{"gene":"DENND1B","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2016,"finding":"DENND1B acts as a guanine nucleotide exchange factor (GEF) for Rab35, and interacts with AP-2 and Rab35 to regulate TCR downmodulation specifically in TH2 cells. Loss of DENND1B, AP-2, or Rab35 causes delayed receptor-induced TCR internalization, enhanced TCR signaling, and increased effector cytokine production in TH2 cells.","method":"Dennd1b knockout mouse generation; genetic epistasis with AP-2 and Rab35 knockouts; TCR downmodulation assay; cytokine production assays; human TH2 cell phenotyping with asthma-associated variants","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic epistasis, KO mouse with defined cellular phenotype, replicated in human cells with multiple orthogonal methods","pmids":["26774822"],"is_preprint":false},{"year":2020,"finding":"DENND1B localizes to novel 'gathered line' structures at the basal side of adherent cells in a manner dependent on its C-terminal region. These structures associate with microtubules (but not F-actin) and appear at spreading lamellipodia edges during EGF-stimulated cell migration, implicating DENND1B in cell motility regulation.","method":"Live-cell imaging, subcellular fractionation/localization, deletion mutant analysis, EGF stimulation assay, fluorescence microscopy of cytoskeletal markers","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiment with functional link to cell migration, single lab, single study","pmids":["33135087"],"is_preprint":false},{"year":2025,"finding":"DENND1B regulates signaling and trafficking of melanocortin 4 receptor (MC4R), a critical controller of energy homeostasis, establishing a role for DENND1B in obesity beyond immune function.","method":"Canine GWAS cross-species validation; functional assays demonstrating MC4R signaling and trafficking regulation","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 — cross-species functional validation of MC4R trafficking, single study but with multiple approaches","pmids":["40048553"],"is_preprint":false}],"current_model":"DENND1B is a DENN-domain GEF for Rab35 that, in complex with AP-2, mediates TCR internalization and downmodulation specifically in TH2 cells to restrain allergic immune responses; it also regulates MC4R trafficking to control energy homeostasis, and its C-terminal domain directs it to basal cytoskeletal structures involved in cell migration."},"narrative":{"teleology":[{"year":2016,"claim":"The central question of how TH2-specific TCR downmodulation is controlled was resolved by demonstrating that DENND1B functions as a Rab35 GEF and, together with AP-2 and Rab35, drives receptor-induced TCR internalization to limit TH2 effector cytokine production.","evidence":"Dennd1b knockout mice, genetic epistasis with AP-2 and Rab35 loss, TCR downmodulation and cytokine assays, replication in human TH2 cells carrying asthma-associated variants","pmids":["26774822"],"confidence":"High","gaps":["Structural basis of DENND1B selectivity for Rab35 over other Rabs is undefined","Whether DENND1B regulates internalization of receptors other than TCR in immune cells was untested","Downstream effectors of Rab35 in TCR endocytic trafficking are uncharacterized"]},{"year":2020,"claim":"The subcellular site of DENND1B action outside the immune system was identified when its C-terminal region was shown to direct it to basal microtubule-associated 'gathered line' structures at spreading lamellipodia, linking DENND1B to EGF-stimulated cell migration.","evidence":"Live-cell imaging, deletion mutant analysis, fluorescence microscopy of cytoskeletal markers in adherent cells stimulated with EGF","pmids":["33135087"],"confidence":"Medium","gaps":["Single-lab observation not yet independently replicated","Whether Rab35 GEF activity is required at these basal structures is untested","The molecular identity and function of 'gathered line' structures remain poorly defined"]},{"year":2025,"claim":"DENND1B's functional repertoire was expanded beyond immunity when cross-species studies demonstrated that it regulates MC4R signaling and trafficking, establishing a mechanistic link between DENND1B and energy homeostasis.","evidence":"Canine GWAS with cross-species validation; functional assays measuring MC4R signaling and trafficking","pmids":["40048553"],"confidence":"Medium","gaps":["Whether Rab35 mediates DENND1B's effects on MC4R trafficking is not established","The specific trafficking step (internalization, recycling, degradation) controlled by DENND1B for MC4R is unresolved","In vivo metabolic phenotyping of DENND1B loss in the context of MC4R-driven energy homeostasis has not been reported"]},{"year":null,"claim":"A unifying model of how DENND1B coordinates Rab35-dependent trafficking across its diverse receptor substrates (TCR, MC4R, and potentially others) and how its C-terminal domain-directed localization integrates with its GEF activity at distinct subcellular sites remains to be constructed.