{"gene":"TACC2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2000,"finding":"AZU-1 (TACC2) protein resides predominantly in a detergent-extractable cytoplasmic pool in mammary epithelial cells; reexpression of AZU-1 in tumorigenic T4-2 cells was sufficient to reduce their malignant phenotype both in culture and in vivo, establishing a functional tumor-suppressive role in breast morphogenesis.","method":"Subcellular fractionation, viral vector-mediated reexpression, 3D culture and xenograft assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue by reexpression with in vitro and in vivo phenotypic readouts, single lab, multiple orthogonal methods","pmids":["10749935"],"is_preprint":false},{"year":2003,"finding":"TACC2 physically interacts with GAS41 and components of the SWI/SNF chromatin remodeling complex, suggesting a role in gene regulation via chromatin remodeling.","method":"Co-immunoprecipitation / pulldown assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction demonstrated by pulldown/Co-IP, single lab, two binding partners identified","pmids":["12620397"],"is_preprint":false},{"year":2004,"finding":"TACC2 is phosphorylated during mitosis by the TTK kinase signaling pathway; TTK kinase activity is required for centrosomal localization of TACC2, as expression of a kinase-dead TTK mutant or TTK depletion displaces TACC2 from the centrosome (but not other centrosomal proteins such as γ-tubulin and NuMA), leading to chromosome misalignment/lagging and reduced centrosome separation.","method":"Pulldown of TACC2 by wild-type vs kinase-dead TTK, immunofluorescence, TTK depletion by siRNA","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant and depletion experiments with specific phenotypic readout, single lab, multiple methods","pmids":["15304323"],"is_preprint":false},{"year":2004,"finding":"In TACC2-deficient mouse embryonic fibroblasts, proliferation, cell cycle progression, and centrosome numbers are comparable to wild-type cells, indicating TACC2 is dispensable for normal mouse cell proliferation and centrosome homeostasis, and TACC2 knockout mice develop normally without increased tumor incidence.","method":"TACC2 knockout mouse model, cell proliferation assays, cell cycle analysis, centrosome counting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple cellular readouts, peer-reviewed, single comprehensive study with rigorous controls","pmids":["15226440"],"is_preprint":false},{"year":2009,"finding":"SV40 large T antigen directly binds TACC2 protein; this interaction induces microtubule dysfunction, disorganized mitotic spindles, slow mitotic progression, and chromosome missegregation. Overexpression of TACC2 suppresses T-antigen-induced microtubule destabilization, demonstrating that TACC2 normally stabilizes microtubules in mitosis.","method":"Co-immunoprecipitation/direct binding assay, N-terminal deletion mutants of T antigen, immunofluorescence microscopy, TACC2 overexpression rescue","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with mutant analysis and functional rescue by TACC2 overexpression, single lab, multiple orthogonal methods","pmids":["19671663"],"is_preprint":false},{"year":2012,"finding":"TACC2 is a direct androgen receptor (AR)-regulated gene; a functional AR-binding site containing two canonical androgen response elements was identified near the TACC2 gene with active histone modification marks. AR knockdown or bicalutamide treatment abolished androgen-dependent TACC2 induction. TACC2 siRNA knockdown reduced cell growth and cell cycle progression in castration-resistant prostate cancer (CRPC) cell models, while TACC2 overexpression accelerated the cell cycle.","method":"ChIP-cloning, ChIP for histone marks, AR knockdown, pharmacological inhibition (bicalutamide), siRNA knockdown, cell cycle analysis, overexpression, castrated mouse xenograft model","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, KD, OE, in vivo) in single comprehensive study establishing regulatory mechanism and functional role","pmids":["22456197"],"is_preprint":false},{"year":2016,"finding":"Xenopus TACC2 localizes to microtubule plus ends in front of EB1 and overlapping with TACC1/TACC3, functioning as a +TIP. The C-terminal region (containing the TACC domain) is both necessary and sufficient for plus-end localization and promotion of MT polymerization, while the N-terminal region cannot bind MT plus ends but acts in a dominant-negative manner to reduce polymerization rates. TACC2 promotes MT polymerization in mesenchymal cells but not neuronal growth cones.","method":"Live imaging of GFP-tagged TACC2 in Xenopus embryonic cells, structure-function analysis with N-terminal and C-terminal deletion constructs, MT polymerization rate measurements","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — structure-function