{"gene":"RUNDC3A","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1998,"finding":"RUNDC3A (RPIP8) was identified as a specific effector of the small GTP-binding protein Rap2A. It interacts specifically with GTP-bound Rap2A and requires an intact effector domain of Rap2A for interaction. Biochemical studies with purified proteins confirmed the yeast two-hybrid genetic results, and co-immunoprecipitation from transfected HIT-T15 cells confirmed that RPIP8 can be immunoprecipitated with both [Val12]Rap2 and wild-type Rap2.","method":"Yeast two-hybrid screen, in vitro binding with purified proteins, co-immunoprecipitation from transfected cells","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic screen confirmed by in vitro reconstitution with purified proteins and orthogonal co-IP in cells; multiple methods in a single focused study","pmids":["9523700"],"is_preprint":false},{"year":2006,"finding":"The crystal structure of the RUN domain of RPIPx (a RPIP8/RUNDC3A homolog) was determined at 2.0 Å resolution. The RUN domain comprises eight anti-parallel alpha-helices forming an extensive hydrophobic core. A positively charged surface conserved between RPIP8 and RPIPx was identified as the likely Rap2-binding interface. The RPIPx RUN domain interacted specifically with Rap2B in vitro in a nucleotide-dependent manner, and the minimum correctly folded fragment (residues 83–255) extended beyond the predicted RUN domain boundaries.","method":"Crystal structure (MAD method, 2.0 Å), NMR for minimum fragment determination, in vitro binding assay with Rap2B","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation (in vitro nucleotide-dependent binding) and NMR; multiple orthogonal methods in single study","pmids":["16928684"],"is_preprint":false},{"year":2022,"finding":"RUNDC3A was identified as an upstream regulator of SNAP25 expression in gastric neuroendocrine carcinoma (GNEC). RUNDC3A regulates SNAP25, which in turn stabilizes AKT protein via modulating its monoubiquitination, promoting AKT protein half-life. RUNDC3A knockdown reduced chemoresistance phenotypes in GNEC cell lines and in vivo, placing RUNDC3A upstream of a SNAP25/AKT axis. The RUNDC3A/SNAP25/AKT axis was also operative in other neuroendocrine carcinomas (intestinal, lung, pancreatic) and small cell lung cancer.","method":"In vitro and in vivo loss-of-function experiments in GNEC cell lines; transcriptome profiling; Western blot for protein half-life; co-IP for SNAP25-AKT interaction","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype plus pathway placement (upstream of SNAP25/AKT), supported by two companion papers from the same group; replicated in multiple NEN contexts","pmids":["35752613","36182960"],"is_preprint":false}],"current_model":"RUNDC3A (RPIP8) is a RUN-domain-containing protein that functions as a specific GTP-dependent effector of the small GTPase Rap2A, binding through a conserved positively charged surface on its RUN domain (structurally resolved at 2.0 Å); in neuroendocrine cancer contexts, RUNDC3A acts upstream of SNAP25, which stabilizes AKT via modulation of monoubiquitination, thereby promoting tumor progression and chemoresistance."},"narrative":{"mechanistic_narrative":"RUNDC3A (RPIP8) is a RUN-domain-containing protein that functions as a specific GTP-dependent effector of the small GTPase Rap2A, interacting selectively with the GTP-bound form and requiring an intact Rap2A effector domain [PMID:9523700]. The Rap2 interaction is mediated by its RUN domain, whose 2.0 Å crystal structure reveals eight anti-parallel alpha-helices forming a hydrophobic core and a conserved positively charged surface that constitutes the likely nucleotide-dependent GTPase-binding interface [PMID:16928684]. In neuroendocrine carcinoma contexts, RUNDC3A acts as an upstream regulator of SNAP25, which stabilizes AKT by modulating its monoubiquitination and extending AKT protein half-life, thereby driving tumor progression and chemoresistance across gastric, intestinal, lung, and pancreatic neuroendocrine carcinomas [PMID:35752613, PMID:36182960]. Beyond these findings, the mechanism connecting RUNDC3A's Rap2 effector function to its role in the SNAP25/AKT axis has not been characterized in the available corpus.","teleology":[{"year":1998,"claim":"Established RUNDC3A as a bona fide effector of an active small GTPase, defining its first molecular function as a GTP-state-selective Rap2A binding partner.","evidence":"Yeast two-hybrid