{"gene":"TNFAIP2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"TNFAIP2 interacts with the small GTPases Rac1 and Cdc42, increasing their activities to remodel the actin cytoskeleton and change cell morphology, thereby promoting cancer cell migration and invasion downstream of KLF5 transcriptional activation.","method":"Co-immunoprecipitation, GTPase activity assays, siRNA knockdown with migration/invasion readouts, luciferase reporter assay for KLF5 binding to TNFAIP2 promoter","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, GTPase activity assays, promoter reporter assay, and functional rescue experiments in multiple cell lines; replicated mechanistically in subsequent papers","pmids":["26189798"],"is_preprint":false},{"year":2013,"finding":"EBV oncoprotein LMP1 transcriptionally induces TNFAIP2 expression via its CTAR2 domain through NF-κB (p65), acting on a newly identified NF-κB binding site at −3,869 to −3,860 bp of the TNFAIP2 promoter. TNFAIP2 then associates with actin and promotes formation of actin-based membrane protrusions and cell motility.","method":"Luciferase reporter assay, siRNA knockdown of p65, ectopic p65 expression, co-immunoprecipitation, immunofluorescence microscopy, transwell migration assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (luciferase reporter, ChIP-equivalent promoter mapping, Co-IP, functional migration assay) in a single rigorous study","pmids":["23975427"],"is_preprint":false},{"year":2023,"finding":"TNFAIP2 directly binds the Kelch domain of KEAP1 via its DLG motif, competing with NRF2 for KEAP1 binding, thereby preventing NRF2 from undergoing ubiquitin-proteasome degradation and resulting in NRF2 accumulation that inhibits ROS-mediated JNK phosphorylation and confers cisplatin resistance.","method":"Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), Western blot, flow cytometry (ROS/apoptosis), xenograft mouse models, siRNA knockdown","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP/MS to identify binding partner, functional mutant analysis (DLG motif), in vitro and in vivo validation across multiple models","pmids":["37525222"],"is_preprint":false},{"year":2023,"finding":"TNFAIP2 interacts with IQGAP1 and Integrin β4; Integrin β4 activates Rac1 through the TNFAIP2/IQGAP1 axis to confer DNA damage-related drug resistance in triple-negative breast cancer.","method":"Co-immunoprecipitation, functional drug resistance assays, siRNA knockdown","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying two binding partners and functional epistasis in drug resistance, single lab","pmids":["37787041"],"is_preprint":false},{"year":2025,"finding":"TNFAIP2 promotes CSF1R aggregate/cluster formation and dimerization in macrophages by binding cellular PIP2; the PIP2-binding motif on TNFAIP2 (and on CSF1R) is required for aggregate formation. TNFAIP2 also enhances CSF1R trafficking to the cell surface via RalA and the exocyst complex, increasing macrophage functional response to CSF-1.","method":"Knockdown/overexpression in 293T and macrophage cells, PIP2 depletion experiments, mutation of PIP2-binding motifs, CSF1R activation assays, exocyst complex perturbation","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (PIP2 binding-motif mutagenesis, PIP2 depletion, RalA knockdown, exocyst perturbation) with functional readouts in two consecutive papers from same group","pmids":["39939179"],"is_preprint":false},{"year":2025,"finding":"TNFAIP2 enhances CSF1R trafficking to the cell surface and clustering via PIP2, RalA, and the exocyst complex, providing an additional mechanism by which TNFAIP2 increases macrophage response to CSF-1 beyond CSF1R clustering alone.","method":"PIP2-binding site mutagenesis of TNFAIP2 and CSF1R, RalA knockdown, exocyst complex inhibition, cell-surface CSF1R trafficking assays","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (mutagenesis, RalA knockdown, exocyst perturbation) with direct trafficking readout, replicates and extends prior study","pmids":["41158107"],"is_preprint":false},{"year":2022,"finding":"TNFAIP2 (M-Sec) is required for tunneling nanotube (TNT) formation in podocytes, enabling transfer of autophagosomes and lysosomes between cells; tnfaip2 knockout in mice exacerbates diabetic nephropathy, podocyte injury, and lysosomal dysfunction, demonstrating a protective role through TNT-mediated organelle exchange.","method":"Tnfaip2 knockout mice (streptozotocin-induced DN model), live-cell imaging of organelle transfer, siRNA knockdown, Tnfaip2 overexpression, lysosomal function assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo combined with in vitro organelle transfer imaging, functional rescue by overexpression, multiple readouts","pmids":["35659195"],"is_preprint":false},{"year":2021,"finding":"STAT1 epigenetically regulates TNFAIP2 expression by recruiting the acetyltransferase EP300 to H3K27ac-enriched enhancer loci of TNFAIP2; phosphorylated STAT1 binds these enhancer regions and EP300 subsequently promotes TNFAIP2 transcription.","method":"ChIP-PCR for STAT1 and H3K27ac, co-immunoprecipitation of STAT1 and EP300, EP300 inhibitor experiments in DSS-induced colitis mouse model","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR and Co-IP demonstrate direct STAT1-EP300 interaction at TNFAIP2 enhancer; single lab, two methods","pmids":["34112215"],"is_preprint":false},{"year":2020,"finding":"Tnfaip2 acts epistatically upstream of vimentin (Vim) to control triacylglycerol (TAG) and lipid droplet synthesis; Tnfaip2-deficient embryonic stem cells fail to induce TAG and lipid droplet formation during differentiation, and supplementation with palmitic acid rescues the differentiation defect, establishing a role for Tnfaip2 in lipid metabolism-driven stem cell differentiation.","method":"Tnfaip2 knockout ESCs, lipidomic analysis, epistasis experiments with Vim, palmitic acid supplementation rescue, planarian Smed-exoc3 knockdown for in vivo confirmation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in ESCs, lipidomics, epistasis with Vim, metabolic rescue, and cross-species validation in planarians; multiple orthogonal methods","pmids":["33300287"],"is_preprint":false},{"year":2019,"finding":"TNFAIP2 translation is tightly suppressed by inhibitory upstream open reading frames (uORFs) in its transcript leader sequence; during monocyte-to-macrophage differentiation, these uORFs are inactivated, enabling a large increase in TNFAIP2 protein expression despite stable mRNA, revealing uORF-dependent translational control.","method":"Luciferase reporter assays with mutant uORF constructs, polysome profiling, stimulus-based overcoming of uORF inhibition (TPA), comparison of monocytes vs. mature macrophages","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro dissection of uORF function with reporter assays and mutagenesis, cell-differentiation context validation; single lab but multiple orthogonal methods","pmids":["31392347"],"is_preprint":false},{"year":2015,"finding":"TNFAIP2 inhibits NF-κB activity and