{"gene":"DBN1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2015,"finding":"C. elegans DBN-1 (drebrin-like protein) binds and bundles actin filaments in vitro, localizes to sarcomeres in body wall muscles, and alternates between myosin- and actin-rich regions during the contraction cycle. In contracted muscle, DBN-1 accumulates at I-bands where it regulates spacing of α-actinin and tropomyosin and protects actin filaments from ADF/cofilin-mediated depolymerization. Loss of DBN-1 results in partial F-actin depolymerization during muscle contraction.","method":"In vitro actin binding/bundling assay, in vivo live imaging in C. elegans, loss-of-function genetic analysis, immunofluorescence co-localization with α-actinin, tropomyosin, and ADF/cofilin","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted in vitro actin-binding assay combined with in vivo imaging and genetic loss-of-function with specific sarcomere phenotype, multiple orthogonal methods in one study","pmids":["26146072"],"is_preprint":false},{"year":2019,"finding":"C. elegans DBN-1 (ortholog of mammalian Drebrin/Abp1) interacts with WIP-1 via the cortactin-binding domain of WIP-1, and DBN-1 binding to F-actin is essential for recruitment of Dynamin-1 (DYN-1) to endocytic sites, thereby promoting scission of clathrin-coated pits in the intestine.","method":"Small-scale genetic screen, in vivo live imaging in C. elegans, loss-of-function analysis, direct binding interaction mapping","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo live imaging and genetic epistasis in C. elegans with defined endocytic scission phenotype, single lab, multiple methods","pmids":["31118234"],"is_preprint":false},{"year":2023,"finding":"Dbn1 is targeted for proteasomal degradation by the SCFβ-TrCP1 ubiquitin ligase in a mechanism driven by ATM-mediated phosphorylation of a previously uncharacterized β-TrCP1 degron containing an SQ motif, triggered by DNA double-strand breaks. This degron is sufficient to induce DNA damage-dependent protein degradation of a model substrate.","method":"UBIMAX (ubiquitin target identification by mass spectrometry in Xenopus egg extracts), proteasome inhibitor assays, degron mutagenesis, reconstitution in Xenopus extracts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution in Xenopus extracts, identification of E3 ligase, degron mutagenesis, and functional validation with model substrate across multiple orthogonal methods","pmids":["38097601"],"is_preprint":false},{"year":2021,"finding":"BAALC physically interacts with DBN1 (identified by mass spectrometry), and DBN1 promotes cell adhesion to bone marrow stromal cells. DBN1 knockdown impedes cell adhesion, resulting in improved sensitivity to cytarabine, suggesting the BAALC-DBN1 interaction contributes to leukemia cell anchoring in the bone marrow and chemoresistance.","method":"Mass spectrometry (pull-down/co-IP to identify binding partners), DBN1 knockdown, cell adhesion assay, cytarabine sensitivity assay","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — binding partner identified by mass spectrometry, functional validation by knockdown with adhesion and drug sensitivity phenotype, single lab","pmids":["33453340"],"is_preprint":false},{"year":2025,"finding":"DBN1 knockdown in T-ALL cells reduces migration and invasion. RNA sequencing revealed that DBN1 depletion reduces GAB2 expression, and downstream PI3K/AKT and MAPK/ERK signaling. GAB2 overexpression restored phosphorylation of AKT and ERK1/2 in DBN1-knockdown cells, placing DBN1 upstream of GAB2 in a signaling cascade promoting T-ALL cell migration and invasion. miR-218-5p was identified as an upstream suppressor that binds the 3'-UTR of DBN1.","method":"Lentiviral knockdown, RNA sequencing, western blotting, Transwell/Matrigel invasion assays, rescue experiments, dual-luciferase reporter assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with RNA-seq pathway analysis, rescue experiments validating GAB2-AKT/ERK axis, dual-luciferase for miR-218-5p, single lab with multiple orthogonal methods","pmids":["40910271"],"is_preprint":false},{"year":2020,"finding":"ITPKA interacts with DBN1 (Drebrin 1) in lung adenocarcinoma cells, and this interaction is mechanistically linked to induction of epithelial-mesenchymal transition (EMT) and promotion of cancer cell malignant