{"gene":"DEPDC7","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2014,"finding":"DEPDC7 was identified as a binding partner of CARMA2 and CARMA3 proteins (components of the CBM complex). DEPDC7 displays cytosolic distribution, and its overexpression induces NF-κB activation. shRNA-mediated knockdown of DEPDC7 impairs NF-κB activation downstream of G protein-coupled receptor stimulation (which requires CARMA2/CARMA3) but not downstream of CARMA1-dependent stimuli, placing DEPDC7 specifically in the CARMA2/3 branch of CBM-NF-κB signaling.","method":"Co-immunoprecipitation (binding partner identification), subcellular localization (cytosolic distribution), shRNA knockdown with NF-κB reporter assays, overexpression with NF-κB reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2/3 / Moderate — reciprocal/Co-IP binding data combined with functional shRNA epistasis across multiple receptor stimuli in a single lab study","pmids":["25541973"],"is_preprint":false},{"year":2017,"finding":"DEPDC7 overexpression in hepatoma cell lines (SK-Hep-1 and Huh-7) inhibits cell proliferation, cell cycle entry, and cell motility/invasion; reciprocally, shRNA knockdown of DEPDC7 in HepG2 cells promotes cell growth, S-phase entry, and cell mobility and invasion, indicating DEPDC7 functions as a tumor suppressor in hepatocellular carcinoma.","method":"Overexpression and shRNA knockdown in hepatoma cell lines; proliferation assays, cell cycle analysis, migration and invasion assays (Matrigel); western blot and immunohistochemistry for expression","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional gain- and loss-of-function with multiple cellular readouts in a single lab, no mechanistic pathway placement beyond phenotype","pmids":["29344171","27016254"],"is_preprint":false},{"year":2026,"finding":"DEPDC7 directly interacts with the JAK1 kinase domain (confirmed by co-immunoprecipitation and molecular docking), and DEPDC7 overexpression in Huh-7 cells suppresses JAK1/STAT3 pathway activity (downregulating JAK1 and STAT3 levels by RNA-seq), inhibits EMT (increasing E-cadherin, reducing N-cadherin and vimentin), promotes cell cycle arrest and apoptosis, and reduces migratory capacity. Structural analysis identified conserved DEP and RhoGAP domains and predicted PTM sites. DEPDC7 was localized to both cytoplasm and nucleus in HCC cells.","method":"Co-immunoprecipitation, molecular docking, RNA-seq pathway analysis, overexpression in Huh-7 cells, western blot for EMT markers, scanning electron microscopy, subcellular localization","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2/3 / Moderate — Co-IP binding plus molecular docking plus RNA-seq pathway analysis and functional assays in a single lab; mechanistic pathway placement via JAK1/STAT3 supported by multiple orthogonal methods but not yet independently replicated","pmids":["41930189"],"is_preprint":false}],"current_model":"DEPDC7 is a cytosolic DEP- and RhoGAP-domain-containing protein that acts as a context-specific regulator of NF-κB signaling by binding CARMA2 and CARMA3 to convey G protein-coupled receptor signals through the CBM complex, and functions as a tumor suppressor in hepatocellular carcinoma by physically interacting with the JAK1 kinase domain to suppress JAK1/STAT3 signaling and epithelial-mesenchymal transition, thereby inhibiting cell proliferation, cycle entry, migration, and invasion."},"narrative":{"mechanistic_narrative":"DEPDC7 is a cytosolic DEP- and RhoGAP-domain-containing protein that functions as a context-specific regulator of NF-κB signaling and as a tumor suppressor [PMID:25541973, PMID:29344171, PMID:27016254]. In the CBM-NF-κB pathway, DEPDC7 binds the CARMA2 and CARMA3 scaffolds, and its overexpression activates NF-κB while its knockdown selectively impairs NF-κB activation downstream of G protein-coupled receptor stimuli (CARMA2/3-dependent) but not CARMA1-dependent stimuli, placing it specifically in the CARMA2/3 branch of CBM signaling [PMID:25541973]. In hepatocellular carcinoma, DEPDC7 acts as a tumor suppressor: gain-of-function inhibits proliferation, cell cycle entry, and motility/invasion, whereas loss-of-function promotes these phenotypes [PMID:29344171, PMID:27016254]. Mechanistically, DEPDC7 directly interacts with the JAK1 kinase domain and suppresses JAK1/STAT3 signaling, thereby inhibiting epithelial-mesenchymal transition (raising E-cadherin while reducing N-cadherin and vimentin) and promoting cell cycle arrest and apoptosis [PMID:41930189].","teleology":[{"year":2014,"claim":"Established DEPDC7's first molecular role by placing it within the CBM-NF-κB signaling module, answering whether