downstream IL-8 production early in the TNFα response, acting as an autoinhibitor of TNFα signaling; a genetic variant (rs8126) that increases TNFAIP2 expression reduces IL-8 and is associated with decreased survival in septic shock.","method":"NF-κB reporter assays, IL-8 measurement, in vitro TNFα stimulation with TNFAIP2 modulation, genetic association in two patient cohorts","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — NF-κB reporter and cytokine measurement support inhibitory function, but mechanistic detail is limited; replicated in two patient cohorts","pmids":["26347487"],"is_preprint":false},{"year":2016,"finding":"TNFAIP2 expression in human macrophages is induced by Legionella pneumophila infection in an NF-κB-dependent manner (H4 acetylation at its promoter); TNFAIP2 knockdown reduces intracellular replication of L. pneumophila, identifying it as a pro-bacterial host factor.","method":"Chromatin immunoprecipitation-sequencing (H4 acetylation), NF-κB inhibition, siRNA knockdown, intracellular bacterial replication assay in A549 cells","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for chromatin mark, functional KD with bacterial replication readout, NF-κB inhibition; single lab","pmids":["27130431"],"is_preprint":false},{"year":2024,"finding":"TNFAIP2 promotes HIF1α transcription in breast cancer by sequentially activating Rac1 and ERK, which then activate AP-1 (c-Jun/Fra1); AP-1 directly binds the HIF1α promoter to enhance its transcription and drive tumor angiogenesis.","method":"Chromatin immunoprecipitation (AP-1 binding to HIF1α promoter), luciferase reporter assay, ERK inhibitor experiments, Rac1 activity assay, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter confirm AP-1/HIF1α promoter interaction; single lab, two orthogonal methods","pmids":["39532855"],"is_preprint":false},{"year":2025,"finding":"TNFAIP2 protects IKKβ from ubiquitin-proteasome degradation (ubiquitination at K63) by competitively binding KEAP1, thereby sustaining NF-κB signaling and promoting EMT and lymphangiogenesis in oral squamous cell carcinoma.","method":"Co-immunoprecipitation, Western blot for ubiquitination, conditional knockout mouse model with 4NQO-induced OSCC, gene enrichment analysis","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating TNFAIP2-KEAP1 interaction and IKKβ ubiquitination rescue, with in vivo conditional KO validation; single lab","pmids":["39948570"],"is_preprint":false},{"year":2017,"finding":"TNFAIP2 knockdown in esophageal squamous cell carcinoma cells decreases expression of downstream Wnt/β-catenin targets (c-Myc, cyclin D1, MMP-7, Snail) and upregulates E-cadherin and p-GSK-3β, placing TNFAIP2 upstream of Wnt/β-catenin signaling.","method":"Lentiviral RNAi knockdown, Western blot for Wnt pathway components, proliferation/invasion assays","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (RNAi + Western blot), no direct binding or epistasis confirmation","pmids":["28393234"],"is_preprint":false},{"year":2019,"finding":"TNFAIP2 knockdown in platinum-resistant urothelial carcinoma cells upregulates E-cadherin and downregulates TWIST1, reversing EMT; global gene expression analysis after TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-driven EMT.","method":"siRNA knockdown, microarray gene expression analysis, Western blot for EMT markers","journal":"Laboratory investigation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gene expression analysis with KD; MTDH relationship identified by microarray without direct binding assay","pmids":["31263157"],"is_preprint":false},{"year":2025,"finding":"TGF-β increases acetylation of KLF5 (Ac-KLF5) in nasopharyngeal carcinoma cells; acetylated KLF5 directly binds the TNFAIP2 promoter and drives its transcription, inducing EMT; the pro-migratory/invasive effects of Ac-KLF5 depend on TNFAIP2.","method":"ChIP assay (KLF5 binding to TNFAIP2 promoter), Western blot for Ac-KLF5, siRNA knockdown of TNFAIP2, in vivo NPC mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional TNFAIP2-dependence tested by knockdown rescue; single lab","pmids":["40054652"],"is_preprint":false},{"year":2000,"finding":"B94/TNFAIP2 is rapidly induced by retinoic acid at the transcriptional level in a PML-RARα-dependent manner in APL cells: induction occurs within 1 hour, does not require new protein synthesis, and is blocked by actinomycin D; PML coiled-coil domain deletion abolishes induction, positioning TNFAIP2 as a transcriptional target downstream of PML-RARα.","method":"cDNA microarray, quantitative RT-PCR with actinomycin D and cycloheximide controls, RA treatment of NB4/UF1/HL-60/TF1-PR cells, dominant-negative PML-RARα deletion mutant","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection (actinomycin D block, protein-synthesis independence) with mutant construct; single lab","pmids":["10766166"],"is_preprint":false},{"year":2011,"finding":"A SNP in the miR-184 seed-binding site of the TNFAIP2 3′-UTR (rs8126 T>C) reduces luciferase reporter activity and is associated with lower endogenous TNFAIP2 mRNA levels, demonstrating that miR-184 post-transcriptionally represses TNFAIP2 and that this SNP disrupts the regulation.","method":"Luciferase reporter assay with WT and variant 3′-UTR constructs, genotype-phenotype mRNA analysis in patient PBMCs","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with allelic comparison and in vivo mRNA correlation; single lab, two methods","pmids":["21934093"],"is_preprint":false}],"current_model":"TNFAIP2 is a TNFα/NF-κB-inducible cytosolic protein that promotes cell migration and invasion by activating the small GTPases Rac1 and Cdc42 (partly via an IQGAP1/Integrin β4 scaffold), drives tumor angiogenesis through a Rac1-ERK-AP1-HIF1α axis, confers cisplatin resistance by competing with NRF2 for KEAP1 binding (via its DLG motif) to stabilize NRF2 and suppress ROS-JNK signaling, sustains NF-κB signaling by protecting IKKβ from KEAP1-mediated ubiquitination, promotes tunneling nanotube (TNT) formation for intercellular organelle exchange, enhances CSF1R clustering and surface trafficking in macrophages through PIP2, RalA, and the exocyst complex, and controls lipid droplet/triacylglycerol metabolism epistatically upstream of vimentin to enable stem cell differentiation; its translation is additionally regulated by inhibitory upstream ORFs that are inactivated during macrophage differentiation."