phenotypes.","method":"Co-immunoprecipitation or pulldown (interaction with Drebrin 1 stated as mechanistic finding), in vitro functional assays for EMT","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction stated but method detail is limited in abstract; single lab, single reported interaction","pmids":["32015686"],"is_preprint":false},{"year":2025,"finding":"Upon chemical LTP (cLTP) stimulation, DBN1 serves as a postsynaptic compartment reporter. DBN1 downregulation causes a significant decrease in the proximity of RNA granule proteins to IGF2BP1 after synaptic stimulation, establishing a causal link between DBN1-dependent postsynaptic events and RNA granule dynamics (shift of translation machinery toward the postsynaptic compartment).","method":"Spatially-restricted biotinylation (proximity labeling) approach, protein accessibility/proximity quantification in postsynaptic and RNA granule subproteomes, DBN1 knockdown with functional readout on RNA granule protein proximity","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, novel proximity-labeling method, mechanistic link is indirect (proximity changes as readout)","pmids":["bio_10.1101_2025.07.16.665171"],"is_preprint":true},{"year":2014,"finding":"DBN1 co-localizes with actin in mouse brain, predominantly in cytoplasm edges and neurites. During neural stem cell (NSC) differentiation, DBN1 expression increases in extending neurites and shows co-localization with actin in neurites and dendritic spines, suggesting DBN1 regulates NSC differentiation by associating with filamentous actin.","method":"Immunohistochemistry, double-labeling immunofluorescence, quantitative RT-PCR during NSC differentiation","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by imaging without direct functional perturbation of DBN1, no loss-of-function experiment, single lab","pmids":["24814707"],"is_preprint":false}],"current_model":"DBN1 (Drebrin 1) is an actin-organizing protein that binds and bundles filamentous actin in sarcomeres and at endocytic sites, protects actin from ADF/cofilin-mediated depolymerization, promotes clathrin-coated pit scission by recruiting Dynamin via F-actin interactions, and is targeted for proteasomal degradation by the SCFβ-TrCP1 E3 ligase in an ATM-phosphorylation-dependent manner following DNA damage; in cancer contexts, DBN1 promotes cell migration and invasion upstream of GAB2/PI3K-AKT/MAPK-ERK signaling, mediates cell adhesion to stromal cells contributing to chemoresistance, and interacts with ITPKA to drive epithelial-mesenchymal transition."},"narrative":{"mechanistic_narrative":"DBN1 (Drebrin 1) is an actin-organizing protein that binds and bundles filamentous actin to shape cytoskeletal architecture in contexts ranging from sarcomeres to endocytic sites [PMID:26146072, PMID:31118234]. In striated muscle, DBN1 alternates between myosin- and actin-rich regions over the contraction cycle, accumulating at I-bands to regulate the spacing of α-actinin and tropomyosin and to protect actin filaments from ADF/cofilin-mediated depolymerization, such that its loss leads to partial F-actin breakdown during contraction [PMID:26146072]. At endocytic sites, DBN1 interacts with WIP-1 through the cortactin-binding domain of WIP-1, and its binding to F-actin is required to recruit Dynamin to promote scission of clathrin-coated pits [PMID:31118234]. DBN1 protein levels are controlled by DNA-damage signaling: ATM-mediated phosphorylation of a β-TrCP1 degron containing an SQ motif targets DBN1 for SCFβ-TrCP1-dependent proteasomal degradation following DNA double-strand breaks [PMID:38097601]. In cancer, DBN1 acts upstream of a GAB2–PI3K/AKT and MAPK/ERK signaling cascade to drive cell migration and invasion, and is itself suppressed by miR-218-5p binding its 3'-UTR [PMID:40910271]; it also mediates adhesion of leukemia cells to bone marrow stromal cells via interaction with BAALC, contributing to chemoresistance [PMID:33453340].","teleology":[{"year":2014,"claim":"Before functional dissection, it was unclear whether DBN1 associated with actin in a developmentally regulated manner in the nervous system; imaging during neural stem cell differentiation placed DBN1 at actin-rich neurites and dendritic spines.","evidence":"Immunohistochemistry, double-labeling immunofluorescence, and RT-PCR during NSC differentiation