenocortical HAC15 cells stimulates proliferation and increases basal aldosterone production [PMID:27333825]. In vivo, YPEL4 is required for normal erythrocyte biology: Ypel4-null mice develop secondary polycythemia with reticulocytosis, and their red blood cells show reduced deformability, ovalocytic morphology, reduced membrane Band 3 levels, and increased clearance from circulation, establishing an intrinsic role in red cell membrane integrity that does not depend on a direct YPEL4–Band 3 interaction [PMID:34354145]. Beyond these findings, the molecular mechanism linking YPEL4 to its cellular phenotypes has not been characterized in the available corpus.","teleology":[{"year":2010,"claim":"Established the first molecular partner and signaling readout for YPEL4 by showing it activates Elk-1 in the MAPK/ERK pathway and that this is gated by MVP binding.","evidence":"Yeast and mammalian two-hybrid, GST pull-down, co-immunoprecipitation, immunocytochemistry and Elk-1 reporter assay","pmids":["20555386"],"confidence":"Medium","gaps":["Mechanism by which YPEL4 activates Elk-1 (direct vs indirect) not resolved","How MVP binding physically blocks the activity is unknown","No endogenous-level validation of the interaction or pathway"]},{"year":2016,"claim":"Linked YPEL4 to a concrete cellular phenotype by showing its overexpression drives adrenocortical proliferation and aldosterone output.","evidence":"Overexpression in HAC15 cells with XTT, crystal violet, and aldosterone measurement","pmids":["27333825"],"confidence":"Medium","gaps":["No pathway placement connecting proliferation to the Elk-1/MVP axis","Loss-of-function in this system not tested","Mechanism of aldosterone induction unknown"]},{"year":2021,"claim":"Demonstrated an essential in vivo role for YPEL4 in red blood cell membrane integrity through a knockout mouse.","evidence":"Ypel4-null mouse with scanning electron microscopy, deformability assays, in vivo clearance, and membrane protein analysis","pmids":["34354145"],"confidence":"Medium","gaps":["Molecular mechanism linking YPEL4 loss to reduced Band 3 not defined","Direct YPEL4–Band 3 interaction explicitly not supported","Relationship to the Elk-1/MVP/proliferation role not established"]},{"year":2023,"claim":"Identified YPEL4 overexpression as selectively cytotoxic to transformed cells, hinting at a context-dependent pro-death activity.","evidence":"Gain-of-function forward genetic screen with cell death readout in mammalian cells","pmids":["37864183"],"confidence":"Low","gaps":["Single screen with no YPEL4-specific mechanistic follow-up","Pathway mediating selective death in transformed cells unknown","Apparent contradiction with pro-proliferative role unresolved"]},{"year":null,"claim":"The unifying molecular mechanism connecting YPEL4's Elk-1 activation, proliferative effects, and erythrocyte membrane role remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical basis for YPEL4 activity","No direct substrate or downstream effector identified","Mechanism controlling Band 3 levels in RBC membranes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["MVP"],"other_free_text":[]}},"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":6,"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":6549,"output_tokens":1111,"usd":0.018156,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7677,"output_tokens":1636,"usd":0.039642,"stage2_stop_reason":"end_turn"},"total_usd":0.057798,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","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 the transcription factor Elk-1 in the MAPK/ERK signaling pathway, as demonstrated by a reporter system.\",\n      \"method\": \"Yeast two-hybrid screen, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, immunocytochemistry, reporter assay\",\n      \"journal\": \"Biochemistry and cell biology = Biochimie et biologie cellulaire\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (GST pull-down, Co-IP, reporter assay) from a single lab confirming interaction and functional consequence\",\n      \"pmids\": [\"20555386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Overexpression of YPEL4 in human adrenocortical HAC15 cells stimulates cell proliferation (measured by XTT assay and crystal violet staining) and increases basal aldosterone production, establishing a direct role for YPEL4 in adrenal cortical cell proliferation.\",\n      \"method\": \"Overexpression in HAC15 cells, XTT proliferation assay, crystal violet staining, aldosterone measurement\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two orthogonal cell-based readouts (XTT + crystal violet) in a single lab; no mechanistic pathway placement beyond association with proliferation\",\n      \"pmids\": [\"27333825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ypel4-null mice display secondary polycythemia with macro- and reticulocytosis, and Ypel4-null red blood cells (RBCs) show increased clearance from circulation, reduced deformability, ovalocytic morphology, and reduced Band 3 protein levels in RBC membranes, establishing an intrinsic role for Ypel4 in maintaining normal red cell membrane integrity. Physical interaction between YPEL4 and Band 3 protein was NOT supported by experimental evidence.