{"gene":"COBLL1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2018,"finding":"COBLL1 interacts with androgen receptor (AR) in the nucleus and enhances complex formation with CDK1, facilitating AR phosphorylation for genomic binding in castration-resistant prostate cancer (CRPC) model cells. COBLL1 also modulates cancer cell morphogenesis to a neuron-like cell shape and promotes cell growth and migration.","method":"Co-immunoprecipitation (Co-IP) of nuclear COBLL1 with AR and CDK1; loss-of-function experiments with specific morphological and proliferation/migration phenotypic readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying binding partners (AR, CDK1) and KD with defined cellular phenotypes, single lab with two orthogonal approaches","pmids":["29686105"],"is_preprint":false},{"year":2017,"finding":"COBLL1 increases IKKγ protein stability, leading to NF-κB activation and reduction of nilotinib-induced apoptosis in CML cells, linking COBLL1 to TKI drug resistance via the NF-κB signaling pathway.","method":"Overexpression and knockdown experiments in CML cell lines with western blot for IKKγ stability and NF-κB activation; apoptosis assays with nilotinib treatment","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with defined pathway placement (IKKγ/NF-κB), single lab with multiple readouts","pmids":["28232743"],"is_preprint":false},{"year":2017,"finding":"COBLL1 was identified as a novel binding partner of ROR1 (a transmembrane tyrosine-protein kinase in the Wnt/planar cell polarity pathway) in CLL cells. High COBLL1 expression was associated with impaired motility and chemotaxis towards CCL19 and CXCL12, and enhanced B-cell receptor signaling (increased PLCγ2 and SYK phosphorylation after IgM stimulation).","method":"Protein interaction assay identifying COBLL1 as ROR1 binding partner; functional assays for chemotaxis, motility, and BCR signaling (phospho-flow or western blot for PLCγ2 and SYK phosphorylation)","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding partner identification plus functional cellular assays (chemotaxis, BCR signaling), single lab","pmids":["29122990"],"is_preprint":false},{"year":2022,"finding":"COBLL1 directly binds PACSIN2, and this interaction competitively displaces SH3BP1 from PACSIN2 (COBLL1 has higher affinity for PACSIN2 than SH3BP1 does). By sequestering PACSIN2, COBLL1 releases SH3BP1 to activate the downstream Rac1 pathway, suppressing TKI-mediated apoptosis and promoting drug resistance in CML. PACSIN2 alone activates TKI-induced apoptosis, and this is suppressed by Cobll1 through Cobll1-PACSIN2 interaction.","method":"Co-immunoprecipitation and binding affinity assays (pulldown) identifying Cobll1-PACSIN2 and PACSIN2-SH3BP1 interactions; competitive binding assays; functional apoptosis assays with TKI treatment; Rac1 pathway readout","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding/Co-IP establishing mechanistic pathway with functional apoptosis readout, single lab with multiple orthogonal methods","pmids":["35352878"],"is_preprint":false},{"year":2018,"finding":"EBNA3C (Epstein-Barr virus nuclear antigen 3C) represses COBLL1 transcription by interacting with the histone lysine demethylase KDM2B; this interaction is required for removal of the activating histone mark H3K4me3 at the COBLL1 locus. Separately, EBNA3C recruits Polycomb proteins BMI1 and SUZ12 to COBLL1, leading to deposition of the repressive mark H3K27me3, via a mechanism involving the HD motif of EBNA3C.","method":"Chromatin immunoprecipitation (ChIP) for histone marks (H3K27me3, H3K4me3) and Polycomb proteins (BMI1, SUZ12) at the COBLL1 locus; Co-IP demonstrating EBNA3C-KDM2B interaction; recombinant virus infection with EBNA3C motif mutants","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with mutagenesis of EBNA3C motifs, single lab, two orthogonal methods establishing epigenetic mechanism","pmids":["30135119"],"is_preprint":false},{"year":2022,"finding":"CRISPR-Cas9 mutagenesis of COBLL1 in Xenopus laevis and Danio rerio produced craniofacial dysmorphologies including cleft-like phenotypes, establishing a direct functional role for COBLL1 in craniofacial/palate development.","method":"CRISPR-Cas9 loss-of-function in Xenopus laevis and Danio rerio with craniofacial morphological phenotypic readout","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in two model organisms with defined craniofacial phenotype, single study","pmids":["36493769"],"is_preprint":false},{"year":2015,"finding":"The equine COBLL1 gene produces two alternatively spliced isoforms (COBLL1a and COBLL1b) differing by inclusion/exclusion of exon 9; the exon 9-encoded region contains three putative phosphorylation sites absent in the short isoform (COBLL1b). Expression of both isoforms decreases in muscle after exercise.","method":"RT-PCR, cloning, Sanger sequencing of equine tissue cDNA; real-time PCR expression analysis across tissues; bioinformatics prediction of phosphorylation sites","journal":"Asian-Australasian journal of animal sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — characterization of isoforms by sequencing and expression profiling; phosphorylation sites only predicted computationally; single lab, no functional validation","pmids":["25925064"],"is_preprint":false}],"current_model":"COBLL1 is an actin-binding domain-containing protein that functions in multiple signaling contexts: in prostate cancer it localizes to the nucleus, binds AR and CDK1 to promote AR phosphorylation and genomic binding; in CML it stabilizes IKKγ to activate NF-κB and competitively binds PACSIN2 to release SH3BP1/Rac1 signaling, both mechanisms suppressing apoptosis and driving TKI resistance; in CLL it interacts with ROR1 and modulates BCR signaling and cell motility; and its transcription is epigenetically silenced by EBV EBNA3C through recruitment of KDM2B (H3K4me3 removal) and Polycomb complexes (H3K27me3 deposition), while loss-of-function in vertebrate models causes craniofacial defects."},"narrative":{"mechanistic_narrative":"COBLL1 is an actin-binding adaptor protein that operates as a context-dependent signaling scaffold across several cancer and developmental settings [PMID:29686105, PMID:35352878]. In castration-resistant prostate cancer it localizes to the nucleus, where it binds the androgen receptor and promotes complex formation with CDK1 to facilitate AR phosphorylation and genomic binding, while driving a neuron-like cell morphology and increased growth and migration [PMID:29686105]. In chronic myeloid leukemia COBLL1 confers tyrosine-kinase-inhibitor resistance through two converging mechanisms: it increases IKKγ protein stability to activate NF-κB and reduce nilotinib-induced apoptosis [PMID:28232743], and it binds PACSIN2 with higher affinity than SH3BP1, competitively displacing SH3BP1 to activate downstream Rac1 signaling and suppress TKI-mediated apoptosis [PMID:35352878]. In chronic lymphocytic leukemia COBLL1 is a binding partner of the ROR1 receptor tyrosine kinase and modulates B-cell receptor signaling (enhanced PLCγ2 and SYK phosphorylation) while impairing chemotaxis and motility [PMID:29122990]. COBLL1 transcription is epigenetically silenced by EBV EBNA3C, which recruits KDM2B to remove activating H3K4me3 and Polycomb proteins BMI1/SUZ12 to deposit repressive H3K27me3 at the locus [PMID:30135119]. Loss-of-function in Xenopus and zebrafish causes craniofacial dysmorphologies, establishing a developmental role in palate formation [PMID:36493769].","teleology":[{"year":2017,"claim":"Linking COBLL1 to a defined drug-resistance pathway addressed how it influences leukemia cell survival; it was shown to stabilize IKKγ and activate NF-κB to blunt TKI-induced apoptosis.","evidence":"Overexpression/knockdown in CML cell lines with western blot for IKKγ and NF-κB readouts plus nilotinib apoptosis assays","pmids":["28232743"],"confidence":"Medium","gaps":["Mechanism by which COBLL1 stabilizes IKKγ (direct binding vs. indirect) not defined","No structural basis for the interaction"]},{"year":2017,"claim":"Identifying COBLL1 as a ROR1 partner placed it in receptor and B-cell receptor signaling, clarifying its role in CLL cell behavior including motility and antigen-receptor responsiveness.","evidence":"Protein interaction assay plus chemotaxis, motility, and phospho-flow/western readouts of PLCγ2 and SYK in CLL cells","pmids":["29122990"],"confidence":"Medium","gaps":["Whether the ROR1 interaction is direct is not resolved","Connection between ROR1 binding and BCR signaling modulation not mechanistically traced"]},{"year":2018,"claim":"Defining a nuclear COBLL1–AR–CDK1 complex answered how COBLL1 promotes prostate cancer progression, showing it facilitates AR phosphorylation and genomic binding.","evidence":"Reciprocal Co-IP of nuclear COBLL1 with AR and CDK1 plus knockdown with morphological, proliferation, and migration phenotypes in CRPC cells","pmids":["29686105"],"confidence":"Medium","gaps":["Whether CDK1 directly phosphorylates AR within the complex not established","Mechanism of COBLL1 nuclear localization unknown"]},{"year":2018,"claim":"Establishing how a viral oncoprotein controls COBLL1 expression revealed the locus is silenced epigenetically, identifying COBLL1 as an EBNA3C target.","evidence":"ChIP for H3K4me3/H3K27me3 and BMI1/SUZ12, Co-IP for EBNA3C-KDM2B, and recombinant virus with EBNA3C motif mutants","pmids":["30135119"],"confidence":"Medium","gaps":["Functional consequence of