},"narrative":{"mechanistic_narrative":"TNFAIP2 is a cytosolic, actin-associated effector that couples inflammatory and oncogenic transcriptional programs to cytoskeletal remodeling, membrane dynamics, and redox signaling, thereby promoting cell migration, invasion, and intercellular communication [PMID:26189798, PMID:23975427]. As a transcriptional output of NF-κB (downstream of EBV LMP1/p65, Legionella infection), KLF5, STAT1/EP300, and PML-RARα, its expression is induced by diverse inflammatory and differentiation cues and is further tuned post-transcriptionally by miR-184 and by inhibitory upstream ORFs that are released during macrophage differentiation [PMID:23975427, PMID:27130431, PMID:34112215, PMID:10766166, PMID:21934093, PMID:31392347]. Mechanistically, TNFAIP2 binds and activates the small GTPases Rac1 and Cdc42 to drive actin-based protrusions and motility, in part through an IQGAP1/Integrin β4 scaffold, and a Rac1→ERK→AP-1→HIF1α axis links this activity to tumor angiogenesis [PMID:26189798, PMID:37787041, PMID:39532855]. Through a DLG motif it directly binds the Kelch domain of KEAP1, competing with NRF2 to stabilize NRF2 and suppress ROS-JNK signaling (conferring cisplatin resistance) and competing for KEAP1 to protect IKKβ from K63-ubiquitination, thereby sustaining NF-κB signaling [PMID:37525222, PMID:39948570]. TNFAIP2 also acts at membranes: it binds PIP2 to promote CSF1R clustering and, via RalA and the exocyst complex, enhances CSF1R surface trafficking in macrophages [PMID:39939179, PMID:41158107]; it is required for tunneling-nanotube–mediated transfer of autophagosomes and lysosomes between cells [PMID:35659195]; and it acts epistatically upstream of vimentin to control triacylglycerol and lipid-droplet synthesis during stem-cell differentiation [PMID:33300287].","teleology":[{"year":2000,"claim":"Established TNFAIP2 (B94) as an immediate transcriptional target, defining it as a rapidly inducible gene wired to differentiation signaling.","evidence":"cDNA microarray and qRT-PCR with actinomycin D/cycloheximide controls and dominant-negative PML-RARα mutant in APL cell lines","pmids":["10766166"],"confidence":"Medium","gaps":["Did not define the protein's biochemical activity","Promoter elements mediating PML-RARα-dependent induction not mapped"]},{"year":2011,"claim":"Showed TNFAIP2 is post-transcriptionally repressed by miR-184, revealing a layer of expression control disrupted by a 3'-UTR SNP.","evidence":"Luciferase reporter assays with WT/variant 3'-UTR and genotype-mRNA correlation in patient PBMCs","pmids":["21934093"],"confidence":"Medium","gaps":["Functional consequence of altered TNFAIP2 levels not tested here","Did not address protein function"]},{"year":2013,"claim":"Connected NF-κB transcriptional induction to TNFAIP2 protein function, showing LMP1/p65 induces TNFAIP2, which associates with actin to drive membrane protrusions and motility.","evidence":"Luciferase reporter and promoter mapping, p65 knockdown/overexpression, Co-IP, immunofluorescence, transwell migration in EBV context","pmids":["23975427"],"confidence":"High","gaps":["Direct mechanism of actin engagement not resolved","Did not identify GTPase intermediates"]},{"year":2015,"claim":"Defined the core motility mechanism: TNFAIP2 binds and activates Rac1 and Cdc42 to remodel actin, downstream of KLF5.","evidence":"Reciprocal Co-IP, GTPase activity assays, siRNA migration/invasion readouts, KLF5 promoter reporter in multiple cancer lines","pmids":["26189798"],"confidence":"High","gaps":["Whether TNFAIP2 acts as a direct GEF or via a scaffold not established","Structural basis of GTPase binding unknown"]},{"year":2015,"claim":"Identified an autoinhibitory role in early TNFα signaling, complicating the simple pro-NF-κB picture and linking a regulatory variant to septic shock outcome.","evidence":"NF-κB reporter and IL-8 assays with TNFAIP2 modulation, genetic association in two patient cohorts","pmids":["26347487"],"confidence":"Medium","gaps":["Mechanism of NF-κB inhibition not defined","Apparent contradiction with later pro-NF-κB findings unreconciled"]},{"year":2016,"claim":"Showed pathogen-driven, NF-κB/chromatin-dependent induction of TNFAIP2 supports intracellular bacterial replication, casting it as a host factor exploited by infection.","evidence":"ChIP-seq for H4 acetylation, NF-κB inhibition, siRNA knockdown, intracellular L. pneumophila replication assay in A549 cells","pmids":["27130431"],"confidence":"Medium","gaps":["Molecular step in bacterial replication supported by TNFAIP2 unknown","Single lab"]},{"year":2019,"claim":"Revealed uORF-dependent translational control as a gate on TNFAIP2 protein output during monocyte-to-macrophage differentiation.","evidence":"Luciferase reporters with mutant uORFs, polysome profiling, TPA stimulation, monocyte vs. macrophage comparison","pmids":["31392347"],"confidence":"High","gaps":["Trans-acting factors controlling uORF inactivation not identified"]},{"year":2020,"claim":"Uncovered a metabolic function: TNFAIP2 acts epistatically upstream of vimentin to drive triacylglycerol/lipid-droplet synthesis required for stem-cell differentiation.","evidence":"Tnfaip2 KO ESCs, lipidomics, Vim epistasis, palmitic acid rescue, planarian Smed-exoc3 cross-species validation","pmids":["33300287"],"confidence":"High","gaps":["Biochemical link between TNFAIP2 and lipid synthesis enzymes unknown","How vimentin executes the downstream step unclear"]},{"year":2021,"claim":"Defined an epigenetic input: phospho-STAT1 recruits EP300 to H3K27ac enhancers to activate TNFAIP2 transcription.","evidence":"ChIP-PCR for STAT1/H3K27ac, STAT1-EP300 Co-IP, EP300 inhibition in DSS colitis model","pmids":["34112215"],"confidence":"Medium","gaps":["Single lab","Downstream functional consequence of STAT1-driven TNFAIP2 not fully resolved"]},{"year":2022,"claim":"Established TNFAIP2 (M-Sec) as required for tunneling-nanotube formation enabling intercellular organelle transfer, with in vivo protection against diabetic nephropathy.","evidence":"Tnfaip2 KO mice (STZ-induced DN), live-cell organelle-transfer imaging, knockdown and overexpression rescue, lysosomal assays in podocytes","pmids":["35659195"],"confidence":"High","gaps":["Molecular mechanism by which TNFAIP2 nucleates TNTs not defined","Link to GTPase/membrane functions not integrated"]},{"year":2023,"claim":"Identified the KEAP1-NRF2 competition mechanism: TNFAIP2's DLG motif binds KEAP1's Kelch domain to stabilize NRF2 and suppress ROS-JNK, conferring chemoresistance.","evidence":"Co-IP/MS, DLG-motif mutant analysis, flow cytometry for ROS/apoptosis, xenografts, siRNA knockdown","pmids":["37525222"],"confidence":"High","gaps":["Whether DLG-KEAP1 binding regulates other KEAP1 substrates not addressed at the time","Structure of the complex not solved"]},{"year":2023,"claim":"Extended the GTPase mechanism by showing an Integrin β4/TNFAIP2/IQGAP1 axis activates Rac1 to confer DNA-damage drug resistance.","evidence":"Reciprocal Co-IP of IQGAP1 and Integrin β4, functional drug-resistance assays, siRNA in TNBC","pmids":["37787041"],"confidence":"Medium","gaps":["Single lab","Direct binding interfaces among the three proteins not mapped"]},{"year":2024,"claim":"Linked TNFAIP2's GTPase activity to angiogenesis through a Rac1→ERK→AP-1→HIF1α transcriptional cascade.","evidence":"ChIP for AP-1 on HIF1α promoter, luciferase reporter, ERK inhibition, Rac1 activity assay, xenograft","pmids":["39532855"],"confidence":"Medium","gaps":["Single lab","Quantitative contribution of this axis to in vivo angiogenesis not isolated"]},{"year":2025,"claim":"Showed TNFAIP2 binds PIP2 to cluster CSF1R