\",\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\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with multiple orthogonal phenotypic readouts (morphology, deformability, clearance, membrane proteomics) from a single study\",\n      \"pmids\": [\"34354145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In a gain-of-function forward genetic screen, YPEL4 was identified as one of 16 anticancer genes whose overexpression induces cell death selectively in transformed mammalian cells.\",\n      \"method\": \"Gain-of-function forward genetic screen in mammalian cells (overexpression, cell death assay)\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single screen identifying YPEL4 as a hit; no mechanistic follow-up specifically for YPEL4; single lab, single method\",\n      \"pmids\": [\"37864183\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YPEL4 is a nuclear, centrosome-associated zinc-finger-like (Yippee domain) protein that activates the MAPK/ERK transcription factor Elk-1, an activity suppressed by its binding partner MVP (Major Vault Protein); it promotes adrenal cortical cell proliferation and aldosterone production when overexpressed, and is required in vivo for normal red blood cell membrane integrity and deformability, as Ypel4-null RBCs display reduced deformability, ovalocytic morphology, and decreased Band 3 protein levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YPEL4 is a Yippee-domain protein that functions in MAPK/ERK signaling and contributes to cell proliferation and red cell membrane integrity. It binds the Major Vault Protein (MVP) and activates the transcription factor Elk-1, an activity that MVP suppresses upon binding [#0]. Consistent with a pro-proliferative role, overexpression of YPEL4 in adrenocortical HAC15 cells stimulates proliferation and increases basal aldosterone production [#1]. In vivo, YPEL4 is required for normal erythrocyte biology: Ypel4-null mice develop secondary polycythemia with reticulocytosis, and their red blood cells show reduced deformability, ovalocytic morphology, reduced membrane Band 3 levels, and increased clearance from circulation, establishing an intrinsic role in red cell membrane integrity that does not depend on a direct YPEL4–Band 3 interaction [#2]. Beyond these findings, the molecular mechanism linking YPEL4 to its cellular phenotypes has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the first molecular partner and signaling readout for YPEL4 by showing it activates Elk-1 in the MAPK/ERK pathway and that this is gated by MVP binding.\",\n      \"evidence\": \"Yeast and mammalian two-hybrid, GST pull-down, co-immunoprecipitation, immunocytochemistry and Elk-1 reporter assay\",\n      \"pmids\": [\"20555386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which YPEL4 activates Elk-1 (direct vs indirect) not resolved\", \"How MVP binding physically blocks the activity is unknown\", \"No endogenous-level validation of the interaction or pathway\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked YPEL4 to a concrete cellular phenotype by showing its overexpression drives adrenocortical proliferation and aldosterone output.\",\n      \"evidence\": \"Overexpression in HAC15 cells with XTT, crystal violet, and aldosterone measurement\",\n      \"pmids\": [\"27333825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No pathway placement connecting proliferation to the Elk-1/MVP axis\", \"Loss-of-function in this system not tested\", \"Mechanism of aldosterone induction unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated an essential in vivo role for YPEL4 in red blood cell membrane integrity through a knockout mouse.\",\n      \"evidence\": \"Ypel4-null mouse with scanning electron microscopy, deformability assays, in vivo clearance, and membrane protein analysis\",\n      \"pmids\": [\"34354145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking YPEL4 loss to reduced Band 3 not defined\", \"Direct YPEL4–Band 3 interaction explicitly not supported\", \"Relationship to the Elk-1/MVP/proliferation role not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified YPEL4 overexpression as selectively cytotoxic to transformed cells, hinting at a context-dependent pro-death activity.\",\n      \"evidence\": \"Gain-of-function forward genetic screen with cell death readout in mammalian cells\",\n      \"pmids\": [\"37864183\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single screen with no YPEL4-specific mechanistic follow-up\", \"Pathway mediating selective death in transformed cells unknown\", \"Apparent contradiction with pro-proliferative role unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying molecular mechanism connecting YPEL4's Elk-1 activation, proliferative effects, and erythrocyte membrane role remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical basis for YPEL4 activity\", \"No direct substrate or downstream effector identified\", \"Mechanism controlling Band 3 levels in RBC membranes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MVP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}