{"gene":"GPBP1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2015,"finding":"GPBP1 contains an extended AT-hook (eAT-hook) motif that functions as a nucleic acid binding domain, binding RNA with approximately one order of magnitude higher affinity than DNA, as demonstrated by microscale thermophoresis and electrophoretic mobility shift assays on the eAT-hook peptide of GPBP1.","method":"Microscale thermophoresis and electrophoretic mobility shift assay (EMSA) using recombinant eAT-hook peptides","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assays with defined peptide and quantitative affinity measurements, but single lab, single study, and only the isolated peptide motif was tested rather than full-length protein","pmids":["26156556"],"is_preprint":false},{"year":2018,"finding":"Loss of GPBP1 causes resistance to cisplatin and PARP inhibitors through regulation of genes involved in homologous recombination, as identified in a quantitative chemical-genetic interaction screen using shRNA knockdown in human mammary epithelial cells.","method":"Quantitative chemical-genetic interaction map using shRNA knockdown of GPBP1 in human mammary epithelial cells, with chemosensitivity assays across 29 drugs","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (drug resistance) and pathway placement (homologous recombination), but single lab and the homologous recombination mechanism is stated without detailed mechanistic follow-up in the abstract","pmids":["29669295"],"is_preprint":false},{"year":2022,"finding":"GPBP1 physically interacts with RTN3 (Reticulon 3) and mediates activation of the IGF2-JAK2-STAT3 pathway; loss of RTN3 in proximal tubular epithelial cells leads to dysregulation through this GPBP1-dependent signaling axis, linking GPBP1 to collagen biosynthesis and mitochondrial function in the kidney.","method":"Co-immunoprecipitation / protein interaction assay in HEK293 cells and primary proximal tubular epithelial cells; RTN3-null mouse model with mechanistic follow-up in vitro","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — interaction identified by Co-IP with functional pathway placement (IGF2-JAK2-STAT3), supported by in vivo KO model, but single lab and abstract does not detail orthogonal validation of the GPBP1-RTN3 interaction","pmids":["35596061"],"is_preprint":false},{"year":2025,"finding":"GPBP1 is a direct target of miR-216a-5p; overexpression of miR-216a-5p in mesenchymal stem cells suppresses GPBP1 and mediates neuroprotective and anti-inflammatory effects in a rat spinal cord injury model.","method":"miRNA target identification (mechanistic studies in rat SCI model with MSC overexpressing miR-216a-5p); functional rescue/suppression assay","journal":"European journal of medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single paper, abstract states GPBP1 is a 'direct target' without specifying the validation method (e.g., luciferase reporter), and no detailed mechanistic dissection of GPBP1 function is provided","pmids":["40708043"],"is_preprint":false}],"current_model":"GPBP1 (GC-rich promoter binding protein 1 / DKFZp761C169) contains an extended AT-hook motif that preferentially binds RNA over DNA; it interacts with RTN3 to regulate the IGF2-JAK2-STAT3 signaling pathway and is required for normal homologous recombination, as its loss confers resistance to PARP inhibitors and cisplatin; it is also a direct post-transcriptional target of miR-216a-5p with downstream anti-inflammatory effects."},"narrative":{"mechanistic_narrative":"GPBP1 is a nucleic acid-binding protein that contributes to genome maintenance and signal transduction across multiple cellular contexts [PMID:26156556, PMID:29669295]. Its extended AT-hook (eAT-hook) motif functions as a binding domain that preferentially associates with RNA over DNA, binding RNA with approximately tenfold higher affinity, indicating a primarily RNA-directed engagement rather than the DNA binding implied by its original naming [PMID:26156556]. Functionally, GPBP1 is required for normal homologous recombination: its loss reprograms expression of recombination genes and confers resistance to cisplatin and PARP inhibitors [PMID:29669295]. In a separate context, GPBP1 physically interacts with RTN3 and operates within an IGF2-JAK2-STAT3 signaling axis that connects RTN3 loss in proximal tubular epithelial cells to dysregulated collagen biosynthesis and mitochondrial function [PMID:35596061]. Beyond these roles, no unified mechanistic model linking the RNA-binding, recombination, and signaling activities has been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Resolved the molecular nature of GPBP1's nucleic acid binding, showing its eAT-hook motif is a binding domain that prefers RNA over DNA — overturning the implication of its 'GC-rich promoter binding' name.","evidence":"Microscale thermophoresis and EMSA with recombinant eAT-hook peptides","pmids":["26156556"],"confidence":"Medium","gaps":["Only the isolated peptide motif was tested, not full-length GPBP1","No specific physiological RNA target identified","Single lab, single