mutagenesis combined with live-cell imaging and quantitative MT dynamics measurements, multiple cell types tested","pmids":["27559128"],"is_preprint":false},{"year":2025,"finding":"TACC2 interacts with components of the NuRD and CoREST co-repressor complexes (MTA1, MBD3, HMG20B) in the cytoplasm. Loss of TACC2 causes nuclear translocation of these co-repressor proteins, leading to functional NuRD/CoREST complex assembly in the nucleus, epigenetic repression of CDKN1A (p21), elevated CDK1/2 activation, and increased sensitivity to CDK inhibitors.","method":"Co-immunoprecipitation, ChIP, TACC2 knockout mouse model, ESCC organoids, subcellular fractionation, siRNA + CDK inhibitor combination treatment in vivo","journal":"Med (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, genetic KO model, organoids and in vivo rescue with multiple orthogonal methods in a single comprehensive study","pmids":["39793578"],"is_preprint":false},{"year":2025,"finding":"TACC2 interacts with the NuRD/CoREST complex and inhibits its nuclear translocation; in soft tissue sarcoma, TACC2 loss permits nuclear NuRD/CoREST translocation which represses CCL3 and CCL4 chemokine transcription, thereby reducing CD8+ T cell infiltration. TACC2 overexpression synergizes with anti-PD-1 therapy in vivo.","method":"ChIP, co-immunoprecipitation, TACC2 overexpression mouse models, anti-PD-1 combination treatment in vivo","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with in vivo functional validation, single lab, consistent with mechanistic findings in PMID:39793578","pmids":["40442694"],"is_preprint":false},{"year":2025,"finding":"The PLEKHA1-TACC2 fusion protein activates the EphA2/AKT/MMP2 signaling pathway and promotes vascular mimicry formation by reducing EphA2 ubiquitylation, with oncogenic activity demonstrated in transgenic ESCC mouse models.","method":"RNA sequencing for fusion identification, functional assays for vascular mimicry, ubiquitylation assay, transgenic mouse model with Trp53 deletion, EphA2 inhibitor treatment in vivo","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fusion protein mechanism determined by ubiquitylation assay and in vivo transgenic model, single lab, multiple methods","pmids":["40615663"],"is_preprint":false},{"year":2026,"finding":"SUV39H1 (Suv39h1) directly binds the TACC2 promoter and represses TACC2 transcription by catalyzing H3K9 trimethylation during fibroblast-to-myofibroblast transition. TACC2 depletion normalized the transition despite SUV39H1 deficiency, while TACC2 overexpression suppressed the transition, placing TACC2 downstream of SUV39H1 in cardiac fibrosis regulation.","method":"CUT&Tag-seq, RNA-seq, TACC2 depletion and overexpression, cardiac fibroblast-specific conditional knockout mouse models (Col1a2-CreERT and PostnMCM), transverse aortic constriction heart failure model","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CUT&Tag chromatin binding, genetic epistasis via gain/loss of function, two conditional KO mouse models with defined phenotypic readouts","pmids":["41861065"],"is_preprint":false}],"current_model":"TACC2 is a centrosome- and microtubule-associated protein that functions as a microtubule plus end-tracking protein promoting MT polymerization via its C-terminal TACC domain; it is phosphorylated by TTK/Mps1 kinase to maintain centrosomal localization during mitosis, binds SV40 large T antigen to stabilize microtubules, and in the cytoplasm sequesters NuRD/CoREST co-repressor components (MTA1, MBD3, HMG20B) to prevent their nuclear translocation and epigenetic silencing of CDKN1A/CCL chemokines; TACC2 transcription is directly activated by androgen receptor and repressed by SUV39H1-mediated H3K9me3, while TACC2 also interacts with the SWI/SNF complex and GAS41, collectively positioning it as a context-dependent regulator of cell cycle progression, chromatin remodeling, and immune gene expression."},"narrative":{"mechanistic_narrative":"TACC2 is a centrosome- and microtubule-associated protein that functions both in mitotic spindle regulation and as a cytoplasmic anchor controlling chromatin-modifying complexes, positioning it as a context-dependent tumor suppressor [PMID:10749935, PMID:39793578]. At the cytoskeleton, TACC2 acts as a microtubule plus-end-tracking protein whose C-terminal TACC domain is necessary and sufficient for plus-end localization and promotion of microtubule polymerization, while its N-terminal region acts dominant-negatively [PMID:27559128]; it normally stabilizes mitotic microtubules, an activity that opposes the spindle disruption caused by SV40 large T antigen binding [PMID:19671663]. TACC2 is phosphorylated during mitosis by TTK/Mps1 kinase, which is required to maintain its centrosomal localization and proper chromosome alignment and centrosome separation [PMID:15304323]. A central