in mouse brain","pmids":["24814707"],"confidence":"Low","gaps":["No loss-of-function perturbation to establish causal role in differentiation","Co-localization alone does not demonstrate direct actin binding in this system","No molecular mechanism linking DBN1 to neurite outgrowth"]},{"year":2015,"claim":"It was unknown how DBN1 acts on actin biochemically; reconstitution plus in vivo analysis established it as an actin bundler that protects filaments from cofilin-mediated depolymerization and organizes sarcomeric architecture.","evidence":"In vitro actin binding/bundling assays, live imaging and loss-of-function in C. elegans, co-localization with α-actinin, tropomyosin, ADF/cofilin","pmids":["26146072"],"confidence":"High","gaps":["Demonstrated in C. elegans sarcomeres; conservation of the I-band role in mammalian muscle not directly tested here","Structural basis of the actin-protective bundling not resolved"]},{"year":2019,"claim":"The role of DBN1 in membrane traffic was undefined; genetic and imaging work showed DBN1 F-actin binding is required to recruit Dynamin and drive clathrin-coated pit scission, linking it to WIP-1.","evidence":"Genetic screen, in vivo live imaging, loss-of-function, and interaction mapping in C. elegans intestine","pmids":["31118234"],"confidence":"Medium","gaps":["Direct biochemical demonstration of DBN1-mediated Dynamin recruitment not reconstituted","Whether the WIP-1 interaction is conserved in mammalian endocytosis not addressed"]},{"year":2020,"claim":"Whether DBN1 contributes to tumor cell plasticity was open; a reported ITPKA-DBN1 interaction was linked to EMT in lung adenocarcinoma.","evidence":"Co-immunoprecipitation/pulldown and in vitro EMT functional assays in lung adenocarcinoma cells","pmids":["32015686"],"confidence":"Low","gaps":["Interaction method detail limited; not reciprocally validated","Molecular mechanism linking the interaction to EMT not defined","Single lab, single reported interaction"]},{"year":2021,"claim":"The basis of DBN1's contribution to leukemia microenvironment anchoring was unknown; mass spectrometry identified BAALC as a partner and knockdown linked DBN1 to stromal adhesion and chemoresistance.","evidence":"Mass spectrometry interaction screen, DBN1 knockdown, cell adhesion and cytarabine sensitivity assays","pmids":["33453340"],"confidence":"Medium","gaps":["Direct vs indirect nature of the BAALC-DBN1 interaction not established","Whether adhesion depends on DBN1 actin-bundling activity not tested","Single lab"]},{"year":2023,"claim":"Regulation of DBN1 abundance was uncharacterized; biochemical reconstitution showed ATM phosphorylation of an SQ-containing β-TrCP1 degron triggers SCFβ-TrCP1-mediated proteasomal degradation after DNA double-strand breaks.","evidence":"UBIMAX mass spectrometry, proteasome inhibitor assays, degron mutagenesis, and reconstitution in Xenopus egg extracts","pmids":["38097601"],"confidence":"High","gaps":["Functional consequence of DBN1 degradation for the DNA damage response not defined","Whether actin-related functions are coupled to this turnover not addressed"]},{"year":2025,"claim":"How DBN1 promotes tumor invasion mechanistically was unresolved; knockdown plus RNA-seq and rescue placed DBN1 upstream of GAB2-driven PI3K/AKT and MAPK/ERK signaling, with miR-218-5p as an upstream repressor.","evidence":"Lentiviral knockdown, RNA-seq, western blot, Transwell/Matrigel invasion, GAB2 rescue, and dual-luciferase reporter in T-ALL cells","pmids":["40910271"],"confidence":"Medium","gaps":["Mechanism by which DBN1 controls GAB2 expression not defined","Connection between DBN1 actin function and the signaling axis unclear","Single lab"]},{"year":2025,"claim":"DBN1's role in synaptic translation compartmentalization was unexplored; proximity labeling used DBN1 as a postsynaptic reporter and linked its downregulation to altered RNA granule protein proximity to IGF2BP1.","evidence":"Spatially-restricted biotinylation proximity labeling and DBN1 knockdown with RNA granule subproteome readout (preprint)","pmids":["bio_10.1101_2025.07.16.665171"],"confidence":"Low","gaps":["Preprint; mechanistic link is indirect (proximity changes as readout)","Direct DBN1 effect on local translation not demonstrated","Single lab, novel method not independently validated"]},{"year":null,"claim":"Whether