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for DENND1B or its complex with Rab35/AP-2 exist","Systematic identification of DENND1B cargo receptors has not been performed","The relative contributions of GEF-dependent versus GEF-independent functions of DENND1B are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["RAB35","AP2A1","MC4R"],"other_free_text":[]},"mechanistic_narrative":"DENND1B is a DENN-domain guanine nucleotide exchange factor (GEF) for Rab35 that, in complex with AP-2, drives clathrin-mediated internalization of surface receptors including the T-cell receptor (TCR) in TH2 cells, thereby restraining TCR signaling and effector cytokine production in allergic immune responses [PMID:26774822]. Beyond immune regulation, DENND1B controls melanocortin 4 receptor (MC4R) signaling and trafficking, linking it to energy homeostasis and obesity [PMID:40048553]. Its C-terminal region directs localization to basal microtubule-associated structures at spreading lamellipodia edges, implicating DENND1B in EGF-stimulated cell migration [PMID:33135087]."},"prefetch_data":{"uniprot":{"accession":"Q6P3S1","full_name":"DENN domain-containing protein 1B","aliases":["Connecdenn 2","Protein FAM31B"],"length_aa":775,"mass_kda":86.6,"function":"Guanine nucleotide exchange factor (GEF) for RAB35 that acts as a regulator of T-cell receptor (TCR) internalization in TH2 cells (PubMed:20154091, PubMed:20937701, PubMed:24520163, PubMed:26774822). Acts by promoting the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form (PubMed:20154091, PubMed:20937701). Plays a role in clathrin-mediated endocytosis (PubMed:20154091). Controls cytokine production in TH2 lymphocytes by controlling the rate of TCR internalization and routing to endosomes: acts by mediating clathrin-mediated endocytosis of TCR via its interaction with the adapter protein complex 2 (AP-2) and GEF activity (PubMed:26774822). Dysregulation leads to impaired TCR down-modulation and recycling, affecting cytokine production in TH2 cells (PubMed:26774822)","subcellular_location":"Cytoplasm, cytosol; Cytoplasmic vesicle, clathrin-coated vesicle","url":"https://www.uniprot.org/uniprotkb/Q6P3S1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DENND1B","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DENND1B","total_profiled":1310},"omim":[{"mim_id":"613634","title":"DENN/MADD DOMAIN-CONTAINING PROTEIN 1C; DENND1C","url":"https://www.omim.org/entry/613634"},{"mim_id":"613633","title":"DENN/MADD DOMAIN-CONTAINING PROTEIN 1A; DENND1A","url":"https://www.omim.org/entry/613633"},{"mim_id":"613292","title":"DENN/MADD DOMAIN-CONTAINING PROTEIN 1B; DENND1B","url":"https://www.omim.org/entry/613292"},{"mim_id":"611403","title":"ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 6","url":"https://www.omim.org/entry/611403"},{"mim_id":"600807","title":"ASTHMA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/600807"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DENND1B"},"hgnc":{"alias_symbol":["MGC27044","FLJ20054"],"prev_symbol":["FAM31B","C1orf218"]},"alphafold":{"accession":"Q6P3S1","domains":[{"cath_id":"3.30.450.200","chopping":"2-142","consensus_level":"medium","plddt":91.8248,"start":2,"end":142},{"cath_id":"-","chopping":"336-440","consensus_level":"medium","plddt":83.0288,"start":336,"end":440}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P3S1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P3S1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P3S1-F1-predicted_aligned_error_v6.png","plddt_mean":66.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DENND1B","jax_strain_url":"https://www.jax.org/strain/search?query=DENND1B"},"sequence":{"accession":"Q6P3S1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P3S1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P3S1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P3S1"}},"corpus_meta":[{"pmid":"20032318","id":"PMC_20032318","title":"Variants of DENND1B associated with asthma in children.","date":"2009","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20032318","citation_count":252,"is_preprint":false},{"pmid":"26774822","id":"PMC_26774822","title":"Regulation of T Cell Receptor Signaling by DENND1B in TH2 Cells and Allergic Disease.