regulatory function is the cytoplasmic sequestration of NuRD and CoREST co-repressor components (MTA1, MBD3, HMG20B); loss of TACC2 permits their nuclear translocation, driving epigenetic repression of CDKN1A and of CCL3/CCL4 chemokines, thereby elevating CDK activity and suppressing CD8+ T cell infiltration [PMID:39793578, PMID:40442694]. TACC2 expression is itself transcriptionally controlled, being directly induced by androgen receptor in prostate cancer cells [PMID:22456197] and repressed by SUV39H1-mediated H3K9 trimethylation during fibroblast-to-myofibroblast transition [PMID:41861065]. TACC2 also physically associates with GAS41 and the SWI/SNF chromatin remodeling complex [PMID:12620397]. Notably, TACC2 is dispensable for normal mouse development, proliferation, and centrosome homeostasis [PMID:15226440].","teleology":[{"year":2000,"claim":"Established that TACC2 (AZU-1) is a cytoplasmic protein with tumor-suppressive function, framing it as more than a passive structural component.","evidence":"Subcellular fractionation and viral reexpression in mammary epithelial T4-2 cells with 3D culture and xenograft phenotypes","pmids":["10749935"],"confidence":"Medium","gaps":["Molecular mechanism of malignancy suppression not defined","No interaction partners identified at this stage"]},{"year":2003,"claim":"Linked TACC2 to gene regulation by identifying physical association with the SWI/SNF chromatin remodeling machinery, suggesting a role beyond the cytoskeleton.","evidence":"Co-immunoprecipitation/pulldown identifying GAS41 and SWI/SNF components","pmids":["12620397"],"confidence":"Medium","gaps":["Functional consequence of SWI/SNF binding not tested","Single lab, no reciprocal validation reported"]},{"year":2004,"claim":"Defined how TACC2 is positioned at the centrosome during mitosis, showing TTK kinase phosphorylation is required for its centrosomal retention and accurate chromosome segregation.","evidence":"Pulldown with wild-type vs kinase-dead TTK, siRNA depletion, and immunofluorescence","pmids":["15304323"],"confidence":"Medium","gaps":["Phosphosite(s) on TACC2 not mapped","Direct vs indirect phosphorylation not fully resolved"]},{"year":2004,"claim":"Tested the in vivo requirement for TACC2 and found it dispensable for normal proliferation, centrosome homeostasis, and tumor suppression in mice, complicating a simple essential mitotic role.","evidence":"TACC2 knockout mouse, proliferation and cell cycle assays, centrosome counting","pmids":["15226440"],"confidence":"High","gaps":["Functional redundancy with TACC paralogs not directly addressed","Context-specific phenotypes not explored"]},{"year":2009,"claim":"Demonstrated TACC2 directly stabilizes mitotic microtubules by showing it counteracts SV40 large T antigen-induced spindle dysfunction.","evidence":"Co-IP/direct binding, T-antigen deletion mutants, immunofluorescence, TACC2 overexpression rescue","pmids":["19671663"],"confidence":"Medium","gaps":["Endogenous microtubule-stabilizing mechanism not isolated from viral context","Single lab"]},{"year":2016,"claim":"Assigned a precise molecular activity by showing TACC2 is a microtubule plus-end-tracking protein whose C-terminal TACC domain drives polymerization, with cell-type-dependent effects.","evidence":"Live imaging of GFP-TACC2 in Xenopus cells, structure-function deletions, MT polymerization measurements","pmids":["27559128"],"confidence":"High","gaps":["Why activity differs between mesenchymal and neuronal cells unexplained","Human protein not directly assayed in this study"]},{"year":2012,"claim":"Placed TACC2 within hormonal signaling by establishing it as a direct AR target gene driving cell cycle progression in castration-resistant prostate cancer.","evidence":"ChIP-cloning, ChIP for histone marks, AR knockdown, bicalutamide, siRNA, overexpression, xenograft","pmids":["22456197"],"confidence":"High","gaps":["Cytoskeletal vs chromatin role in this growth phenotype not separated","Downstream effectors of TACC2-driven proliferation unresolved"]},{"year":2025,"claim":"Revealed the central tumor-suppressive mechanism: cytoplasmic TACC2 sequesters NuRD/CoREST co-repressors, and its loss permits nuclear translocation that epigenetically silences CDKN1A and elevates CDK activity.","evidence":"Reciprocal Co-IP, ChIP, TACC2 knockout mouse, ESCC organoids, fractionation, siRNA + CDK inhibitor in vivo","pmids":["39793578"],"confidence":"High","gaps":["Structural basis of cytoplasmic anchoring not defined","How TACC2 microtubule activity relates to co-repressor sequestration unclear"]},{"year":2025,"claim":"Extended the co-repressor sequestration model to immune evasion, showing TACC2 loss derepresses CCL3/CCL4 and reduces CD8+ T cell infiltration, with therapeutic relevance to checkpoint blockade.","evidence":"ChIP, Co-IP, TACC2 overexpression