and uses RalA/exocyst to traffic CSF1R to the surface, amplifying macrophage CSF-1 responses.","evidence":"PIP2-binding motif mutagenesis on TNFAIP2 and CSF1R, PIP2 depletion, RalA knockdown, exocyst perturbation, surface-trafficking and activation assays (two consecutive studies)","pmids":["39939179","41158107"],"confidence":"High","gaps":["Whether PIP2 binding underlies TNFAIP2's other membrane functions (TNTs, GTPase activation) not tested","Structural basis of PIP2 recognition unresolved"]},{"year":2025,"claim":"Resolved the pro-NF-κB arm: TNFAIP2 competitively binds KEAP1 to protect IKKβ from K63-ubiquitination, sustaining NF-κB to drive EMT and lymphangiogenesis.","evidence":"Co-IP, ubiquitination Western blots, conditional KO mice in 4NQO-induced OSCC","pmids":["39948570"],"confidence":"Medium","gaps":["Single lab","Relationship to the earlier reported NF-κB autoinhibition not reconciled"]},{"year":null,"claim":"It remains unresolved how TNFAIP2's distinct biochemical activities — GTPase activation, KEAP1/DLG competition, PIP2/membrane binding, and TNT formation — are integrated into one structural/regulatory framework, and whether they reflect context-specific modules of a single mechanism.","evidence":"No discovery in the corpus integrates these activities or provides a structural model","pmids":[],"confidence":"Low","gaps":["No structure of TNFAIP2 or its complexes reported","Domain-level mapping of the multiple binding functions incomplete","Apparent contradictory roles in NF-κB signaling not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,13]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,13]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,12,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,11]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,13,6]}],"complexes":["exocyst"],"partners":["RAC1","CDC42","KEAP1","IQGAP1","ITGB4","CSF1R","RALA","IKBKB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03169","full_name":"Tumor necrosis factor alpha-induced protein 2","aliases":["Primary response gene B94 protein"],"length_aa":654,"mass_kda":72.7,"function":"May play a role as a mediator of inflammation and angiogenesis","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q03169/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNFAIP2","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":[],"url":"https://opencell.sf.czbiohub.org/search/TNFAIP2","total_profiled":1310},"omim":[{"mim_id":"603300","title":"TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 2; TNFAIP2","url":"https://www.omim.org/entry/603300"},{"mim_id":"191163","title":"TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 3; TNFAIP3","url":"https://www.omim.org/entry/191163"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"urinary bladder","ntpm":258.7}],"url":"https://www.proteinatlas.org/search/TNFAIP2"},"hgnc":{"alias_symbol":["B94","EXOC3L3"],"prev_symbol":[]},"alphafold":{"accession":"Q03169","domains":[{"cath_id":"-","chopping":"80-170","consensus_level":"medium","plddt":90.9793,"start":80,"end":170},{"cath_id":"-","chopping":"193-309","consensus_level":"medium","plddt":90.1509,"start":193,"end":309},{"cath_id":"1.10.357,1.10.357","chopping":"315-461","consensus_level":"high","plddt":94.6122,"start":315,"end":461},{"cath_id":"1.10.357.70","chopping":"485-651","consensus_level":"high","plddt":92.1243,"start":485,"end":651}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03169","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q03169-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q03169-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNFAIP2","jax_strain_url":"https://www.jax.org/strain/search?query=TNFAIP2"},"sequence":{"accession":"Q03169","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03169.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03169/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03169"}},"corpus_meta":[{"pmid":"26189798","id":"PMC_26189798","title":"KLF5 promotes breast cancer proliferation, migration and invasion in part by upregulating the transcription of TNFAIP2.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26189798","citation_count":129,"is_preprint":false},{"pmid":"35659195","id":"PMC_35659195","title":"Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35659195","citation_count":87,"is_preprint":false},{"pmid":"30145807","id":"PMC_30145807","title":"The roles of TNFAIP2 in cancers and infectious diseases.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30145807","citation_count":80,"is_preprint":false},{"pmid":"25888093","id":"PMC_25888093","title":"MicroRNA-184 inhibits cell proliferation and invasion, and specifically targets TNFAIP2 in Glioma.","date":"2015","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/25888093","citation_count":68,"is_preprint":false},{"pmid":"10766166","id":"PMC_10766166","title":"Identification of B94 (TNFAIP2) as a potential retinoic acid target gene in acute promyelocytic leukemia.","date":"2000","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10766166","citation_count":65,"is_preprint":false},{"pmid":"21934093","id":"PMC_21934093","title":"A functional variant at the miR-184 binding site in TNFAIP2 and risk of squamous cell carcinoma of the head and neck.","date":"2011","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/21934093","citation_count":64,"is_preprint":false},{"pmid":"8106408","id":"PMC_8106408","title":"B94, a primary response gene inducible by tumor necrosis factor-alpha, is expressed in developing hematopoietic tissues and the sperm acrosome.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8106408","citation_count":62,"is_preprint":false},{"pmid":"23975427","id":"PMC_23975427","title":"NF-κB-mediated transcriptional upregulation of TNFAIP2 by the Epstein-Barr virus oncoprotein, LMP1, promotes cell motility in nasopharyngeal carcinoma.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23975427","citation_count":62,"is_preprint":false},{"pmid":"21057457","id":"PMC_21057457","title":"A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma.","date":"2010","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/21057457","citation_count":50,"is_preprint":false},{"pmid":"37525222","id":"PMC_37525222","title":"TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1/NRF2 signaling.","date":"2023","source":"Journal of experimental & clinical 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morphologically and phenotypically similar lymphomas.","date":"2011","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21921781","citation_count":20,"is_preprint":false},{"pmid":"11839676","id":"PMC_11839676","title":"Utilization of the human genome sequence localizes human papillomavirus type 16 DNA integrated into the TNFAIP2 gene in a fatal cervical cancer from a 39-year-old woman.","date":"2002","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/11839676","citation_count":19,"is_preprint":false},{"pmid":"25383966","id":"PMC_25383966","title":"A functional TNFAIP2 3'-UTR rs8126 genetic polymorphism contributes to risk of esophageal squamous cell carcinoma.