study"]},{"year":2018,"claim":"Placed GPBP1 in the DNA damage response by showing its loss alters homologous recombination genes and produces resistance to cisplatin and PARP inhibitors, defining a chemosensitivity phenotype.","evidence":"Quantitative chemical-genetic interaction map with shRNA knockdown in human mammary epithelial cells across 29 drugs","pmids":["29669295"],"confidence":"Medium","gaps":["Mechanistic link from RNA binding to homologous recombination not established","Direct molecular role of GPBP1 in the HR machinery undefined","No structural or biochemical follow-up on how GPBP1 regulates HR genes"]},{"year":2022,"claim":"Identified a physical partner (RTN3) and a signaling pathway (IGF2-JAK2-STAT3) for GPBP1, linking it to collagen biosynthesis and mitochondrial function in kidney epithelium.","evidence":"Co-IP in HEK293 and primary proximal tubular epithelial cells plus an RTN3-null mouse model","pmids":["35596061"],"confidence":"Medium","gaps":["GPBP1-RTN3 interaction lacks orthogonal validation in the report","How GPBP1 mechanistically activates the IGF2-JAK2-STAT3 axis is unspecified","Connection between this signaling role and GPBP1's RNA-binding/HR functions is unknown"]},{"year":2025,"claim":"Positioned GPBP1 as a post-transcriptional target of miR-216a-5p whose suppression mediates anti-inflammatory and neuroprotective effects.","evidence":"miR-216a-5p overexpression in mesenchymal stem cells in a rat spinal cord injury model","pmids":["40708043"],"confidence":"Low","gaps":["Direct targeting claimed without a stated validation method such as luciferase reporter","No mechanistic dissection of GPBP1's role downstream of miR-216a-5p","Single study in one injury model"]},{"year":null,"claim":"It remains unknown how GPBP1's RNA-binding activity mechanistically connects to its roles in homologous recombination and IGF2-JAK2-STAT3 signaling, and whether these represent one unified function or context-specific activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No physiological RNA substrate identified","No structure of full-length GPBP1 or its complexes","No mechanism connecting binding activity to downstream phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["RTN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86WP2","full_name":"Vasculin","aliases":["GC-rich promoter-binding protein 1","Vascular wall-linked protein"],"length_aa":473,"mass_kda":53.3,"function":"Functions as a GC-rich promoter-specific transactivating transcription factor","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q86WP2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPBP1","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GPBP1","total_profiled":1310},"omim":[{"mim_id":"608412","title":"GC-RICH PROMOTER-BINDING PROTEIN 1; GPBP1","url":"https://www.omim.org/entry/608412"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GPBP1"},"hgnc":{"alias_symbol":["DKFZp761C169"],"prev_symbol":[]},"alphafold":{"accession":"Q86WP2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WP2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WP2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WP2-F1-predicted_aligned_error_v6.png","plddt_mean":54.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPBP1","jax_strain_url":"https://www.jax.org/strain/search?query=GPBP1"},"sequence":{"accession":"Q86WP2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86WP2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86WP2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WP2"}},"corpus_meta":[{"pmid":"26156556","id":"PMC_26156556","title":"The extended AT-hook is a novel RNA binding motif.","date":"2015","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/26156556","citation_count":42,"is_preprint":false},{"pmid":"29669295","id":"PMC_29669295","title":"A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29669295","citation_count":34,"is_preprint":false},{"pmid":"8363571","id":"PMC_8363571","title":"An insulin receptor peptide (1135-1156) stimulates guanosine 5'-[gamma-thio]triphosphate binding to the 67 kDa G-protein associated with the insulin receptor.","date":"1993","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8363571","citation_count":19,"is_preprint":false},{"pmid":"34829754","id":"PMC_34829754","title":"Identification of Disease-Related Genes That Are Common between Alzheimer's and Cardiovascular Disease Using Blood Genome-Wide Transcriptome Analysis.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34829754","citation_count":16,"is_preprint":false},{"pmid":"35596061","id":"PMC_35596061","title":"Loss of RTN3 phenocopies chronic kidney disease and results in activation of the IGF2-JAK2 pathway in proximal tubular epithelial cells.","date":"2022","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35596061","citation_count":13,"is_preprint":false},{"pmid":"21832087","id":"PMC_21832087","title":"Goodpasture antigen-binding protein (GPBP) directs myofibril formation: identification of intracellular downstream effector 130-kDa GPBP-interacting protein (GIP130).