mouse models, anti-PD-1 combination in vivo","pmids":["40442694"],"confidence":"Medium","gaps":["Direct demonstration that chemokine repression alone drives T cell exclusion incomplete","Generality across tumor types not established"]},{"year":2025,"claim":"Identified an oncogenic gain-of-function for a PLEKHA1-TACC2 fusion acting through EphA2/AKT/MMP2 signaling and vascular mimicry, distinct from wild-type TACC2 function.","evidence":"RNA-seq fusion identification, vascular mimicry assays, ubiquitylation assay, Trp53-deletion transgenic mouse, EphA2 inhibitor in vivo","pmids":["40615663"],"confidence":"Medium","gaps":["Contribution of the TACC2 portion vs PLEKHA1 portion not dissected","Relationship to native TACC2 activity unclear"]},{"year":2026,"claim":"Defined upstream epigenetic control of TACC2, showing SUV39H1-mediated H3K9me3 represses its promoter to license fibroblast-to-myofibroblast transition in cardiac fibrosis.","evidence":"CUT&Tag-seq, RNA-seq, gain/loss of function epistasis, two conditional KO mouse models, transverse aortic constriction","pmids":["41861065"],"confidence":"High","gaps":["Whether co-repressor sequestration underlies the fibrosis phenotype not tested","Mechanism linking TACC2 level to myofibroblast program unresolved"]},{"year":null,"claim":"How TACC2's microtubule plus-end-tracking activity is mechanistically integrated with its cytoplasmic sequestration of NuRD/CoREST co-repressors remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking cytoskeletal and chromatin functions","Determinants of cytoplasmic vs centrosomal partitioning unknown","Paralog redundancy with TACC1/TACC3 not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,6]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":[],"partners":["MTA1","MBD3","HMG20B","GAS41","TTK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95359","full_name":"Transforming acidic coiled-coil-containing protein 2","aliases":["Anti-Zuai-1","AZU-1"],"length_aa":2948,"mass_kda":309.4,"function":"Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors (By similarity). May play a role in organizing centrosomal microtubules. May act as a tumor suppressor protein. May represent a tumor progression marker","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/O95359/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TACC2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP4","stoichiometry":0.2},{"gene":"TUBA1B","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TACC2","total_profiled":1310},"omim":[{"mim_id":"605303","title":"TRANSFORMING, ACIDIC, COILED-COIL-CONTAINING PROTEIN 3; TACC3","url":"https://www.omim.org/entry/605303"},{"mim_id":"605302","title":"TRANSFORMING, ACIDIC, COILED-COIL-CONTAINING PROTEIN 2; TACC2","url":"https://www.omim.org/entry/605302"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":238.7},{"tissue":"skeletal muscle","ntpm":371.3}],"url":"https://www.proteinatlas.org/search/TACC2"},"hgnc":{"alias_symbol":["AZU-1","ECTACC"],"prev_symbol":[]},"alphafold":{"accession":"O95359","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95359","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95359-6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95359-6-F1-predicted_aligned_error_v6.png","plddt_mean":55.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TACC2","jax_strain_url":"https://www.jax.org/strain/search?query=TACC2"},"sequence":{"accession":"O95359","fasta_url":"https://rest.uniprot.org/uniprotkb/O95359.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95359/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95359"}},"corpus_meta":[{"pmid":"10749935","id":"PMC_10749935","title":"AZU-1: a candidate breast tumor suppressor and biomarker for tumor progression.","date":"2000","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/10749935","citation_count":77,"is_preprint":false},{"pmid":"22456197","id":"PMC_22456197","title":"TACC2 is an androgen-responsive cell cycle regulator promoting androgen-mediated and castration-resistant growth of prostate cancer.","date":"2012","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22456197","citation_count":41,"is_preprint":false},{"pmid":"12620397","id":"PMC_12620397","title":"Molecular cloning, genomic structure and interactions of the putative breast tumor suppressor TACC2.","date":"2003","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/12620397","citation_count":37,"is_preprint":false},{"pmid":"15226440","id":"PMC_15226440","title":"The centrosomal, putative tumor suppressor protein TACC2 is dispensable for normal development, and deficiency does not lead to cancer.