screen confirmed by in vitro binding with purified proteins and co-immunoprecipitation from transfected HIT-T15 cells","pmids":["9523700"],"confidence":"High","gaps":["Downstream consequence of Rap2A binding not defined","Cellular process engaged by the Rap2A-RUNDC3A complex unknown","Domain responsible for the interaction not yet mapped"]},{"year":2006,"claim":"Resolved the structural basis of GTPase recognition, identifying the RUN domain fold and a conserved positively charged surface as the nucleotide-dependent Rap2-binding interface.","evidence":"2.0 Å crystal structure (MAD) of the RUN domain of an RPIP8/RUNDC3A homolog, NMR fragment mapping, and in vitro nucleotide-dependent Rap2B binding","pmids":["16928684"],"confidence":"High","gaps":["Structure solved for a homolog rather than RUNDC3A itself","No co-crystal of the RUN domain bound to Rap2","Functional output downstream of binding still undefined"]},{"year":2022,"claim":"Placed RUNDC3A in a disease-relevant signaling axis, showing it acts upstream of SNAP25 to stabilize AKT and promote chemoresistance in neuroendocrine carcinomas.","evidence":"Loss-of-function (knockdown) in GNEC cell lines and in vivo, transcriptome profiling, protein half-life Western blots, and co-IP for the SNAP25-AKT interaction; replicated across multiple neuroendocrine carcinoma types","pmids":["35752613","36182960"],"confidence":"Medium","gaps":["Molecular mechanism by which RUNDC3A regulates SNAP25 not defined","Whether the Rap2A effector function contributes to the SNAP25/AKT axis is unaddressed","Direct vs indirect regulation of SNAP25 not distinguished"]},{"year":null,"claim":"How RUNDC3A's role as a Rap2A GTPase effector mechanistically connects to its regulation of the SNAP25/AKT axis in neuroendocrine cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No link established between Rap2 effector activity and SNAP25 regulation","No physiological (non-cancer) cellular role characterized","Endogenous interactome beyond Rap2 and SNAP25 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["RAP2A","RAP2B","SNAP25"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q59EK9","full_name":"RUN domain-containing protein 3A","aliases":["Rap2-interacting protein 8","RPIP-8"],"length_aa":446,"mass_kda":49.7,"function":"May act as an effector of RAP2A in neuronal cells","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q59EK9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RUNDC3A","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RUNDC3A","total_profiled":1310},"omim":[{"mim_id":"617295","title":"RUN DOMAIN-CONTAINING PROTEIN 3B; RUNDC3B","url":"https://www.omim.org/entry/617295"},{"mim_id":"605448","title":"RUN DOMAIN-CONTAINING PROTEIN 3A; RUNDC3A","url":"https://www.omim.org/entry/605448"},{"mim_id":"138945","title":"GRANULIN PRECURSOR; GRN","url":"https://www.omim.org/entry/138945"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":297.6},{"tissue":"pituitary gland","ntpm":94.7}],"url":"https://www.proteinatlas.org/search/RUNDC3A"},"hgnc":{"alias_symbol":["RPIP8","RAP2IP"],"prev_symbol":[]},"alphafold":{"accession":"Q59EK9","domains":[{"cath_id":"1.20.58.900","chopping":"16-80_87-203","consensus_level":"high","plddt":88.693,"start":16,"end":203},{"cath_id":"1.20.5","chopping":"245-319","consensus_level":"medium","plddt":92.7333,"start":245,"end":319}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q59EK9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q59EK9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q59EK9-F1-predicted_aligned_error_v6.png","plddt_mean":68.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RUNDC3A","jax_strain_url":"https://www.jax.org/strain/search?query=RUNDC3A"},"sequence":{"accession":"Q59EK9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q59EK9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q59EK9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q59EK9"}},"corpus_meta":[{"pmid":"20406420","id":"PMC_20406420","title":"SKIP, the host target of the Salmonella virulence factor SifA, promotes kinesin-1-dependent vacuolar membrane exchanges.","date":"2010","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/20406420","citation_count":91,"is_preprint":false},{"pmid":"18157829","id":"PMC_18157829","title":"Progranulin locus deletion in frontotemporal dementia.","date":"2008","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/18157829","citation_count":78,"is_preprint":false},{"pmid":"9523700","id":"PMC_9523700","title":"Identification of a specific effector of the small GTP-binding protein Rap2.","date":"1998","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9523700","citation_count":48,"is_preprint":false},{"pmid":"29923329","id":"PMC_29923329","title":"Identification of differential expressed lncRNAs in human thyroid cancer by a genome-wide analyses.","date":"2018","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29923329","citation_count":47,"is_preprint":false},{"pmid":"22069496","id":"PMC_22069496","title":"Mll5 is required for normal spermatogenesis.