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25383966","citation_count":18,"is_preprint":false},{"pmid":"36084515","id":"PMC_36084515","title":"Tnfaip2 promotes atherogenesis by enhancing oxidative stress induced inflammation.","date":"2022","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36084515","citation_count":17,"is_preprint":false},{"pmid":"33300287","id":"PMC_33300287","title":"Tnfaip2/exoc3-driven lipid metabolism is essential for stem cell differentiation and organ homeostasis.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33300287","citation_count":17,"is_preprint":false},{"pmid":"39532855","id":"PMC_39532855","title":"TNFAIP2 promotes HIF1α transcription and breast cancer angiogenesis by activating the Rac1-ERK-AP1 signaling axis.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39532855","citation_count":13,"is_preprint":false},{"pmid":"34262558","id":"PMC_34262558","title":"Functional miR-142a-3p Induces Apoptosis and Macrophage Polarization by Targeting tnfaip2 and glut3 in Grass Carp (Ctenopharyngodon idella).","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34262558","citation_count":13,"is_preprint":false},{"pmid":"27130431","id":"PMC_27130431","title":"Genome-wide Chromatin Profiling of Legionella pneumophila-Infected Human Macrophages Reveals Activation of the Probacterial Host Factor TNFAIP2.","date":"2016","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27130431","citation_count":13,"is_preprint":false},{"pmid":"31392347","id":"PMC_31392347","title":"Translation of TNFAIP2 is tightly controlled by upstream open reading frames.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/31392347","citation_count":10,"is_preprint":false},{"pmid":"39948570","id":"PMC_39948570","title":"TNFAIP2 promotes NF-κB signaling mediate lymph node metastasis of oral squamous cell carcinoma by protecting IKKβ from ubiquitin proteasome degradation.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39948570","citation_count":8,"is_preprint":false},{"pmid":"39939179","id":"PMC_39939179","title":"Identification of TNFAIP2 as a unique cellular regulator of CSF-1 receptor activation.","date":"2025","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39939179","citation_count":7,"is_preprint":false},{"pmid":"37819535","id":"PMC_37819535","title":"Targeting TNFAIP2 induces immunogenic cell death and sensitizes glioblastoma multiforme to anti-PD-1 therapy.","date":"2023","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37819535","citation_count":6,"is_preprint":false},{"pmid":"38688431","id":"PMC_38688431","title":"TNFAIP2 as an emerging therapeutic target in cancer therapy and its underlying mechanisms.","date":"2024","source":"Pharmacological 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treatment","url":"https://pubmed.ncbi.nlm.nih.gov/36254562","citation_count":1,"is_preprint":false},{"pmid":"41158107","id":"PMC_41158107","title":"TNFAIP2 increases macrophage response to CSF-1 through multiple effects on CSF-1 receptor.","date":"2025","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/41158107","citation_count":0,"is_preprint":false},{"pmid":"41694594","id":"PMC_41694594","title":"Human umbilical cord mesenchymal stem cell delivery of mitochondria to melanocytes enhances skin repigmentation efficacy in autologous epidermal cell suspension transplantation through the TNFAIP2-TNT system.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41694594","citation_count":0,"is_preprint":false},{"pmid":"40731142","id":"PMC_40731142","title":"Targeting TNFAIP2 with NIR-II CRISPR-Cas9 nanosystem to overcome cisplatin resistance in laryngeal cancer.","date":"2025","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40731142","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24164,"output_tokens":5048,"usd":0.074106,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13277,"output_tokens":4996,"usd":0.095643,"stage2_stop_reason":"end_turn"},"total_usd":0.169749,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"TNFAIP2 interacts with the small GTPases Rac1 and Cdc42, increasing their activities to remodel the actin cytoskeleton and change cell morphology, thereby promoting cancer cell migration and invasion downstream of KLF5 transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation, GTPase activity assays, siRNA knockdown with migration/invasion readouts, luciferase reporter assay for KLF5 binding to TNFAIP2 promoter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, GTPase activity assays, promoter reporter assay, and functional rescue experiments in multiple cell lines; replicated mechanistically in subsequent papers\",\n      \"pmids\": [\"26189798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EBV oncoprotein LMP1 transcriptionally induces TNFAIP2 expression via its CTAR2 domain through NF-κB (p65), acting on a newly identified NF-κB binding site at −3,869 to −3,860 bp of the TNFAIP2 promoter. TNFAIP2 then associates with actin and promotes formation of actin-based membrane protrusions and cell motility.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown of p65, ectopic p65 expression, co-immunoprecipitation, immunofluorescence microscopy, transwell migration assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (luciferase reporter, ChIP-equivalent promoter mapping, Co-IP, functional migration assay) in a single rigorous study\",\n      \"pmids\": [\"23975427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNFAIP2 directly binds the Kelch domain of KEAP1 via its DLG motif, competing with NRF2 for KEAP1 binding, thereby preventing NRF2 from undergoing ubiquitin-proteasome degradation and resulting in NRF2 accumulation that inhibits ROS-mediated JNK phosphorylation and confers cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), Western blot, flow cytometry (ROS/apoptosis), xenograft mouse models, siRNA knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP/MS to identify binding partner, functional mutant analysis (DLG motif), in vitro and in vivo validation across multiple models\",\n      \"pmids\": [\"37525222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNFAIP2 interacts with IQGAP1 and Integrin β4; Integrin β4 activates Rac1 through the TNFAIP2/IQGAP1 axis to confer DNA damage-related drug resistance in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, functional drug resistance assays, siRNA knockdown\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying two binding partners and functional epistasis in drug resistance, single lab\",\n      \"pmids\": [\"37787041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TNFAIP2 promotes CSF1R aggregate/cluster formation and dimerization in macrophages by binding cellular PIP2; the PIP2-binding motif on TNFAIP2 (and on CSF1R) is required for aggregate formation. TNFAIP2 also enhances CSF1R trafficking to the cell surface via RalA and the exocyst complex, increasing macrophage functional response to CSF-1.