COBLL1 silencing for EBV-transformed cells not defined","Whether EBNA3C binds the COBLL1 locus directly or via cofactors unclear"]},{"year":2022,"claim":"Resolving the molecular basis of COBLL1-driven TKI resistance showed it acts as a competitive scaffold, sequestering PACSIN2 to release SH3BP1 and activate Rac1.","evidence":"Co-IP, competitive binding/pulldown affinity assays, and TKI apoptosis assays with Rac1 pathway readout in CML","pmids":["35352878"],"confidence":"Medium","gaps":["Structural basis for differential PACSIN2 affinity not determined","Relationship between this Rac1 axis and the NF-κB mechanism not integrated"]},{"year":2022,"claim":"Genetic loss-of-function in vertebrate models established a developmental requirement for COBLL1, linking it to craniofacial and palate formation.","evidence":"CRISPR-Cas9 knockout in Xenopus laevis and Danio rerio with craniofacial morphological readout","pmids":["36493769"],"confidence":"Medium","gaps":["Molecular pathway underlying the craniofacial defect not identified","Relevance to human craniofacial disease not demonstrated in the corpus"]},{"year":null,"claim":"How COBLL1's distinct scaffolding activities (AR/CDK1, IKKγ, PACSIN2, ROR1) relate to a unified biochemical function, and how its actin-binding domain contributes mechanistically, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of COBLL1 or its domains in the corpus","No unifying biochemical activity connecting its multiple partner interactions","Phosphorylation regulation only computationally predicted [#6]"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","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":[1,2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4]}],"complexes":[],"partners":["AR","CDK1","IKKG","PACSIN2","SH3BP1","ROR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53SF7","full_name":"Cordon-bleu protein-like 1","aliases":[],"length_aa":1128,"mass_kda":123.9,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q53SF7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COBLL1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTG1","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"PACSIN2","stoichiometry":0.2},{"gene":"PACSIN3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COBLL1","total_profiled":1310},"omim":[{"mim_id":"610318","title":"COBL-LIKE PROTEIN 1: COBLL1","url":"https://www.omim.org/entry/610318"},{"mim_id":"602463","title":"DIHYDROPYRIMIDINASE-LIKE 2; DPYSL2","url":"https://www.omim.org/entry/602463"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":100.6}],"url":"https://www.proteinatlas.org/search/COBLL1"},"hgnc":{"alias_symbol":["KIAA0977"],"prev_symbol":[]},"alphafold":{"accession":"Q53SF7","domains":[{"cath_id":"3.10.20.90","chopping":"49-135","consensus_level":"high","plddt":89.2974,"start":49,"end":135},{"cath_id":"3.10.20.90","chopping":"148-221","consensus_level":"high","plddt":89.8736,"start":148,"end":221}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53SF7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53SF7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53SF7-F1-predicted_aligned_error_v6.png","plddt_mean":50.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COBLL1","jax_strain_url":"https://www.jax.org/strain/search?query=COBLL1"},"sequence":{"accession":"Q53SF7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53SF7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53SF7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53SF7"}},"corpus_meta":[{"pmid":"29686105","id":"PMC_29686105","title":"COBLL1 modulates cell morphology and facilitates androgen receptor genomic binding in advanced prostate cancer.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29686105","citation_count":27,"is_preprint":false},{"pmid":"28232743","id":"PMC_28232743","title":"Cobll1 is linked to drug resistance and blastic transformation in chronic myeloid leukemia.","date":"2017","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/28232743","citation_count":23,"is_preprint":false},{"pmid":"23463496","id":"PMC_23463496","title":"The COBLL1 C allele is associated with lower serum insulin levels and lower insulin resistance in overweight and obese children.","date":"2013","source":"Diabetes/metabolism research and reviews","url":"https://pubmed.ncbi.nlm.nih.gov/23463496","citation_count":19,"is_preprint":false},{"pmid":"29122990","id":"PMC_29122990","title":"Expression of COBLL1 encoding novel ROR1 binding partner is robust predictor of survival in chronic lymphocytic leukemia.","date":"2017","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/29122990","citation_count":18,"is_preprint":false},{"pmid":"34355838","id":"PMC_34355838","title":"Long non-coding RNA NORAD aggravates acute myocardial infarction by promoting fibrosis and apoptosis via miR-577/COBLL1 axis.","date":"2021","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34355838","citation_count":18,"is_preprint":false},{"pmid":"36493769","id":"PMC_36493769","title":"Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36493769","citation_count":15,"is_preprint":false},{"pmid":"30135119","id":"PMC_30135119","title":"Epstein-Barr Virus Nuclear Antigen 3C Inhibits Expression of COBLL1 and the ADAM28-ADAMDEC1 Locus via Interaction with the Histone Lysine Demethylase KDM2B.