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22069496","citation_count":39,"is_preprint":false},{"pmid":"16928684","id":"PMC_16928684","title":"Crystal structure of the RUN domain of the RAP2-interacting protein x.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16928684","citation_count":34,"is_preprint":false},{"pmid":"23519112","id":"PMC_23519112","title":"RUFY, Rab and Rap Family Proteins Involved in a Regulation of Cell Polarity and Membrane Trafficking.","date":"2013","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23519112","citation_count":28,"is_preprint":false},{"pmid":"31044550","id":"PMC_31044550","title":"Long noncoding RNA RP11-547D24.1 regulates proliferation and migration in papillary thyroid carcinoma: Identification and validation of a novel long noncoding RNA through integrated analysis of TCGA database.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31044550","citation_count":20,"is_preprint":false},{"pmid":"19914042","id":"PMC_19914042","title":"Suggestive evidence for a new locus for epilepsy with heterogeneous phenotypes on chromosome 17q.","date":"2009","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/19914042","citation_count":16,"is_preprint":false},{"pmid":"35752613","id":"PMC_35752613","title":"RUNDC3A regulates SNAP25-mediated chemotherapy resistance by binding AKT in gastric neuroendocrine carcinoma (GNEC).","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35752613","citation_count":15,"is_preprint":false},{"pmid":"12898585","id":"PMC_12898585","title":"Extended investigation of tau and mutation screening of other candidate genes on chromosome 17q21 in a Swedish FTDP-17 family.","date":"2003","source":"American journal of medical genetics. 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It interacts specifically with GTP-bound Rap2A and requires an intact effector domain of Rap2A for interaction. Biochemical studies with purified proteins confirmed the yeast two-hybrid genetic results, and co-immunoprecipitation from transfected HIT-T15 cells confirmed that RPIP8 can be immunoprecipitated with both [Val12]Rap2 and wild-type Rap2.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding with purified proteins, co-immunoprecipitation from transfected cells\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic screen confirmed by in vitro reconstitution with purified proteins and orthogonal co-IP in cells; multiple methods in a single focused study\",\n      \"pmids\": [\"9523700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The crystal structure of the RUN domain of RPIPx (a RPIP8/RUNDC3A homolog) was determined at 2.0 Å resolution. The RUN domain comprises eight anti-parallel alpha-helices forming an extensive hydrophobic core. A positively charged surface conserved between RPIP8 and RPIPx was identified as the likely Rap2-binding interface. The RPIPx RUN domain interacted specifically with Rap2B in vitro in a nucleotide-dependent manner, and the minimum correctly folded fragment (residues 83–255) extended beyond the predicted RUN domain boundaries.\",\n      \"method\": \"Crystal structure (MAD method, 2.0 Å), NMR for minimum fragment determination, in vitro binding assay with Rap2B\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation (in vitro nucleotide-dependent binding) and NMR; multiple orthogonal methods in single study\",\n      \"pmids\": [\"16928684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUNDC3A was identified as an upstream regulator of SNAP25 expression in gastric neuroendocrine carcinoma (GNEC). RUNDC3A regulates SNAP25, which in turn stabilizes AKT protein via modulating its monoubiquitination, promoting AKT protein half-life. RUNDC3A knockdown reduced chemoresistance phenotypes in GNEC cell lines and in vivo, placing RUNDC3A upstream of a SNAP25/AKT axis. The RUNDC3A/SNAP25/AKT axis was also operative in other neuroendocrine carcinomas (intestinal, lung, pancreatic) and small cell lung cancer.