\",\n      \"method\": \"Knockdown/overexpression in 293T and macrophage cells, PIP2 depletion experiments, mutation of PIP2-binding motifs, CSF1R activation assays, exocyst complex perturbation\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (PIP2 binding-motif mutagenesis, PIP2 depletion, RalA knockdown, exocyst perturbation) with functional readouts in two consecutive papers from same group\",\n      \"pmids\": [\"39939179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TNFAIP2 enhances CSF1R trafficking to the cell surface and clustering via PIP2, RalA, and the exocyst complex, providing an additional mechanism by which TNFAIP2 increases macrophage response to CSF-1 beyond CSF1R clustering alone.\",\n      \"method\": \"PIP2-binding site mutagenesis of TNFAIP2 and CSF1R, RalA knockdown, exocyst complex inhibition, cell-surface CSF1R trafficking assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (mutagenesis, RalA knockdown, exocyst perturbation) with direct trafficking readout, replicates and extends prior study\",\n      \"pmids\": [\"41158107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TNFAIP2 (M-Sec) is required for tunneling nanotube (TNT) formation in podocytes, enabling transfer of autophagosomes and lysosomes between cells; tnfaip2 knockout in mice exacerbates diabetic nephropathy, podocyte injury, and lysosomal dysfunction, demonstrating a protective role through TNT-mediated organelle exchange.\",\n      \"method\": \"Tnfaip2 knockout mice (streptozotocin-induced DN model), live-cell imaging of organelle transfer, siRNA knockdown, Tnfaip2 overexpression, lysosomal function assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo combined with in vitro organelle transfer imaging, functional rescue by overexpression, multiple readouts\",\n      \"pmids\": [\"35659195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STAT1 epigenetically regulates TNFAIP2 expression by recruiting the acetyltransferase EP300 to H3K27ac-enriched enhancer loci of TNFAIP2; phosphorylated STAT1 binds these enhancer regions and EP300 subsequently promotes TNFAIP2 transcription.\",\n      \"method\": \"ChIP-PCR for STAT1 and H3K27ac, co-immunoprecipitation of STAT1 and EP300, EP300 inhibitor experiments in DSS-induced colitis mouse model\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR and Co-IP demonstrate direct STAT1-EP300 interaction at TNFAIP2 enhancer; single lab, two methods\",\n      \"pmids\": [\"34112215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tnfaip2 acts epistatically upstream of vimentin (Vim) to control triacylglycerol (TAG) and lipid droplet synthesis; Tnfaip2-deficient embryonic stem cells fail to induce TAG and lipid droplet formation during differentiation, and supplementation with palmitic acid rescues the differentiation defect, establishing a role for Tnfaip2 in lipid metabolism-driven stem cell differentiation.\",\n      \"method\": \"Tnfaip2 knockout ESCs, lipidomic analysis, epistasis experiments with Vim, palmitic acid supplementation rescue, planarian Smed-exoc3 knockdown for in vivo confirmation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in ESCs, lipidomics, epistasis with Vim, metabolic rescue, and cross-species validation in planarians; multiple orthogonal methods\",\n      \"pmids\": [\"33300287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TNFAIP2 translation is tightly suppressed by inhibitory upstream open reading frames (uORFs) in its transcript leader sequence; during monocyte-to-macrophage differentiation, these uORFs are inactivated, enabling a large increase in TNFAIP2 protein expression despite stable mRNA, revealing uORF-dependent translational control.\",\n      \"method\": \"Luciferase reporter assays with mutant uORF constructs, polysome profiling, stimulus-based overcoming of uORF inhibition (TPA), comparison of monocytes vs. mature macrophages\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro dissection of uORF function with reporter assays and mutagenesis, cell-differentiation context validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31392347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TNFAIP2 inhibits NF-κB activity and downstream IL-8 production early in the TNFα response, acting as an autoinhibitor of TNFα signaling; a genetic variant (rs8126) that increases TNFAIP2 expression reduces IL-8 and is associated with decreased survival in septic shock.\",\n      \"method\": \"NF-κB reporter assays, IL-8 measurement, in vitro TNFα stimulation with TNFAIP2 modulation, genetic association in two patient cohorts\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — NF-κB reporter and cytokine measurement support inhibitory function, but mechanistic detail is limited; replicated in two patient cohorts\",\n      \"pmids\": [\"26347487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TNFAIP2 expression in human macrophages is induced by Legionella pneumophila infection in an NF-κB-dependent manner (H4 acetylation at its promoter); TNFAIP2 knockdown reduces intracellular replication of L. pneumophila, identifying it as a pro-bacterial host factor.\",\n      \"method\": \"Chromatin immunoprecipitation-sequencing (H4 acetylation), NF-κB inhibition, siRNA knockdown, intracellular bacterial replication assay in A549 cells\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for chromatin mark, functional KD with bacterial replication readout, NF-κB inhibition; single lab\",\n      \"pmids\": [\"27130431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TNFAIP2 promotes HIF1α transcription in breast cancer by sequentially activating Rac1 and ERK, which then activate AP-1 (c-Jun/Fra1); AP-1 directly binds the HIF1α promoter to enhance its transcription and drive tumor angiogenesis.\",\n      \"method\": \"Chromatin immunoprecipitation (AP-1 binding to HIF1α promoter), luciferase reporter assay, ERK inhibitor experiments, Rac1 activity assay, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter confirm AP-1/HIF1α promoter interaction; single lab, two orthogonal methods\",\n      \"pmids\": [\"39532855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TNFAIP2 protects IKKβ from ubiquitin-proteasome degradation (ubiquitination at K63) by competitively binding KEAP1, thereby sustaining NF-κB signaling and promoting EMT and lymphangiogenesis in oral squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for ubiquitination, conditional knockout mouse model with 4NQO-induced OSCC, gene enrichment analysis\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating TNFAIP2-KEAP1 interaction and IKKβ ubiquitination rescue, with in vivo conditional KO validation; single lab\",\n      \"pmids\": [\"39948570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TNFAIP2 knockdown in esophageal squamous cell carcinoma cells decreases expression of downstream Wnt/β-catenin targets (c-Myc, cyclin D1, MMP-7, Snail) and upregulates E-cadherin and p-GSK-3β, placing TNFAIP2 upstream of Wnt/β-catenin signaling.