DBN1's actin-bundling/anti-cofilin activity is the unifying mechanism beneath its endocytic, oncogenic-signaling, and synaptic roles, and how its DNA-damage-triggered turnover intersects these functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study connects the actin function to the GAB2 signaling axis","No structural model of DBN1-F-actin interaction in the corpus","Functional purpose of DNA-damage-dependent DBN1 degradation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]}],"complexes":[],"partners":["WIP-1","DYN-1","BAALC","ITPKA","GAB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16643","full_name":"Drebrin","aliases":["Developmentally-regulated brain protein"],"length_aa":649,"mass_kda":71.4,"function":"Actin cytoskeleton-organizing protein that plays a role in the formation of cell projections (PubMed:20215400). Required for actin polymerization at immunological synapses (IS) and for the recruitment of the chemokine receptor CXCR4 to IS (PubMed:20215400). Plays a role in dendritic spine morphogenesis and organization, including the localization of the dopamine receptor DRD1 to the dendritic spines (By similarity). Involved in memory-related synaptic plasticity in the hippocampus (By similarity)","subcellular_location":"Cytoplasm; Cell projection, dendrite; Cytoplasm, cell cortex; Cell junction; Cell projection, growth cone","url":"https://www.uniprot.org/uniprotkb/Q16643/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DBN1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTTN","stoichiometry":4.0},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DBN1","total_profiled":1310},"omim":[{"mim_id":"610106","title":"DREBRIN-LIKE; DBNL","url":"https://www.omim.org/entry/610106"},{"mim_id":"603256","title":"LEUCINE-RICH REPEAT IN FLII-INTERACTING PROTEIN 1; LRRFIP1","url":"https://www.omim.org/entry/603256"},{"mim_id":"126660","title":"DREBRIN E; DBN1","url":"https://www.omim.org/entry/126660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DBN1"},"hgnc":{"alias_symbol":[],"prev_symbol":["D0S117E"]},"alphafold":{"accession":"Q16643","domains":[{"cath_id":"3.40.20.10","chopping":"10-143","consensus_level":"high","plddt":91.1974,"start":10,"end":143},{"cath_id":"1.20.5","chopping":"178-284","consensus_level":"high","plddt":85.7675,"start":178,"end":284}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16643","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16643-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16643-F1-predicted_aligned_error_v6.png","plddt_mean":61.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DBN1","jax_strain_url":"https://www.jax.org/strain/search?query=DBN1"},"sequence":{"accession":"Q16643","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16643.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16643/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16643"}},"corpus_meta":[{"pmid":"32015686","id":"PMC_32015686","title":"TFAP2A Induced ITPKA Serves as an Oncogene and Interacts with DBN1 in Lung Adenocarcinoma.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32015686","citation_count":35,"is_preprint":false},{"pmid":"24610677","id":"PMC_24610677","title":"iTRAQ analysis of colorectal cancer cell lines suggests Drebrin (DBN1) is overexpressed during liver metastasis.","date":"2014","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/24610677","citation_count":31,"is_preprint":false},{"pmid":"33324629","id":"PMC_33324629","title":"Long Non-coding RNA H19 Regulates Porcine Satellite Cell Differentiation Through miR-140-5p/SOX4 and DBN1.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33324629","citation_count":26,"is_preprint":false},{"pmid":"26146072","id":"PMC_26146072","title":"Drebrin-like protein DBN-1 is a sarcomere component that stabilizes actin filaments during muscle contraction.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26146072","citation_count":18,"is_preprint":false},{"pmid":"34092977","id":"PMC_34092977","title":"Upregulation of long noncoding RNA W42 promotes tumor development by binding with DBN1 in hepatocellular carcinoma.","date":"2021","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/34092977","citation_count":13,"is_preprint":false},{"pmid":"24814707","id":"PMC_24814707","title":"Expression of Dbn1 during mouse brain development and neural stem cell differentiation.