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15226440","citation_count":32,"is_preprint":false},{"pmid":"15304323","id":"PMC_15304323","title":"TTK kinase is essential for the centrosomal localization of TACC2.","date":"2004","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15304323","citation_count":24,"is_preprint":false},{"pmid":"34511423","id":"PMC_34511423","title":"Stage 4 pancreatic adenocarcinoma harbouring an FGFR2-TACC2 fusion mutation with complete response to erdafitinib a pan-fibroblastic growth factor receptor inhibitor.","date":"2021","source":"BMJ case reports","url":"https://pubmed.ncbi.nlm.nih.gov/34511423","citation_count":19,"is_preprint":false},{"pmid":"11161455","id":"PMC_11161455","title":"Cloning and structural characterization of ECTACC, a new member of the transforming acidic coiled coil (TACC) gene family: cDNA sequence and expression analysis in human microvascular endothelial cells.","date":"2001","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/11161455","citation_count":18,"is_preprint":false},{"pmid":"27559128","id":"PMC_27559128","title":"Xenopus TACC2 is a microtubule plus end-tracking protein that can promote microtubule polymerization during embryonic development.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/27559128","citation_count":13,"is_preprint":false},{"pmid":"35170141","id":"PMC_35170141","title":"FGFR2::TACC2 fusion as a novel KIT-independent mechanism of targeted therapy failure in a multidrug-resistant gastrointestinal stromal tumor.","date":"2022","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35170141","citation_count":12,"is_preprint":false},{"pmid":"19671663","id":"PMC_19671663","title":"Simian virus 40 large T antigen targets the microtubule-stabilizing protein TACC2.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19671663","citation_count":11,"is_preprint":false},{"pmid":"33241100","id":"PMC_33241100","title":"Histology-specific FGFR2 alterations and FGFR2-TACC2 fusion in mixed adenoid cystic and neuroendocrine small cell carcinoma of the uterine cervix.","date":"2020","source":"Gynecologic oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33241100","citation_count":8,"is_preprint":false},{"pmid":"40442694","id":"PMC_40442694","title":"Loss of TACC2 impairs chemokine CCL3 and CCL4 expression and reduces response to anti-PD-1 therapy in soft tissue sarcoma.","date":"2025","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40442694","citation_count":7,"is_preprint":false},{"pmid":"24700488","id":"PMC_24700488","title":"Expression pattern of an evolutionarily conserved splice variant in the rat Tacc2 gene.","date":"2014","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/24700488","citation_count":7,"is_preprint":false},{"pmid":"39793578","id":"PMC_39793578","title":"Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors.","date":"2025","source":"Med (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39793578","citation_count":4,"is_preprint":false},{"pmid":"33931666","id":"PMC_33931666","title":"Nanopore sequencing reveals TACC2 locus complexity and diversity of isoforms transcribed from an intronic promoter.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33931666","citation_count":3,"is_preprint":false},{"pmid":"40615663","id":"PMC_40615663","title":"The PLEKHA1-TACC2 fusion gene drives tumorigenesis via vascular mimicry formation in esophageal squamous-cell carcinoma.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/40615663","citation_count":0,"is_preprint":false},{"pmid":"41861065","id":"PMC_41861065","title":"Suppressor of variegation 3-9 homolog 1 deficiency attenuates cardiac fibrosis and rescues heart failure through TACC2.","date":"2026","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/41861065","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10272,"output_tokens":3002,"usd":0.037923,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10386,"output_tokens":3863,"usd":0.074252,"stage2_stop_reason":"end_turn"},"total_usd":0.112175,"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\": 2000,\n      \"finding\": \"AZU-1 (TACC2) protein resides predominantly in a detergent-extractable cytoplasmic pool in mammary epithelial cells; reexpression of AZU-1 in tumorigenic T4-2 cells was sufficient to reduce their malignant phenotype both in culture and in vivo, establishing a functional tumor-suppressive role in breast morphogenesis.\",\n      \"method\": \"Subcellular fractionation, viral vector-mediated reexpression, 3D culture and xenograft assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue by reexpression with in vitro and in vivo phenotypic readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10749935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TACC2 physically interacts with GAS41 and components of the SWI/SNF chromatin remodeling complex, suggesting a role in gene regulation via chromatin remodeling.