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/30135119","citation_count":9,"is_preprint":false},{"pmid":"36009479","id":"PMC_36009479","title":"COBLL1 and IRS1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36009479","citation_count":7,"is_preprint":false},{"pmid":"35352878","id":"PMC_35352878","title":"Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia.","date":"2022","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35352878","citation_count":7,"is_preprint":false},{"pmid":"35955692","id":"PMC_35955692","title":"Metabolic Effects of the Waist-To-Hip Ratio Associated Locus GRB14/COBLL1 Are Related to GRB14 Expression in Adipose Tissue.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35955692","citation_count":6,"is_preprint":false},{"pmid":"36835164","id":"PMC_36835164","title":"Gene-Nutrient Interactions in Obesity: COBLL1 Genetic Variants Interact with Dietary Fat Intake to Modulate the Incidence of Obesity.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36835164","citation_count":4,"is_preprint":false},{"pmid":"36037128","id":"PMC_36037128","title":"Evaluation of miRNA 223/125a and COBLL1 Expressions and ROR-1 Levels as Reliable Markers in B- chronic Lymphocytic Leukemia.","date":"2022","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/36037128","citation_count":3,"is_preprint":false},{"pmid":"25925064","id":"PMC_25925064","title":"Molecular Analysis of Alternative Transcripts of the Equine Cordon-Bleu WH2 Repeat Protein-Like 1 (COBLL1) Gene.","date":"2015","source":"Asian-Australasian journal of animal sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25925064","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9509,"output_tokens":2142,"usd":0.030329,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9094,"output_tokens":2594,"usd":0.05516,"stage2_stop_reason":"end_turn"},"total_usd":0.085489,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"COBLL1 interacts with androgen receptor (AR) in the nucleus and enhances complex formation with CDK1, facilitating AR phosphorylation for genomic binding in castration-resistant prostate cancer (CRPC) model cells. COBLL1 also modulates cancer cell morphogenesis to a neuron-like cell shape and promotes cell growth and migration.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) of nuclear COBLL1 with AR and CDK1; loss-of-function experiments with specific morphological and proliferation/migration phenotypic readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying binding partners (AR, CDK1) and KD with defined cellular phenotypes, single lab with two orthogonal approaches\",\n      \"pmids\": [\"29686105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COBLL1 increases IKKγ protein stability, leading to NF-κB activation and reduction of nilotinib-induced apoptosis in CML cells, linking COBLL1 to TKI drug resistance via the NF-κB signaling pathway.\",\n      \"method\": \"Overexpression and knockdown experiments in CML cell lines with western blot for IKKγ stability and NF-κB activation; apoptosis assays with nilotinib treatment\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with defined pathway placement (IKKγ/NF-κB), single lab with multiple readouts\",\n      \"pmids\": [\"28232743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COBLL1 was identified as a novel binding partner of ROR1 (a transmembrane tyrosine-protein kinase in the Wnt/planar cell polarity pathway) in CLL cells. High COBLL1 expression was associated with impaired motility and chemotaxis towards CCL19 and CXCL12, and enhanced B-cell receptor signaling (increased PLCγ2 and SYK phosphorylation after IgM stimulation).\",\n      \"method\": \"Protein interaction assay identifying COBLL1 as ROR1 binding partner; functional assays for chemotaxis, motility, and BCR signaling (phospho-flow or western blot for PLCγ2 and SYK phosphorylation)\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding partner identification plus functional cellular assays (chemotaxis, BCR signaling), single lab\",\n      \"pmids\": [\"29122990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"COBLL1 directly binds PACSIN2, and this interaction competitively displaces SH3BP1 from PACSIN2 (COBLL1 has higher affinity for PACSIN2 than SH3BP1 does). By sequestering PACSIN2, COBLL1 releases SH3BP1 to activate the downstream Rac1 pathway, suppressing TKI-mediated apoptosis and promoting drug resistance in CML. PACSIN2 alone activates TKI-induced apoptosis, and this is suppressed by Cobll1 through Cobll1-PACSIN2 interaction.