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24814707","citation_count":9,"is_preprint":false},{"pmid":"31118234","id":"PMC_31118234","title":"WIP-1 and DBN-1 promote scission of endocytic vesicles by bridging actin and Dynamin-1 in the C. elegans intestine.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31118234","citation_count":8,"is_preprint":false},{"pmid":"32545448","id":"PMC_32545448","title":"Integrated Analysis of Key Differentially Expressed Genes Identifies DBN1 as a Predictive Marker of Response to Endocrine Therapy in Luminal Breast Cancer.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32545448","citation_count":7,"is_preprint":false},{"pmid":"30880752","id":"PMC_30880752","title":"Downregulation of DBN1 is related to vincristine resistance in colon cancer cells.","date":"2019","source":"Journal of cancer research and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/30880752","citation_count":5,"is_preprint":false},{"pmid":"40910271","id":"PMC_40910271","title":"DBN1‑mediated upregulation of GAB2 facilitates the migration and invasion of T‑cell acute lymphoblastic leukemia cells.","date":"2025","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40910271","citation_count":3,"is_preprint":false},{"pmid":"33453340","id":"PMC_33453340","title":"Physical interaction between BAALC and DBN1 induces chemoresistance in leukemia.","date":"2021","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/33453340","citation_count":3,"is_preprint":false},{"pmid":"38097601","id":"PMC_38097601","title":"Profiling ubiquitin signalling with UBIMAX reveals DNA damage- and SCFβ-Trcp1-dependent ubiquitylation of the actin-organizing protein Dbn1.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38097601","citation_count":1,"is_preprint":false},{"pmid":"41655191","id":"PMC_41655191","title":"ANXA2, DBN1, ZNF385D, and IL6ST: Endothelial cell biomarkers linking atherosclerosis progression to immune microenvironment dysregulation.","date":"2026","source":"Clinical and experimental hypertension (New York, N.Y. : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/41655191","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.16.665171","title":"Concerted remodelling of the postsynaptic spine and RNA granule by cLTP","date":"2025-07-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.16.665171","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.02.679723","title":"SPP1  <sup>+</sup>  macrophages promote the growth and metastasis of intrahepatic cholangiocarcinoma via OSM and THBS1 signaling","date":"2025-10-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.02.679723","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9733,"output_tokens":2324,"usd":0.03203,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9434,"output_tokens":3243,"usd":0.064122,"stage2_stop_reason":"end_turn"},"total_usd":0.096152,"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\": 2015,\n      \"finding\": \"C. elegans DBN-1 (drebrin-like protein) binds and bundles actin filaments in vitro, localizes to sarcomeres in body wall muscles, and alternates between myosin- and actin-rich regions during the contraction cycle. In contracted muscle, DBN-1 accumulates at I-bands where it regulates spacing of α-actinin and tropomyosin and protects actin filaments from ADF/cofilin-mediated depolymerization. Loss of DBN-1 results in partial F-actin depolymerization during muscle contraction.\",\n      \"method\": \"In vitro actin binding/bundling assay, in vivo live imaging in C. elegans, loss-of-function genetic analysis, immunofluorescence co-localization with α-actinin, tropomyosin, and ADF/cofilin\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted in vitro actin-binding assay combined with in vivo imaging and genetic loss-of-function with specific sarcomere phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26146072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C. elegans DBN-1 (ortholog of mammalian Drebrin/Abp1) interacts with WIP-1 via the cortactin-binding domain of WIP-1, and DBN-1 binding to F-actin is essential for recruitment of Dynamin-1 (DYN-1) to endocytic sites, thereby promoting scission of clathrin-coated pits in the intestine.