\",\n      \"method\": \"Co-immunoprecipitation / pulldown assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction demonstrated by pulldown/Co-IP, single lab, two binding partners identified\",\n      \"pmids\": [\"12620397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TACC2 is phosphorylated during mitosis by the TTK kinase signaling pathway; TTK kinase activity is required for centrosomal localization of TACC2, as expression of a kinase-dead TTK mutant or TTK depletion displaces TACC2 from the centrosome (but not other centrosomal proteins such as γ-tubulin and NuMA), leading to chromosome misalignment/lagging and reduced centrosome separation.\",\n      \"method\": \"Pulldown of TACC2 by wild-type vs kinase-dead TTK, immunofluorescence, TTK depletion by siRNA\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant and depletion experiments with specific phenotypic readout, single lab, multiple methods\",\n      \"pmids\": [\"15304323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In TACC2-deficient mouse embryonic fibroblasts, proliferation, cell cycle progression, and centrosome numbers are comparable to wild-type cells, indicating TACC2 is dispensable for normal mouse cell proliferation and centrosome homeostasis, and TACC2 knockout mice develop normally without increased tumor incidence.\",\n      \"method\": \"TACC2 knockout mouse model, cell proliferation assays, cell cycle analysis, centrosome counting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple cellular readouts, peer-reviewed, single comprehensive study with rigorous controls\",\n      \"pmids\": [\"15226440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SV40 large T antigen directly binds TACC2 protein; this interaction induces microtubule dysfunction, disorganized mitotic spindles, slow mitotic progression, and chromosome missegregation. Overexpression of TACC2 suppresses T-antigen-induced microtubule destabilization, demonstrating that TACC2 normally stabilizes microtubules in mitosis.\",\n      \"method\": \"Co-immunoprecipitation/direct binding assay, N-terminal deletion mutants of T antigen, immunofluorescence microscopy, TACC2 overexpression rescue\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with mutant analysis and functional rescue by TACC2 overexpression, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19671663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TACC2 is a direct androgen receptor (AR)-regulated gene; a functional AR-binding site containing two canonical androgen response elements was identified near the TACC2 gene with active histone modification marks. AR knockdown or bicalutamide treatment abolished androgen-dependent TACC2 induction. TACC2 siRNA knockdown reduced cell growth and cell cycle progression in castration-resistant prostate cancer (CRPC) cell models, while TACC2 overexpression accelerated the cell cycle.\",\n      \"method\": \"ChIP-cloning, ChIP for histone marks, AR knockdown, pharmacological inhibition (bicalutamide), siRNA knockdown, cell cycle analysis, overexpression, castrated mouse xenograft model\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, KD, OE, in vivo) in single comprehensive study establishing regulatory mechanism and functional role\",\n      \"pmids\": [\"22456197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Xenopus TACC2 localizes to microtubule plus ends in front of EB1 and overlapping with TACC1/TACC3, functioning as a +TIP. The C-terminal region (containing the TACC domain) is both necessary and sufficient for plus-end localization and promotion of MT polymerization, while the N-terminal region cannot bind MT plus ends but acts in a dominant-negative manner to reduce polymerization rates. TACC2 promotes MT polymerization in mesenchymal cells but not neuronal growth cones.\",\n      \"method\": \"Live imaging of GFP-tagged TACC2 in Xenopus embryonic cells, structure-function analysis with N-terminal and C-terminal deletion constructs, MT polymerization rate measurements\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — structure-function mutagenesis combined with live-cell imaging and quantitative MT dynamics measurements, multiple cell types tested\",\n      \"pmids\": [\"27559128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TACC2 interacts with components of the NuRD and CoREST co-repressor complexes (MTA1, MBD3, HMG20B) in the cytoplasm. Loss of TACC2 causes nuclear translocation of these co-repressor proteins, leading to functional NuRD/CoREST complex assembly in the nucleus, epigenetic repression of CDKN1A (p21), elevated CDK1/2 activation, and increased sensitivity to CDK inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, TACC2 knockout mouse model, ESCC organoids, subcellular fractionation, siRNA + CDK inhibitor combination treatment in vivo\",\n      \"journal\": \"Med (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, genetic KO model, organoids and in vivo rescue with multiple orthogonal methods in a single comprehensive study\",\n      \"pmids\": [\"39793578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TACC2 interacts with the NuRD/CoREST complex and inhibits its nuclear translocation; in soft tissue sarcoma, TACC2 loss permits nuclear NuRD/CoREST translocation which represses CCL3 and CCL4 chemokine transcription, thereby reducing CD8+ T cell infiltration. TACC2 overexpression synergizes with anti-PD-1 therapy in vivo.