this DEP-domain protein had a defined pathway function.","evidence":"Co-immunoprecipitation with CARMA2/CARMA3, subcellular localization, and shRNA knockdown with NF-κB reporter assays across distinct receptor stimuli in cell lines","pmids":["25541973"],"confidence":"Medium","gaps":["Reciprocal binding and the structural basis of the CARMA2/3 interaction not resolved","Whether DEPDC7's RhoGAP domain contributes catalytically to NF-κB activation is untested","Single-lab study without independent replication"]},{"year":2017,"claim":"Defined DEPDC7 as a tumor suppressor in hepatocellular carcinoma through bidirectional functional perturbation, addressing whether its expression causally affects cancer cell behavior.","evidence":"Overexpression and shRNA knockdown in hepatoma cell lines with proliferation, cell cycle, migration, and invasion assays","pmids":["29344171","27016254"],"confidence":"Medium","gaps":["No mechanistic pathway placement linking DEPDC7 to the observed phenotypes","No in vivo tumor model","Relationship to its earlier NF-κB role left unexplored"]},{"year":2026,"claim":"Provided the mechanistic basis for DEPDC7's tumor-suppressive phenotype by identifying JAK1 as a direct binding partner and JAK1/STAT3 suppression as the operative pathway.","evidence":"Co-immunoprecipitation and molecular docking against the JAK1 kinase domain, RNA-seq pathway analysis, and functional assays in Huh-7 cells with EMT marker western blots and electron microscopy","pmids":["41930189"],"confidence":"Medium","gaps":["Direct JAK1 binding supported by Co-IP plus docking but not by structural or reconstitution methods","Whether DEPDC7 acts through its RhoGAP or DEP domain to inhibit JAK1 is unknown","Not independently replicated; nuclear localization role uncharacterized"]},{"year":null,"claim":"How DEPDC7's two reported activities — CARMA2/3-dependent NF-κB activation and JAK1/STAT3 suppression — are reconciled within a single protein, and the catalytic role of its RhoGAP domain, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural characterization of DEP or RhoGAP domain function","GAP substrate (if any) not identified","Cell-type context determining NF-κB versus JAK1/STAT3 output is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["CARMA2","CARMA3","JAK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QD5","full_name":"DEP domain-containing protein 7","aliases":["Protein TR2/D15"],"length_aa":511,"mass_kda":58.3,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96QD5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DEPDC7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DEPDC7","total_profiled":1310},"omim":[{"mim_id":"612294","title":"DEP DOMAIN-CONTAINING PROTEIN 7; DEPDC7","url":"https://www.omim.org/entry/612294"},{"mim_id":"609641","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT M; EIF3M","url":"https://www.omim.org/entry/609641"},{"mim_id":"600367","title":"CLEAVAGE STIMULATION FACTOR, 3-PRIME PRE-RNA, SUBUNIT 3, 77-KD; CSTF3","url":"https://www.omim.org/entry/600367"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":27.3},{"tissue":"kidney","ntpm":18.2},{"tissue":"liver","ntpm":69.2},{"tissue":"testis","ntpm":26.4}],"url":"https://www.proteinatlas.org/search/DEPDC7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96QD5","domains":[{"cath_id":"1.10.10.10","chopping":"27-138_171-192","consensus_level":"medium","plddt":76.0216,"start":27,"end":192},{"cath_id":"-","chopping":"196-227_425-452","consensus_level":"medium","plddt":75.35,"start":196,"end":452},{"cath_id":"1.10.555.10","chopping":"262-421","consensus_level":"high","plddt":85.6081,"start":262,"end":421},{"cath_id":"-","chopping":"458-510","consensus_level":"high","plddt":82.9298,"start":458,"end":510}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QD5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QD5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QD5-F1-predicted_aligned_error_v6.png","plddt_mean":73.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DEPDC7","jax_strain_url":"https://www.jax.org/strain/search?query=DEPDC7"},"sequence":{"accession":"Q96QD5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QD5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QD5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QD5"}},"corpus_meta":[{"pmid":"32636717","id":"PMC_32636717","title":"The plasma peptides of sepsis.","date":"2020","source":"Clinical proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32636717","citation_count":26,"is_preprint":false},{"pmid":"25541973","id":"PMC_25541973","title":"The Dishevelled, EGL-10 and pleckstrin (DEP) domain-containing protein DEPDC7 binds to CARMA2 and CARMA3 proteins, and regulates NF-κB activation.