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26774822","citation_count":55,"is_preprint":false},{"pmid":"24712925","id":"PMC_24712925","title":"Reduced expression of TLR3, TLR10 and TREM1 by human macrophages in Chronic cavitary pulmonary aspergillosis, and novel associations of VEGFA, DENND1B and PLAT.","date":"2014","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24712925","citation_count":33,"is_preprint":false},{"pmid":"34828435","id":"PMC_34828435","title":"CircNFIC Balances Inflammation and Apoptosis by Sponging miR-30e-3p and Regulating DENND1B Expression.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34828435","citation_count":17,"is_preprint":false},{"pmid":"28668455","id":"PMC_28668455","title":"Polymorphisms in DENND1B gene are associated with asthma and atopy phenotypes in Brazilian children.","date":"2017","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28668455","citation_count":10,"is_preprint":false},{"pmid":"40048553","id":"PMC_40048553","title":"Canine genome-wide association study identifies DENND1B as an obesity gene in dogs and humans.","date":"2025","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40048553","citation_count":9,"is_preprint":false},{"pmid":"24347560","id":"PMC_24347560","title":"DENND1B gene variants associate with elevated exhaled nitric oxide in healthy high-risk neonates.","date":"2013","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/24347560","citation_count":9,"is_preprint":false},{"pmid":"36578555","id":"PMC_36578555","title":"circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis.","date":"2022","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36578555","citation_count":3,"is_preprint":false},{"pmid":"33135087","id":"PMC_33135087","title":"A novel DENND1B-localized structure found at the basal side of adherent cells.","date":"2020","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33135087","citation_count":2,"is_preprint":false},{"pmid":"31608842","id":"PMC_31608842","title":"Variation at DENND1B and Asthma on the Island of Tristan da Cunha.","date":"2019","source":"Twin research and human genetics : the official journal of the International Society for Twin Studies","url":"https://pubmed.ncbi.nlm.nih.gov/31608842","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.26.25334362","title":"Genome-wide meta-analysis and integrative fine-mapping identify novel susceptibility loci and effector genes in psoriatic arthritis","date":"2025-08-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.26.25334362","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.04.641446","title":"Sex-biased Transcriptome in <i>in vitro</i> Produced Bovine Early Embryos","date":"2025-03-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.04.641446","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7889,"output_tokens":784,"usd":0.017714},"stage2":{"model":"claude-opus-4-6","input_tokens":3966,"output_tokens":1364,"usd":0.080895},"total_usd":0.098609,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"DENND1B acts as a guanine nucleotide exchange factor (GEF) for Rab35, and interacts with AP-2 and Rab35 to regulate TCR downmodulation specifically in TH2 cells. Loss of DENND1B, AP-2, or Rab35 causes delayed receptor-induced TCR internalization, enhanced TCR signaling, and increased effector cytokine production in TH2 cells.\",\n      \"method\": \"Dennd1b knockout mouse generation; genetic epistasis with AP-2 and Rab35 knockouts; TCR downmodulation assay; cytokine production assays; human TH2 cell phenotyping with asthma-associated variants\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic epistasis, KO mouse with defined cellular phenotype, replicated in human cells with multiple orthogonal methods\",\n      \"pmids\": [\"26774822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DENND1B localizes to novel 'gathered line' structures at the basal side of adherent cells in a manner dependent on its C-terminal region. These structures associate with microtubules (but not F-actin) and appear at spreading lamellipodia edges during EGF-stimulated cell migration, implicating DENND1B in cell motility regulation.\",\n      \"method\": \"Live-cell imaging, subcellular fractionation/localization, deletion mutant analysis, EGF stimulation assay, fluorescence microscopy of cytoskeletal markers\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment with functional link to cell migration, single lab, single study\",\n      \"pmids\": [\"33135087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DENND1B regulates signaling and trafficking of melanocortin 4 receptor (MC4R), a critical controller of energy homeostasis, establishing a role for DENND1B in obesity beyond immune function.