\",\n      \"method\": \"Small-scale genetic screen, in vivo live imaging in C. elegans, loss-of-function analysis, direct binding interaction mapping\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo live imaging and genetic epistasis in C. elegans with defined endocytic scission phenotype, single lab, multiple methods\",\n      \"pmids\": [\"31118234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Dbn1 is targeted for proteasomal degradation by the SCFβ-TrCP1 ubiquitin ligase in a mechanism driven by ATM-mediated phosphorylation of a previously uncharacterized β-TrCP1 degron containing an SQ motif, triggered by DNA double-strand breaks. This degron is sufficient to induce DNA damage-dependent protein degradation of a model substrate.\",\n      \"method\": \"UBIMAX (ubiquitin target identification by mass spectrometry in Xenopus egg extracts), proteasome inhibitor assays, degron mutagenesis, reconstitution in Xenopus extracts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution in Xenopus extracts, identification of E3 ligase, degron mutagenesis, and functional validation with model substrate across multiple orthogonal methods\",\n      \"pmids\": [\"38097601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAALC physically interacts with DBN1 (identified by mass spectrometry), and DBN1 promotes cell adhesion to bone marrow stromal cells. DBN1 knockdown impedes cell adhesion, resulting in improved sensitivity to cytarabine, suggesting the BAALC-DBN1 interaction contributes to leukemia cell anchoring in the bone marrow and chemoresistance.\",\n      \"method\": \"Mass spectrometry (pull-down/co-IP to identify binding partners), DBN1 knockdown, cell adhesion assay, cytarabine sensitivity assay\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — binding partner identified by mass spectrometry, functional validation by knockdown with adhesion and drug sensitivity phenotype, single lab\",\n      \"pmids\": [\"33453340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DBN1 knockdown in T-ALL cells reduces migration and invasion. RNA sequencing revealed that DBN1 depletion reduces GAB2 expression, and downstream PI3K/AKT and MAPK/ERK signaling. GAB2 overexpression restored phosphorylation of AKT and ERK1/2 in DBN1-knockdown cells, placing DBN1 upstream of GAB2 in a signaling cascade promoting T-ALL cell migration and invasion. miR-218-5p was identified as an upstream suppressor that binds the 3'-UTR of DBN1.\",\n      \"method\": \"Lentiviral knockdown, RNA sequencing, western blotting, Transwell/Matrigel invasion assays, rescue experiments, dual-luciferase reporter assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with RNA-seq pathway analysis, rescue experiments validating GAB2-AKT/ERK axis, dual-luciferase for miR-218-5p, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40910271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITPKA interacts with DBN1 (Drebrin 1) in lung adenocarcinoma cells, and this interaction is mechanistically linked to induction of epithelial-mesenchymal transition (EMT) and promotion of cancer cell malignant phenotypes.\",\n      \"method\": \"Co-immunoprecipitation or pulldown (interaction with Drebrin 1 stated as mechanistic finding), in vitro functional assays for EMT\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction stated but method detail is limited in abstract; single lab, single reported interaction\",\n      \"pmids\": [\"32015686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Upon chemical LTP (cLTP) stimulation, DBN1 serves as a postsynaptic compartment reporter. DBN1 downregulation causes a significant decrease in the proximity of RNA granule proteins to IGF2BP1 after synaptic stimulation, establishing a causal link between DBN1-dependent postsynaptic events and RNA granule dynamics (shift of translation machinery toward the postsynaptic compartment).\",\n      \"method\": \"Spatially-restricted biotinylation (proximity labeling) approach, protein accessibility/proximity quantification in postsynaptic and RNA granule subproteomes, DBN1 knockdown with functional readout on RNA granule protein proximity\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, novel proximity-labeling method, mechanistic link is indirect (proximity changes as readout)\",\n      \"pmids\": [\"bio_10.1101_2025.07.16.665171\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DBN1 co-localizes with actin in mouse brain, predominantly in cytoplasm edges and neurites. During neural stem cell (NSC) differentiation, DBN1 expression increases in extending neurites and shows co-localization with actin in neurites and dendritic spines, suggesting DBN1 regulates NSC differentiation by associating with filamentous actin.