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25541973","citation_count":22,"is_preprint":false},{"pmid":"24912414","id":"PMC_24912414","title":"A novel Alu-mediated microdeletion at 11p13 removes WT1 in a patient with cryptorchidism and azoospermia.","date":"2014","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/24912414","citation_count":18,"is_preprint":false},{"pmid":"25952135","id":"PMC_25952135","title":"Further evidence of DEPDC7 DNA hypomethylation in depression: A study in adult twins.","date":"2015","source":"European psychiatry : the journal of the Association of European Psychiatrists","url":"https://pubmed.ncbi.nlm.nih.gov/25952135","citation_count":11,"is_preprint":false},{"pmid":"29344171","id":"PMC_29344171","title":"DEPDC7 inhibits cell proliferation, migration and invasion in hepatoma cells.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29344171","citation_count":11,"is_preprint":false},{"pmid":"27016254","id":"PMC_27016254","title":"Construction and Identification of the RNAi Recombinant Lentiviral Vector Targeting Human DEPDC7 Gene.","date":"2016","source":"Interdisciplinary sciences, computational life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27016254","citation_count":10,"is_preprint":false},{"pmid":"41930189","id":"PMC_41930189","title":"DEPDC7 as a potential tumor suppressor in hepatocellular carcinoma: preliminary evidence for targeting the JAK1/STAT3 axis.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41930189","citation_count":0,"is_preprint":false},{"pmid":"37672513","id":"PMC_37672513","title":"Identification of candidate genes for developmental colour agnosia in a single unique family.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37672513","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6259,"output_tokens":1084,"usd":0.017518,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7697,"output_tokens":1780,"usd":0.041493,"stage2_stop_reason":"end_turn"},"total_usd":0.059011,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPDC7 was identified as a binding partner of CARMA2 and CARMA3 proteins (components of the CBM complex). DEPDC7 displays cytosolic distribution, and its overexpression induces NF-κB activation. shRNA-mediated knockdown of DEPDC7 impairs NF-κB activation downstream of G protein-coupled receptor stimulation (which requires CARMA2/CARMA3) but not downstream of CARMA1-dependent stimuli, placing DEPDC7 specifically in the CARMA2/3 branch of CBM-NF-κB signaling.\",\n      \"method\": \"Co-immunoprecipitation (binding partner identification), subcellular localization (cytosolic distribution), shRNA knockdown with NF-κB reporter assays, overexpression with NF-κB reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 / Moderate — reciprocal/Co-IP binding data combined with functional shRNA epistasis across multiple receptor stimuli in a single lab study\",\n      \"pmids\": [\"25541973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DEPDC7 overexpression in hepatoma cell lines (SK-Hep-1 and Huh-7) inhibits cell proliferation, cell cycle entry, and cell motility/invasion; reciprocally, shRNA knockdown of DEPDC7 in HepG2 cells promotes cell growth, S-phase entry, and cell mobility and invasion, indicating DEPDC7 functions as a tumor suppressor in hepatocellular carcinoma.\",\n      \"method\": \"Overexpression and shRNA knockdown in hepatoma cell lines; proliferation assays, cell cycle analysis, migration and invasion assays (Matrigel); western blot and immunohistochemistry for expression\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional gain- and loss-of-function with multiple cellular readouts in a single lab, no mechanistic pathway placement beyond phenotype\",\n      \"pmids\": [\"29344171\", \"27016254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DEPDC7 directly interacts with the JAK1 kinase domain (confirmed by co-immunoprecipitation and molecular docking), and DEPDC7 overexpression in Huh-7 cells suppresses JAK1/STAT3 pathway activity (downregulating JAK1 and STAT3 levels by RNA-seq), inhibits EMT (increasing E-cadherin, reducing N-cadherin and vimentin), promotes cell cycle arrest and apoptosis, and reduces migratory capacity. Structural analysis identified conserved DEP and RhoGAP domains and predicted PTM sites. DEPDC7 was localized to both cytoplasm and nucleus in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation, molecular docking, RNA-seq pathway analysis, overexpression in Huh-7 cells, western blot for EMT markers, scanning electron microscopy, subcellular localization\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 / Moderate — Co-IP binding plus molecular docking plus RNA-seq pathway analysis and functional assays in a single lab; mechanistic pathway placement via JAK1/STAT3 supported by multiple orthogonal methods but not yet independently replicated\",\n      \"pmids\": [\"41930189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DEPDC7 is a cytosolic DEP- and RhoGAP-domain-containing protein that acts as a context-specific regulator of NF-κB signaling by binding CARMA2 and CARMA3 to convey G protein-coupled receptor signals through the CBM complex, and functions as a tumor suppressor in hepatocellular carcinoma by physically interacting with the JAK1 kinase domain to suppress JAK1/STAT3 signaling and epithelial-mesenchymal transition, thereby inhibiting cell proliferation, cycle entry, migration, and invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DEPDC7 is a cytosolic DEP- and RhoGAP-domain-containing protein that functions as a context-specific regulator of NF-κB signaling and as a tumor suppressor [#0, #1]. In the CBM-NF-κB pathway, DEPDC7 binds the CARMA2 and CARMA3 scaffolds, and its overexpression activates NF-κB while its knockdown selectively impairs NF-κB activation downstream of G protein-coupled receptor stimuli (CARMA2/3-dependent) but not CARMA1-dependent stimuli, placing it specifically in the CARMA2/3 branch of CBM signaling [#0]. In hepatocellular carcinoma, DEPDC7 acts as a tumor suppressor: gain-of-function inhibits proliferation, cell cycle entry, and motility/invasion, whereas loss-of-function promotes these phenotypes [#1]. Mechanistically, DEPDC7 directly interacts with the JAK1 kinase domain and suppresses JAK1/STAT3 signaling, thereby inhibiting epithelial-mesenchymal transition (raising E-cadherin while reducing N-cadherin and vimentin) and promoting cell cycle arrest and apoptosis [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established DEPDC7's first molecular role by placing it within the CBM-NF-κB signaling module, answering whether this DEP-domain protein had a defined pathway function.\",\n      \"evidence\": \"Co-immunoprecipitation with CARMA2/CARMA3, subcellular localization, and shRNA knockdown with NF-κB reporter assays across distinct receptor stimuli in cell lines\",\n      \"pmids\": [\"25541973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal binding and the structural basis of the CARMA2/3 interaction not resolved\",\n        \"Whether DEPDC7's RhoGAP domain contributes catalytically to NF-κB activation is untested\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined DEPDC7 as a tumor suppressor in hepatocellular carcinoma through bidirectional functional perturbation, addressing whether its expression causally affects cancer cell behavior.\",\n      \"evidence\": \"Overexpression and shRNA knockdown in hepatoma cell lines with proliferation, cell cycle, migration, and invasion assays\",\n      \"pmids\": [\"29344171\", \"27016254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mechanistic pathway placement linking DEPDC7 to the observed phenotypes\",\n        \"No in vivo tumor model\",\n        \"Relationship to its earlier NF-κB role left unexplored\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the mechanistic basis for DEPDC7's tumor-suppressive phenotype by identifying JAK1 as a direct binding partner and JAK1/STAT3 suppression as the operative pathway.\",\n      \"evidence\": \"Co-immunoprecipitation and molecular docking against the JAK1 kinase domain, RNA-seq pathway analysis, and functional assays in Huh-7 cells with EMT marker western blots and electron microscopy\",\n      \"pmids\": [\"41930189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct JAK1 binding supported by Co-IP plus docking but not by structural or reconstitution methods\",\n        \"Whether DEPDC7 acts through its RhoGAP or DEP domain to inhibit JAK1 is unknown\",\n        \"Not independently replicated; nuclear localization role uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DEPDC7's two reported activities — CARMA2/3-dependent NF-κB activation and JAK1/STAT3 suppression — are reconciled within a single protein, and the catalytic role of its RhoGAP domain, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural characterization of DEP or RhoGAP domain function\",\n        \"GAP substrate (if any) not identified\",\n        \"Cell-type context determining NF-κB versus JAK1/STAT3 output is undefined\"\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:0005829\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CARMA2\", \"CARMA3\", \"JAK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}