\",\n      \"method\": \"Co-immunoprecipitation and binding affinity assays (pulldown) identifying Cobll1-PACSIN2 and PACSIN2-SH3BP1 interactions; competitive binding assays; functional apoptosis assays with TKI treatment; Rac1 pathway readout\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding/Co-IP establishing mechanistic pathway with functional apoptosis readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35352878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EBNA3C (Epstein-Barr virus nuclear antigen 3C) represses COBLL1 transcription by interacting with the histone lysine demethylase KDM2B; this interaction is required for removal of the activating histone mark H3K4me3 at the COBLL1 locus. Separately, EBNA3C recruits Polycomb proteins BMI1 and SUZ12 to COBLL1, leading to deposition of the repressive mark H3K27me3, via a mechanism involving the HD motif of EBNA3C.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for histone marks (H3K27me3, H3K4me3) and Polycomb proteins (BMI1, SUZ12) at the COBLL1 locus; Co-IP demonstrating EBNA3C-KDM2B interaction; recombinant virus infection with EBNA3C motif mutants\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with mutagenesis of EBNA3C motifs, single lab, two orthogonal methods establishing epigenetic mechanism\",\n      \"pmids\": [\"30135119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR-Cas9 mutagenesis of COBLL1 in Xenopus laevis and Danio rerio produced craniofacial dysmorphologies including cleft-like phenotypes, establishing a direct functional role for COBLL1 in craniofacial/palate development.\",\n      \"method\": \"CRISPR-Cas9 loss-of-function in Xenopus laevis and Danio rerio with craniofacial morphological phenotypic readout\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in two model organisms with defined craniofacial phenotype, single study\",\n      \"pmids\": [\"36493769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The equine COBLL1 gene produces two alternatively spliced isoforms (COBLL1a and COBLL1b) differing by inclusion/exclusion of exon 9; the exon 9-encoded region contains three putative phosphorylation sites absent in the short isoform (COBLL1b). Expression of both isoforms decreases in muscle after exercise.\",\n      \"method\": \"RT-PCR, cloning, Sanger sequencing of equine tissue cDNA; real-time PCR expression analysis across tissues; bioinformatics prediction of phosphorylation sites\",\n      \"journal\": \"Asian-Australasian journal of animal sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — characterization of isoforms by sequencing and expression profiling; phosphorylation sites only predicted computationally; single lab, no functional validation\",\n      \"pmids\": [\"25925064\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COBLL1 is an actin-binding domain-containing protein that functions in multiple signaling contexts: in prostate cancer it localizes to the nucleus, binds AR and CDK1 to promote AR phosphorylation and genomic binding; in CML it stabilizes IKKγ to activate NF-κB and competitively binds PACSIN2 to release SH3BP1/Rac1 signaling, both mechanisms suppressing apoptosis and driving TKI resistance; in CLL it interacts with ROR1 and modulates BCR signaling and cell motility; and its transcription is epigenetically silenced by EBV EBNA3C through recruitment of KDM2B (H3K4me3 removal) and Polycomb complexes (H3K27me3 deposition), while loss-of-function in vertebrate models causes craniofacial defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COBLL1 is an actin-binding adaptor protein that operates as a context-dependent signaling scaffold across several cancer and developmental settings [#0, #3]. In castration-resistant prostate cancer it localizes to the nucleus, where it binds the androgen receptor and promotes complex formation with CDK1 to facilitate AR phosphorylation and genomic binding, while driving a neuron-like cell morphology and increased growth and migration [#0]. In chronic myeloid leukemia COBLL1 confers tyrosine-kinase-inhibitor resistance through two converging mechanisms: it increases IKK\\u03b3 protein stability to activate NF-\\u03baB and reduce nilotinib-induced apoptosis [#1], and it binds PACSIN2 with higher affinity than SH3BP1, competitively displacing SH3BP1 to activate downstream Rac1 signaling and suppress TKI-mediated apoptosis [#3]. In chronic