\",\n      \"method\": \"Lentiviral RNAi knockdown, Western blot for Wnt pathway components, proliferation/invasion assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RNAi + Western blot), no direct binding or epistasis confirmation\",\n      \"pmids\": [\"28393234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TNFAIP2 knockdown in platinum-resistant urothelial carcinoma cells upregulates E-cadherin and downregulates TWIST1, reversing EMT; global gene expression analysis after TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-driven EMT.\",\n      \"method\": \"siRNA knockdown, microarray gene expression analysis, Western blot for EMT markers\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gene expression analysis with KD; MTDH relationship identified by microarray without direct binding assay\",\n      \"pmids\": [\"31263157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β increases acetylation of KLF5 (Ac-KLF5) in nasopharyngeal carcinoma cells; acetylated KLF5 directly binds the TNFAIP2 promoter and drives its transcription, inducing EMT; the pro-migratory/invasive effects of Ac-KLF5 depend on TNFAIP2.\",\n      \"method\": \"ChIP assay (KLF5 binding to TNFAIP2 promoter), Western blot for Ac-KLF5, siRNA knockdown of TNFAIP2, in vivo NPC mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional TNFAIP2-dependence tested by knockdown rescue; single lab\",\n      \"pmids\": [\"40054652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"B94/TNFAIP2 is rapidly induced by retinoic acid at the transcriptional level in a PML-RARα-dependent manner in APL cells: induction occurs within 1 hour, does not require new protein synthesis, and is blocked by actinomycin D; PML coiled-coil domain deletion abolishes induction, positioning TNFAIP2 as a transcriptional target downstream of PML-RARα.\",\n      \"method\": \"cDNA microarray, quantitative RT-PCR with actinomycin D and cycloheximide controls, RA treatment of NB4/UF1/HL-60/TF1-PR cells, dominant-negative PML-RARα deletion mutant\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection (actinomycin D block, protein-synthesis independence) with mutant construct; single lab\",\n      \"pmids\": [\"10766166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A SNP in the miR-184 seed-binding site of the TNFAIP2 3′-UTR (rs8126 T>C) reduces luciferase reporter activity and is associated with lower endogenous TNFAIP2 mRNA levels, demonstrating that miR-184 post-transcriptionally represses TNFAIP2 and that this SNP disrupts the regulation.\",\n      \"method\": \"Luciferase reporter assay with WT and variant 3′-UTR constructs, genotype-phenotype mRNA analysis in patient PBMCs\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with allelic comparison and in vivo mRNA correlation; single lab, two methods\",\n      \"pmids\": [\"21934093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNFAIP2 is a TNFα/NF-κB-inducible cytosolic protein that promotes cell migration and invasion by activating the small GTPases Rac1 and Cdc42 (partly via an IQGAP1/Integrin β4 scaffold), drives tumor angiogenesis through a Rac1-ERK-AP1-HIF1α axis, confers cisplatin resistance by competing with NRF2 for KEAP1 binding (via its DLG motif) to stabilize NRF2 and suppress ROS-JNK signaling, sustains NF-κB signaling by protecting IKKβ from KEAP1-mediated ubiquitination, promotes tunneling nanotube (TNT) formation for intercellular organelle exchange, enhances CSF1R clustering and surface trafficking in macrophages through PIP2, RalA, and the exocyst complex, and controls lipid droplet/triacylglycerol metabolism epistatically upstream of vimentin to enable stem cell differentiation; its translation is additionally regulated by inhibitory upstream ORFs that are inactivated during macrophage differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TNFAIP2 is a cytosolic, actin-associated effector that couples inflammatory and oncogenic transcriptional programs to cytoskeletal remodeling, membrane dynamics, and redox signaling, thereby promoting cell migration, invasion, and intercellular communication [#0, #1]. As a transcriptional output of NF-\\u03baB (downstream of EBV LMP1/p65, Legionella infection), KLF5, STAT1/EP300, and PML-RAR\\u03b1, its expression is induced by diverse inflammatory and differentiation cues and is further tuned post-transcriptionally by miR-184 and by inhibitory upstream ORFs that are released during macrophage differentiation [#1, #11, #7, #17, #18, #9]. Mechanistically, TNFAIP2 binds and activates the small GTPases Rac1 and Cdc42 to drive actin-based protrusions and motility, in part through an IQGAP1/Integrin \\u03b24 scaffold, and a Rac1\\u2192ERK\\u2192AP-1\\u2192HIF1\\u03b1 axis links this activity to tumor angiogenesis [#0, #3, #12]. Through a DLG motif it directly binds the Kelch domain of KEAP1, competing with NRF2 to stabilize NRF2 and suppress ROS-JNK signaling (conferring cisplatin resistance) and competing for KEAP1 to protect IKK\\u03b2 from K63-ubiquitination, thereby sustaining NF-\\u03baB signaling [#2, #13]. TNFAIP2 also acts at membranes: it binds PIP2 to promote CSF1R clustering and, via RalA and the exocyst complex, enhances CSF1R surface trafficking in macrophages [#4, #5]; it is required for tunneling-nanotube\\u2013mediated transfer of autophagosomes and lysosomes between cells [#6]; and it acts epistatically upstream of vimentin to control triacylglycerol and lipid-droplet synthesis during stem-cell differentiation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established TNFAIP2 (B94) as an immediate transcriptional target, defining it as a rapidly inducible gene wired to differentiation signaling.\",\n      \"evidence\": \"cDNA microarray and qRT-PCR with actinomycin D/cycloheximide controls and dominant-negative PML-RAR\\u03b1 mutant in APL cell lines\",\n      \"pmids\": [\"10766166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the protein's biochemical activity\", \"Promoter elements mediating PML-RAR\\u03b1-dependent induction not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed TNFAIP2 is post-transcriptionally repressed by miR-184, revealing a layer of expression control disrupted by a 3'-UTR SNP.\",\n      \"evidence\": \"Luciferase reporter assays with WT/variant 3'-UTR and genotype-mRNA correlation in patient PBMCs\",\n      \"pmids\": [\"21934093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of altered TNFAIP2 levels not tested here\", \"Did not address protein function\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected NF-\\u03baB transcriptional induction to TNFAIP2 protein function, showing LMP1/p65 induces TNFAIP2, which associates with actin to drive membrane protrusions and motility.\",\n      \"evidence\": \"Luciferase reporter and promoter mapping, p65 knockdown/overexpression, Co-IP, immunofluorescence, transwell migration in EBV context\",\n      \"pmids\": [\"23975427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of actin engagement not resolved\", \"Did not identify GTPase intermediates\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the core motility mechanism: TNFAIP2 binds and activates Rac1 and Cdc42 to remodel actin, downstream of KLF5.