\",\n      \"method\": \"In vitro and in vivo loss-of-function experiments in GNEC cell lines; transcriptome profiling; Western blot for protein half-life; co-IP for SNAP25-AKT interaction\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype plus pathway placement (upstream of SNAP25/AKT), supported by two companion papers from the same group; replicated in multiple NEN contexts\",\n      \"pmids\": [\"35752613\", \"36182960\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RUNDC3A (RPIP8) is a RUN-domain-containing protein that functions as a specific GTP-dependent effector of the small GTPase Rap2A, binding through a conserved positively charged surface on its RUN domain (structurally resolved at 2.0 Å); in neuroendocrine cancer contexts, RUNDC3A acts upstream of SNAP25, which stabilizes AKT via modulation of monoubiquitination, thereby promoting tumor progression and chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RUNDC3A (RPIP8) is a RUN-domain-containing protein that functions as a specific GTP-dependent effector of the small GTPase Rap2A, interacting selectively with the GTP-bound form and requiring an intact Rap2A effector domain [#0]. The Rap2 interaction is mediated by its RUN domain, whose 2.0 Å crystal structure reveals eight anti-parallel alpha-helices forming a hydrophobic core and a conserved positively charged surface that constitutes the likely nucleotide-dependent GTPase-binding interface [#1]. In neuroendocrine carcinoma contexts, RUNDC3A acts as an upstream regulator of SNAP25, which stabilizes AKT by modulating its monoubiquitination and extending AKT protein half-life, thereby driving tumor progression and chemoresistance across gastric, intestinal, lung, and pancreatic neuroendocrine carcinomas [#2]. Beyond these findings, the mechanism connecting RUNDC3A's Rap2 effector function to its role in the SNAP25/AKT axis has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established RUNDC3A as a bona fide effector of an active small GTPase, defining its first molecular function as a GTP-state-selective Rap2A binding partner.\",\n      \"evidence\": \"Yeast two-hybrid screen confirmed by in vitro binding with purified proteins and co-immunoprecipitation from transfected HIT-T15 cells\",\n      \"pmids\": [\"9523700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream consequence of Rap2A binding not defined\", \"Cellular process engaged by the Rap2A-RUNDC3A complex unknown\", \"Domain responsible for the interaction not yet mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the structural basis of GTPase recognition, identifying the RUN domain fold and a conserved positively charged surface as the nucleotide-dependent Rap2-binding interface.\",\n      \"evidence\": \"2.0 Å crystal structure (MAD) of the RUN domain of an RPIP8/RUNDC3A homolog, NMR fragment mapping, and in vitro nucleotide-dependent Rap2B binding\",\n      \"pmids\": [\"16928684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure solved for a homolog rather than RUNDC3A itself\", \"No co-crystal of the RUN domain bound to Rap2\", \"Functional output downstream of binding still undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed RUNDC3A in a disease-relevant signaling axis, showing it acts upstream of SNAP25 to stabilize AKT and promote chemoresistance in neuroendocrine carcinomas.\",\n      \"evidence\": \"Loss-of-function (knockdown) in GNEC cell lines and in vivo, transcriptome profiling, protein half-life Western blots, and co-IP for the SNAP25-AKT interaction; replicated across multiple neuroendocrine carcinoma types\",\n      \"pmids\": [\"35752613\", \"36182960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which RUNDC3A regulates SNAP25 not defined\", \"Whether the Rap2A effector function contributes to the SNAP25/AKT axis is unaddressed\", \"Direct vs indirect regulation of SNAP25 not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RUNDC3A's role as a Rap2A GTPase effector mechanistically connects to its regulation of the SNAP25/AKT axis in neuroendocrine cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No link established between Rap2 effector activity and SNAP25 regulation\", \"No physiological (non-cancer) cellular role characterized\", \"Endogenous interactome beyond Rap2 and SNAP25 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAP2A\", \"RAP2B\", \"SNAP25\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}