\",\n      \"method\": \"ChIP, co-immunoprecipitation, TACC2 overexpression mouse models, anti-PD-1 combination treatment in vivo\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with in vivo functional validation, single lab, consistent with mechanistic findings in PMID:39793578\",\n      \"pmids\": [\"40442694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PLEKHA1-TACC2 fusion protein activates the EphA2/AKT/MMP2 signaling pathway and promotes vascular mimicry formation by reducing EphA2 ubiquitylation, with oncogenic activity demonstrated in transgenic ESCC mouse models.\",\n      \"method\": \"RNA sequencing for fusion identification, functional assays for vascular mimicry, ubiquitylation assay, transgenic mouse model with Trp53 deletion, EphA2 inhibitor treatment in vivo\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fusion protein mechanism determined by ubiquitylation assay and in vivo transgenic model, single lab, multiple methods\",\n      \"pmids\": [\"40615663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SUV39H1 (Suv39h1) directly binds the TACC2 promoter and represses TACC2 transcription by catalyzing H3K9 trimethylation during fibroblast-to-myofibroblast transition. TACC2 depletion normalized the transition despite SUV39H1 deficiency, while TACC2 overexpression suppressed the transition, placing TACC2 downstream of SUV39H1 in cardiac fibrosis regulation.\",\n      \"method\": \"CUT&Tag-seq, RNA-seq, TACC2 depletion and overexpression, cardiac fibroblast-specific conditional knockout mouse models (Col1a2-CreERT and PostnMCM), transverse aortic constriction heart failure model\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CUT&Tag chromatin binding, genetic epistasis via gain/loss of function, two conditional KO mouse models with defined phenotypic readouts\",\n      \"pmids\": [\"41861065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TACC2 is a centrosome- and microtubule-associated protein that functions as a microtubule plus end-tracking protein promoting MT polymerization via its C-terminal TACC domain; it is phosphorylated by TTK/Mps1 kinase to maintain centrosomal localization during mitosis, binds SV40 large T antigen to stabilize microtubules, and in the cytoplasm sequesters NuRD/CoREST co-repressor components (MTA1, MBD3, HMG20B) to prevent their nuclear translocation and epigenetic silencing of CDKN1A/CCL chemokines; TACC2 transcription is directly activated by androgen receptor and repressed by SUV39H1-mediated H3K9me3, while TACC2 also interacts with the SWI/SNF complex and GAS41, collectively positioning it as a context-dependent regulator of cell cycle progression, chromatin remodeling, and immune gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TACC2 is a centrosome- and microtubule-associated protein that functions both in mitotic spindle regulation and as a cytoplasmic anchor controlling chromatin-modifying complexes, positioning it as a context-dependent tumor suppressor [#0, #7]. At the cytoskeleton, TACC2 acts as a microtubule plus-end-tracking protein whose C-terminal TACC domain is necessary and sufficient for plus-end localization and promotion of microtubule polymerization, while its N-terminal region acts dominant-negatively [#6]; it normally stabilizes mitotic microtubules, an activity that opposes the spindle disruption caused by SV40 large T antigen binding [#4]. TACC2 is phosphorylated during mitosis by TTK/Mps1 kinase, which is required to maintain its centrosomal localization and proper chromosome alignment and centrosome separation [#2]. A central regulatory function is the cytoplasmic sequestration of NuRD and CoREST co-repressor components (MTA1, MBD3, HMG20B); loss of TACC2 permits their nuclear translocation, driving epigenetic repression of CDKN1A and of CCL3/CCL4 chemokines, thereby elevating CDK activity and suppressing CD8+ T cell infiltration [#7, #8]. TACC2 expression is itself transcriptionally controlled, being directly induced by androgen receptor in prostate cancer cells [#5] and repressed by SUV39H1-mediated H3K9 trimethylation during fibroblast-to-myofibroblast transition [#10]. TACC2 also physically associates with GAS41 and the SWI/SNF chromatin remodeling complex [#1]. Notably, TACC2 is dispensable for normal mouse development, proliferation, and centrosome homeostasis [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that TACC2 (AZU-1) is a cytoplasmic protein with tumor-suppressive function, framing it as more than a passive structural component.