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832087","citation_count":9,"is_preprint":false},{"pmid":"30377252","id":"PMC_30377252","title":"Unicellular ancestry and mechanisms of diversification of Goodpasture antigen-binding protein.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30377252","citation_count":5,"is_preprint":false},{"pmid":"40708043","id":"PMC_40708043","title":"Transplantation of miR-216a-5p-overexpressing mesenchymal stem cells encapsulated in a thermosensitive hydrogel promotes functional recovery in a rat model of spinal cord injury.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/40708043","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5540,"output_tokens":1651,"usd":0.020692,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7706,"output_tokens":1806,"usd":0.04184,"stage2_stop_reason":"end_turn"},"total_usd":0.062532,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully classify these papers before extracting discoveries.\n\n**Paper [1]**: About eAT-hook motif — describes GPBP1 biochemically as having an extended AT-hook that binds RNA. This appears to be about the human GPBP1 gene (GC-rich promoter binding protein 1). INCLUDE.\n\n**Paper [2]**: About chemical-genetic interaction map — mentions GPBP1 loss causes resistance to cisplatin and PARP inhibitors through regulation of homologous recombination genes. INCLUDE.\n\n**Paper [3]**: This paper uses \"GPBP1\" as a peptide name (G-protein binding peptide 1) derived from insulin receptor sequences — this is NOT the gene GPBP1/DKFZp761C169. This is a peptide designation. EXCLUDE (symbol collision).\n\n**Paper [4]**: Expression/transcriptomics/GRN study identifying GPBP1 as an upstream hub gene — no direct mechanistic experiment on GPBP1. EXCLUDE.\n\n**Paper [5]**: RTN3 interacts with GPBP1 and activates IGF2-JAK2-STAT3 pathway — mechanistic finding about GPBP1 as a binding partner. INCLUDE.\n\n**Paper [6]**: About GPBP-1 (Goodpasture antigen-binding protein 1) — this is a different gene (GPBP/CEACAM1 family, Ser/Thr kinase). The HGNC aliases for GPBP1 are DKFZp761C169, which is GC-rich promoter binding protein 1, distinct from Goodpasture antigen-binding protein. EXCLUDE (symbol collision).\n\n**Paper [7]**: About Goodpasture antigen-binding protein — same collision as paper [6]. EXCLUDE.\n\n**Paper [8]**: miR-216a-5p targets GPBP1 in spinal cord injury model. This identifies GPBP1 as a direct target of miR-216a-5p. INCLUDE (though mechanism is limited).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"GPBP1 contains an extended AT-hook (eAT-hook) motif that functions as a nucleic acid binding domain, binding RNA with approximately one order of magnitude higher affinity than DNA, as demonstrated by microscale thermophoresis and electrophoretic mobility shift assays on the eAT-hook peptide of GPBP1.\",\n      \"method\": \"Microscale thermophoresis and electrophoretic mobility shift assay (EMSA) using recombinant eAT-hook peptides\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assays with defined peptide and quantitative affinity measurements, but single lab, single study, and only the isolated peptide motif was tested rather than full-length protein\",\n      \"pmids\": [\"26156556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of GPBP1 causes resistance to cisplatin and PARP inhibitors through regulation of genes involved in homologous recombination, as identified in a quantitative chemical-genetic interaction screen using shRNA knockdown in human mammary epithelial cells.\",\n      \"method\": \"Quantitative chemical-genetic interaction map using shRNA knockdown of GPBP1 in human mammary epithelial cells, with chemosensitivity assays across 29 drugs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (drug resistance) and pathway placement (homologous recombination), but single lab and the homologous recombination mechanism is stated without detailed mechanistic follow-up in the abstract\",\n      \"pmids\": [\"29669295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPBP1 physically interacts with RTN3 (Reticulon 3) and mediates activation of the IGF2-JAK2-STAT3 pathway; loss of RTN3 in proximal tubular epithelial cells leads to dysregulation through this GPBP1-dependent signaling axis, linking GPBP1 to collagen biosynthesis and mitochondrial function in the kidney.\",\n      \"method\": \"Co-immunoprecipitation / protein interaction assay in HEK293 cells and primary proximal tubular epithelial cells; RTN3-null mouse model with mechanistic follow-up in vitro\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — interaction identified by Co-IP with functional pathway placement (IGF2-JAK2-STAT3), supported by in vivo KO model, but single lab and abstract does not detail orthogonal validation of the GPBP1-RTN3 interaction\",\n      \"pmids\": [\"35596061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPBP1 is a direct target of miR-216a-5p; overexpression of miR-216a-5p in mesenchymal stem cells suppresses GPBP1 and mediates neuroprotective and anti-inflammatory effects in a rat spinal cord injury model.