\",\n      \"evidence\": \"Reciprocal Co-IP, GTPase activity assays, siRNA migration/invasion readouts, KLF5 promoter reporter in multiple cancer lines\",\n      \"pmids\": [\"26189798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TNFAIP2 acts as a direct GEF or via a scaffold not established\", \"Structural basis of GTPase binding unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an autoinhibitory role in early TNF\\u03b1 signaling, complicating the simple pro-NF-\\u03baB picture and linking a regulatory variant to septic shock outcome.\",\n      \"evidence\": \"NF-\\u03baB reporter and IL-8 assays with TNFAIP2 modulation, genetic association in two patient cohorts\",\n      \"pmids\": [\"26347487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of NF-\\u03baB inhibition not defined\", \"Apparent contradiction with later pro-NF-\\u03baB findings unreconciled\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed pathogen-driven, NF-\\u03baB/chromatin-dependent induction of TNFAIP2 supports intracellular bacterial replication, casting it as a host factor exploited by infection.\",\n      \"evidence\": \"ChIP-seq for H4 acetylation, NF-\\u03baB inhibition, siRNA knockdown, intracellular L. pneumophila replication assay in A549 cells\",\n      \"pmids\": [\"27130431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular step in bacterial replication supported by TNFAIP2 unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed uORF-dependent translational control as a gate on TNFAIP2 protein output during monocyte-to-macrophage differentiation.\",\n      \"evidence\": \"Luciferase reporters with mutant uORFs, polysome profiling, TPA stimulation, monocyte vs. macrophage comparison\",\n      \"pmids\": [\"31392347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting factors controlling uORF inactivation not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered a metabolic function: TNFAIP2 acts epistatically upstream of vimentin to drive triacylglycerol/lipid-droplet synthesis required for stem-cell differentiation.\",\n      \"evidence\": \"Tnfaip2 KO ESCs, lipidomics, Vim epistasis, palmitic acid rescue, planarian Smed-exoc3 cross-species validation\",\n      \"pmids\": [\"33300287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link between TNFAIP2 and lipid synthesis enzymes unknown\", \"How vimentin executes the downstream step unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an epigenetic input: phospho-STAT1 recruits EP300 to H3K27ac enhancers to activate TNFAIP2 transcription.\",\n      \"evidence\": \"ChIP-PCR for STAT1/H3K27ac, STAT1-EP300 Co-IP, EP300 inhibition in DSS colitis model\",\n      \"pmids\": [\"34112215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Downstream functional consequence of STAT1-driven TNFAIP2 not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established TNFAIP2 (M-Sec) as required for tunneling-nanotube formation enabling intercellular organelle transfer, with in vivo protection against diabetic nephropathy.\",\n      \"evidence\": \"Tnfaip2 KO mice (STZ-induced DN), live-cell organelle-transfer imaging, knockdown and overexpression rescue, lysosomal assays in podocytes\",\n      \"pmids\": [\"35659195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which TNFAIP2 nucleates TNTs not defined\", \"Link to GTPase/membrane functions not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the KEAP1-NRF2 competition mechanism: TNFAIP2's DLG motif binds KEAP1's Kelch domain to stabilize NRF2 and suppress ROS-JNK, conferring chemoresistance.\",\n      \"evidence\": \"Co-IP/MS, DLG-motif mutant analysis, flow cytometry for ROS/apoptosis, xenografts, siRNA knockdown\",\n      \"pmids\": [\"37525222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DLG-KEAP1 binding regulates other KEAP1 substrates not addressed at the time\", \"Structure of the complex not solved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the GTPase mechanism by showing an Integrin \\u03b24/TNFAIP2/IQGAP1 axis activates Rac1 to confer DNA-damage drug resistance.\",\n      \"evidence\": \"Reciprocal Co-IP of IQGAP1 and Integrin \\u03b24, functional drug-resistance assays, siRNA in TNBC\",\n      \"pmids\": [\"37787041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct binding interfaces among the three proteins not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked TNFAIP2's GTPase activity to angiogenesis through a Rac1\\u2192ERK\\u2192AP-1\\u2192HIF1\\u03b1 transcriptional cascade.\",\n      \"evidence\": \"ChIP for AP-1 on HIF1\\u03b1 promoter, luciferase reporter, ERK inhibition, Rac1 activity assay, xenograft\",\n      \"pmids\": [\"39532855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Quantitative contribution of this axis to in vivo angiogenesis not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed TNFAIP2 binds PIP2 to cluster CSF1R and uses RalA/exocyst to traffic CSF1R to the surface, amplifying macrophage CSF-1 responses.\",\n      \"evidence\": \"PIP2-binding motif mutagenesis on TNFAIP2 and CSF1R, PIP2 depletion, RalA knockdown, exocyst perturbation, surface-trafficking and activation assays (two consecutive studies)\",\n      \"pmids\": [\"39939179\", \"41158107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIP2 binding underlies TNFAIP2's other membrane functions (TNTs, GTPase activation) not tested\", \"Structural basis of PIP2 recognition unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the pro-NF-\\u03baB arm: TNFAIP2 competitively binds KEAP1 to protect IKK\\u03b2 from K63-ubiquitination, sustaining NF-\\u03baB to drive EMT and lymphangiogenesis.\",\n      \"evidence\": \"Co-IP, ubiquitination Western blots, conditional KO mice in 4NQO-induced OSCC\",\n      \"pmids\": [\"39948570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relationship to the earlier reported NF-\\u03baB autoinhibition not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how TNFAIP2's distinct biochemical activities — GTPase activation, KEAP1/DLG competition, PIP2/membrane binding, and TNT formation — are integrated into one structural/regulatory framework, and whether they reflect context-specific modules of a single mechanism.\",\n      \"evidence\": \"No discovery in the corpus integrates these activities or provides a structural model\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of TNFAIP2 or its complexes reported\", \"Domain-level mapping of the multiple binding functions incomplete\", \"Apparent contradictory roles in NF-\\u03baB signaling not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 12, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 11]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 13, 6]}\n    ],\n    \"complexes\": [\"exocyst\"],\n    \"partners\": [\"Rac1\", \"Cdc42\", \"KEAP1\", \"IQGAP1\", \"ITGB4\", \"CSF1R\", \"RalA\", \"IKBKB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}