lymphocytic leukemia COBLL1 is a binding partner of the ROR1 receptor tyrosine kinase and modulates B-cell receptor signaling (enhanced PLC\\u03b32 and SYK phosphorylation) while impairing chemotaxis and motility [#2]. COBLL1 transcription is epigenetically silenced by EBV EBNA3C, which recruits KDM2B to remove activating H3K4me3 and Polycomb proteins BMI1/SUZ12 to deposit repressive H3K27me3 at the locus [#4]. Loss-of-function in Xenopus and zebrafish causes craniofacial dysmorphologies, establishing a developmental role in palate formation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking COBLL1 to a defined drug-resistance pathway addressed how it influences leukemia cell survival; it was shown to stabilize IKK\\u03b3 and activate NF-\\u03baB to blunt TKI-induced apoptosis.\",\n      \"evidence\": \"Overexpression/knockdown in CML cell lines with western blot for IKK\\u03b3 and NF-\\u03baB readouts plus nilotinib apoptosis assays\",\n      \"pmids\": [\"28232743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which COBLL1 stabilizes IKK\\u03b3 (direct binding vs. indirect) not defined\", \"No structural basis for the interaction\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying COBLL1 as a ROR1 partner placed it in receptor and B-cell receptor signaling, clarifying its role in CLL cell behavior including motility and antigen-receptor responsiveness.\",\n      \"evidence\": \"Protein interaction assay plus chemotaxis, motility, and phospho-flow/western readouts of PLC\\u03b32 and SYK in CLL cells\",\n      \"pmids\": [\"29122990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the ROR1 interaction is direct is not resolved\", \"Connection between ROR1 binding and BCR signaling modulation not mechanistically traced\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining a nuclear COBLL1\\u2013AR\\u2013CDK1 complex answered how COBLL1 promotes prostate cancer progression, showing it facilitates AR phosphorylation and genomic binding.\",\n      \"evidence\": \"Reciprocal Co-IP of nuclear COBLL1 with AR and CDK1 plus knockdown with morphological, proliferation, and migration phenotypes in CRPC cells\",\n      \"pmids\": [\"29686105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDK1 directly phosphorylates AR within the complex not established\", \"Mechanism of COBLL1 nuclear localization unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing how a viral oncoprotein controls COBLL1 expression revealed the locus is silenced epigenetically, identifying COBLL1 as an EBNA3C target.\",\n      \"evidence\": \"ChIP for H3K4me3/H3K27me3 and BMI1/SUZ12, Co-IP for EBNA3C-KDM2B, and recombinant virus with EBNA3C motif mutants\",\n      \"pmids\": [\"30135119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of COBLL1 silencing for EBV-transformed cells not defined\", \"Whether EBNA3C binds the COBLL1 locus directly or via cofactors unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolving the molecular basis of COBLL1-driven TKI resistance showed it acts as a competitive scaffold, sequestering PACSIN2 to release SH3BP1 and activate Rac1.\",\n      \"evidence\": \"Co-IP, competitive binding/pulldown affinity assays, and TKI apoptosis assays with Rac1 pathway readout in CML\",\n      \"pmids\": [\"35352878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for differential PACSIN2 affinity not determined\", \"Relationship between this Rac1 axis and the NF-\\u03baB mechanism not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic loss-of-function in vertebrate models established a developmental requirement for COBLL1, linking it to craniofacial and palate formation.\",\n      \"evidence\": \"CRISPR-Cas9 knockout in Xenopus laevis and Danio rerio with craniofacial morphological readout\",\n      \"pmids\": [\"36493769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway underlying the craniofacial defect not identified\", \"Relevance to human craniofacial disease not demonstrated in the corpus\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COBLL1's distinct scaffolding activities (AR/CDK1, IKK\\u03b3, PACSIN2, ROR1) relate to a unified biochemical function, and how its actin-binding domain contributes mechanistically, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of COBLL1 or its domains in the corpus\", \"No unifying biochemical activity connecting its multiple partner interactions\", \"Phosphorylation regulation only computationally predicted [#6]\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0008092\", \"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\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AR\", \"CDK1\", \"IKKG\", \"PACSIN2\", \"SH3BP1\", \"ROR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}