\",\n      \"method\": \"miRNA target identification (mechanistic studies in rat SCI model with MSC overexpressing miR-216a-5p); functional rescue/suppression assay\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single paper, abstract states GPBP1 is a 'direct target' without specifying the validation method (e.g., luciferase reporter), and no detailed mechanistic dissection of GPBP1 function is provided\",\n      \"pmids\": [\"40708043\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPBP1 (GC-rich promoter binding protein 1 / DKFZp761C169) contains an extended AT-hook motif that preferentially binds RNA over DNA; it interacts with RTN3 to regulate the IGF2-JAK2-STAT3 signaling pathway and is required for normal homologous recombination, as its loss confers resistance to PARP inhibitors and cisplatin; it is also a direct post-transcriptional target of miR-216a-5p with downstream anti-inflammatory effects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPBP1 is a nucleic acid-binding protein that contributes to genome maintenance and signal transduction across multiple cellular contexts [#0, #1]. Its extended AT-hook (eAT-hook) motif functions as a binding domain that preferentially associates with RNA over DNA, binding RNA with approximately tenfold higher affinity, indicating a primarily RNA-directed engagement rather than the DNA binding implied by its original naming [#0]. Functionally, GPBP1 is required for normal homologous recombination: its loss reprograms expression of recombination genes and confers resistance to cisplatin and PARP inhibitors [#1]. In a separate context, GPBP1 physically interacts with RTN3 and operates within an IGF2-JAK2-STAT3 signaling axis that connects RTN3 loss in proximal tubular epithelial cells to dysregulated collagen biosynthesis and mitochondrial function [#2]. Beyond these roles, no unified mechanistic model linking the RNA-binding, recombination, and signaling activities has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the molecular nature of GPBP1's nucleic acid binding, showing its eAT-hook motif is a binding domain that prefers RNA over DNA — overturning the implication of its 'GC-rich promoter binding' name.\",\n      \"evidence\": \"Microscale thermophoresis and EMSA with recombinant eAT-hook peptides\",\n      \"pmids\": [\"26156556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only the isolated peptide motif was tested, not full-length GPBP1\",\n        \"No specific physiological RNA target identified\",\n        \"Single lab, single study\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed GPBP1 in the DNA damage response by showing its loss alters homologous recombination genes and produces resistance to cisplatin and PARP inhibitors, defining a chemosensitivity phenotype.\",\n      \"evidence\": \"Quantitative chemical-genetic interaction map with shRNA knockdown in human mammary epithelial cells across 29 drugs\",\n      \"pmids\": [\"29669295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link from RNA binding to homologous recombination not established\",\n        \"Direct molecular role of GPBP1 in the HR machinery undefined\",\n        \"No structural or biochemical follow-up on how GPBP1 regulates HR genes\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a physical partner (RTN3) and a signaling pathway (IGF2-JAK2-STAT3) for GPBP1, linking it to collagen biosynthesis and mitochondrial function in kidney epithelium.\",\n      \"evidence\": \"Co-IP in HEK293 and primary proximal tubular epithelial cells plus an RTN3-null mouse model\",\n      \"pmids\": [\"35596061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"GPBP1-RTN3 interaction lacks orthogonal validation in the report\",\n        \"How GPBP1 mechanistically activates the IGF2-JAK2-STAT3 axis is unspecified\",\n        \"Connection between this signaling role and GPBP1's RNA-binding/HR functions is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned GPBP1 as a post-transcriptional target of miR-216a-5p whose suppression mediates anti-inflammatory and neuroprotective effects.\",\n      \"evidence\": \"miR-216a-5p overexpression in mesenchymal stem cells in a rat spinal cord injury model\",\n      \"pmids\": [\"40708043\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Direct targeting claimed without a stated validation method such as luciferase reporter\",\n        \"No mechanistic dissection of GPBP1's role downstream of miR-216a-5p\",\n        \"Single study in one injury model\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how GPBP1's RNA-binding activity mechanistically connects to its roles in homologous recombination and IGF2-JAK2-STAT3 signaling, and whether these represent one unified function or context-specific activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No physiological RNA substrate identified\",\n        \"No structure of full-length GPBP1 or its complexes\",\n        \"No mechanism connecting binding activity to downstream phenotypes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RTN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}