\",\n      \"method\": \"Immunohistochemistry, double-labeling immunofluorescence, quantitative RT-PCR during NSC differentiation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by imaging without direct functional perturbation of DBN1, no loss-of-function experiment, single lab\",\n      \"pmids\": [\"24814707\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DBN1 (Drebrin 1) is an actin-organizing protein that binds and bundles filamentous actin in sarcomeres and at endocytic sites, protects actin from ADF/cofilin-mediated depolymerization, promotes clathrin-coated pit scission by recruiting Dynamin via F-actin interactions, and is targeted for proteasomal degradation by the SCFβ-TrCP1 E3 ligase in an ATM-phosphorylation-dependent manner following DNA damage; in cancer contexts, DBN1 promotes cell migration and invasion upstream of GAB2/PI3K-AKT/MAPK-ERK signaling, mediates cell adhesion to stromal cells contributing to chemoresistance, and interacts with ITPKA to drive epithelial-mesenchymal transition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DBN1 (Drebrin 1) is an actin-organizing protein that binds and bundles filamentous actin to shape cytoskeletal architecture in contexts ranging from sarcomeres to endocytic sites [#0, #1]. In striated muscle, DBN1 alternates between myosin- and actin-rich regions over the contraction cycle, accumulating at I-bands to regulate the spacing of \\u03b1-actinin and tropomyosin and to protect actin filaments from ADF/cofilin-mediated depolymerization, such that its loss leads to partial F-actin breakdown during contraction [#0]. At endocytic sites, DBN1 interacts with WIP-1 through the cortactin-binding domain of WIP-1, and its binding to F-actin is required to recruit Dynamin to promote scission of clathrin-coated pits [#1]. DBN1 protein levels are controlled by DNA-damage signaling: ATM-mediated phosphorylation of a \\u03b2-TrCP1 degron containing an SQ motif targets DBN1 for SCF\\u03b2-TrCP1-dependent proteasomal degradation following DNA double-strand breaks [#2]. In cancer, DBN1 acts upstream of a GAB2\\u2013PI3K/AKT and MAPK/ERK signaling cascade to drive cell migration and invasion, and is itself suppressed by miR-218-5p binding its 3'-UTR [#4]; it also mediates adhesion of leukemia cells to bone marrow stromal cells via interaction with BAALC, contributing to chemoresistance [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Before functional dissection, it was unclear whether DBN1 associated with actin in a developmentally regulated manner in the nervous system; imaging during neural stem cell differentiation placed DBN1 at actin-rich neurites and dendritic spines.\",\n      \"evidence\": \"Immunohistochemistry, double-labeling immunofluorescence, and RT-PCR during NSC differentiation in mouse brain\",\n      \"pmids\": [\"24814707\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No loss-of-function perturbation to establish causal role in differentiation\",\n        \"Co-localization alone does not demonstrate direct actin binding in this system\",\n        \"No molecular mechanism linking DBN1 to neurite outgrowth\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"It was unknown how DBN1 acts on actin biochemically; reconstitution plus in vivo analysis established it as an actin bundler that protects filaments from cofilin-mediated depolymerization and organizes sarcomeric architecture.\",\n      \"evidence\": \"In vitro actin binding/bundling assays, live imaging and loss-of-function in C. elegans, co-localization with \\u03b1-actinin, tropomyosin, ADF/cofilin\",\n      \"pmids\": [\"26146072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Demonstrated in C. elegans sarcomeres; conservation of the I-band role in mammalian muscle not directly tested here\",\n        \"Structural basis of the actin-protective bundling not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The role of DBN1 in membrane traffic was undefined; genetic and imaging work showed DBN1 F-actin binding is required to recruit Dynamin and drive clathrin-coated pit scission, linking it to WIP-1.