\",\n      \"method\": \"Canine GWAS cross-species validation; functional assays demonstrating MC4R signaling and trafficking regulation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-species functional validation of MC4R trafficking, single study but with multiple approaches\",\n      \"pmids\": [\"40048553\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DENND1B is a DENN-domain GEF for Rab35 that, in complex with AP-2, mediates TCR internalization and downmodulation specifically in TH2 cells to restrain allergic immune responses; it also regulates MC4R trafficking to control energy homeostasis, and its C-terminal domain directs it to basal cytoskeletal structures involved in cell migration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DENND1B is a DENN-domain guanine nucleotide exchange factor (GEF) for Rab35 that, in complex with AP-2, drives clathrin-mediated internalization of surface receptors including the T-cell receptor (TCR) in TH2 cells, thereby restraining TCR signaling and effector cytokine production in allergic immune responses [PMID:26774822]. Beyond immune regulation, DENND1B controls melanocortin 4 receptor (MC4R) signaling and trafficking, linking it to energy homeostasis and obesity [PMID:40048553]. Its C-terminal region directs localization to basal microtubule-associated structures at spreading lamellipodia edges, implicating DENND1B in EGF-stimulated cell migration [PMID:33135087].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"The central question of how TH2-specific TCR downmodulation is controlled was resolved by demonstrating that DENND1B functions as a Rab35 GEF and, together with AP-2 and Rab35, drives receptor-induced TCR internalization to limit TH2 effector cytokine production.\",\n      \"evidence\": \"Dennd1b knockout mice, genetic epistasis with AP-2 and Rab35 loss, TCR downmodulation and cytokine assays, replication in human TH2 cells carrying asthma-associated variants\",\n      \"pmids\": [\"26774822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of DENND1B selectivity for Rab35 over other Rabs is undefined\",\n        \"Whether DENND1B regulates internalization of receptors other than TCR in immune cells was untested\",\n        \"Downstream effectors of Rab35 in TCR endocytic trafficking are uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The subcellular site of DENND1B action outside the immune system was identified when its C-terminal region was shown to direct it to basal microtubule-associated 'gathered line' structures at spreading lamellipodia, linking DENND1B to EGF-stimulated cell migration.\",\n      \"evidence\": \"Live-cell imaging, deletion mutant analysis, fluorescence microscopy of cytoskeletal markers in adherent cells stimulated with EGF\",\n      \"pmids\": [\"33135087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab observation not yet independently replicated\",\n        \"Whether Rab35 GEF activity is required at these basal structures is untested\",\n        \"The molecular identity and function of 'gathered line' structures remain poorly defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DENND1B's functional repertoire was expanded beyond immunity when cross-species studies demonstrated that it regulates MC4R signaling and trafficking, establishing a mechanistic link between DENND1B and energy homeostasis.\",\n      \"evidence\": \"Canine GWAS with cross-species validation; functional assays measuring MC4R signaling and trafficking\",\n      \"pmids\": [\"40048553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Rab35 mediates DENND1B's effects on MC4R trafficking is not established\",\n        \"The specific trafficking step (internalization, recycling, degradation) controlled by DENND1B for MC4R is unresolved\",\n        \"In vivo metabolic phenotyping of DENND1B loss in the context of MC4R-driven energy homeostasis has not been reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying model of how DENND1B coordinates Rab35-dependent trafficking across its diverse receptor substrates (TCR, MC4R, and potentially others) and how its C-terminal domain-directed localization integrates with its GEF activity at distinct subcellular sites remains to be constructed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data for DENND1B or its complex with Rab35/AP-2 exist\",\n        \"Systematic identification of DENND1B cargo receptors has not been performed\",\n        \"The relative contributions of GEF-dependent versus GEF-independent functions of DENND1B are unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RAB35\",\n      \"AP2A1\",\n      \"MC4R\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}