\",\n      \"evidence\": \"Genetic screen, in vivo live imaging, loss-of-function, and interaction mapping in C. elegans intestine\",\n      \"pmids\": [\"31118234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical demonstration of DBN1-mediated Dynamin recruitment not reconstituted\",\n        \"Whether the WIP-1 interaction is conserved in mammalian endocytosis not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether DBN1 contributes to tumor cell plasticity was open; a reported ITPKA-DBN1 interaction was linked to EMT in lung adenocarcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown and in vitro EMT functional assays in lung adenocarcinoma cells\",\n      \"pmids\": [\"32015686\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Interaction method detail limited; not reciprocally validated\",\n        \"Molecular mechanism linking the interaction to EMT not defined\",\n        \"Single lab, single reported interaction\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The basis of DBN1's contribution to leukemia microenvironment anchoring was unknown; mass spectrometry identified BAALC as a partner and knockdown linked DBN1 to stromal adhesion and chemoresistance.\",\n      \"evidence\": \"Mass spectrometry interaction screen, DBN1 knockdown, cell adhesion and cytarabine sensitivity assays\",\n      \"pmids\": [\"33453340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct vs indirect nature of the BAALC-DBN1 interaction not established\",\n        \"Whether adhesion depends on DBN1 actin-bundling activity not tested\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Regulation of DBN1 abundance was uncharacterized; biochemical reconstitution showed ATM phosphorylation of an SQ-containing \\u03b2-TrCP1 degron triggers SCF\\u03b2-TrCP1-mediated proteasomal degradation after DNA double-strand breaks.\",\n      \"evidence\": \"UBIMAX mass spectrometry, proteasome inhibitor assays, degron mutagenesis, and reconstitution in Xenopus egg extracts\",\n      \"pmids\": [\"38097601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of DBN1 degradation for the DNA damage response not defined\",\n        \"Whether actin-related functions are coupled to this turnover not addressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How DBN1 promotes tumor invasion mechanistically was unresolved; knockdown plus RNA-seq and rescue placed DBN1 upstream of GAB2-driven PI3K/AKT and MAPK/ERK signaling, with miR-218-5p as an upstream repressor.\",\n      \"evidence\": \"Lentiviral knockdown, RNA-seq, western blot, Transwell/Matrigel invasion, GAB2 rescue, and dual-luciferase reporter in T-ALL cells\",\n      \"pmids\": [\"40910271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which DBN1 controls GAB2 expression not defined\",\n        \"Connection between DBN1 actin function and the signaling axis unclear\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DBN1's role in synaptic translation compartmentalization was unexplored; proximity labeling used DBN1 as a postsynaptic reporter and linked its downregulation to altered RNA granule protein proximity to IGF2BP1.\",\n      \"evidence\": \"Spatially-restricted biotinylation proximity labeling and DBN1 knockdown with RNA granule subproteome readout (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.16.665171\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Preprint; mechanistic link is indirect (proximity changes as readout)\",\n        \"Direct DBN1 effect on local translation not demonstrated\",\n        \"Single lab, novel method not independently validated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether DBN1's actin-bundling/anti-cofilin activity is the unifying mechanism beneath its endocytic, oncogenic-signaling, and synaptic roles, and how its DNA-damage-triggered turnover intersects these functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study connects the actin function to the GAB2 signaling axis\",\n        \"No structural model of DBN1-F-actin interaction in the corpus\",\n        \"Functional purpose of DNA-damage-dependent DBN1 degradation undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WIP-1\", \"DYN-1\", \"BAALC\", \"ITPKA\", \"GAB2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}