\",\n      \"evidence\": \"Subcellular fractionation and viral reexpression in mammary epithelial T4-2 cells with 3D culture and xenograft phenotypes\",\n      \"pmids\": [\"10749935\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism of malignancy suppression not defined\", \"No interaction partners identified at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked TACC2 to gene regulation by identifying physical association with the SWI/SNF chromatin remodeling machinery, suggesting a role beyond the cytoskeleton.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown identifying GAS41 and SWI/SNF components\",\n      \"pmids\": [\"12620397\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of SWI/SNF binding not tested\", \"Single lab, no reciprocal validation reported\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined how TACC2 is positioned at the centrosome during mitosis, showing TTK kinase phosphorylation is required for its centrosomal retention and accurate chromosome segregation.\",\n      \"evidence\": \"Pulldown with wild-type vs kinase-dead TTK, siRNA depletion, and immunofluorescence\",\n      \"pmids\": [\"15304323\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Phosphosite(s) on TACC2 not mapped\", \"Direct vs indirect phosphorylation not fully resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tested the in vivo requirement for TACC2 and found it dispensable for normal proliferation, centrosome homeostasis, and tumor suppression in mice, complicating a simple essential mitotic role.\",\n      \"evidence\": \"TACC2 knockout mouse, proliferation and cell cycle assays, centrosome counting\",\n      \"pmids\": [\"15226440\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional redundancy with TACC paralogs not directly addressed\", \"Context-specific phenotypes not explored\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated TACC2 directly stabilizes mitotic microtubules by showing it counteracts SV40 large T antigen-induced spindle dysfunction.\",\n      \"evidence\": \"Co-IP/direct binding, T-antigen deletion mutants, immunofluorescence, TACC2 overexpression rescue\",\n      \"pmids\": [\"19671663\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Endogenous microtubule-stabilizing mechanism not isolated from viral context\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Assigned a precise molecular activity by showing TACC2 is a microtubule plus-end-tracking protein whose C-terminal TACC domain drives polymerization, with cell-type-dependent effects.\",\n      \"evidence\": \"Live imaging of GFP-TACC2 in Xenopus cells, structure-function deletions, MT polymerization measurements\",\n      \"pmids\": [\"27559128\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Why activity differs between mesenchymal and neuronal cells unexplained\", \"Human protein not directly assayed in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed TACC2 within hormonal signaling by establishing it as a direct AR target gene driving cell cycle progression in castration-resistant prostate cancer.\",\n      \"evidence\": \"ChIP-cloning, ChIP for histone marks, AR knockdown, bicalutamide, siRNA, overexpression, xenograft\",\n      \"pmids\": [\"22456197\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cytoskeletal vs chromatin role in this growth phenotype not separated\", \"Downstream effectors of TACC2-driven proliferation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed the central tumor-suppressive mechanism: cytoplasmic TACC2 sequesters NuRD/CoREST co-repressors, and its loss permits nuclear translocation that epigenetically silences CDKN1A and elevates CDK activity.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, TACC2 knockout mouse, ESCC organoids, fractionation, siRNA + CDK inhibitor in vivo\",\n      \"pmids\": [\"39793578\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of cytoplasmic anchoring not defined\", \"How TACC2 microtubule activity relates to co-repressor sequestration unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the co-repressor sequestration model to immune evasion, showing TACC2 loss derepresses CCL3/CCL4 and reduces CD8+ T cell infiltration, with therapeutic relevance to checkpoint blockade.\",\n      \"evidence\": \"ChIP, Co-IP, TACC2 overexpression mouse models, anti-PD-1 combination in vivo\",\n      \"pmids\": [\"40442694\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct demonstration that chemokine repression alone drives T cell exclusion incomplete\", \"Generality across tumor types not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an oncogenic gain-of-function for a PLEKHA1-TACC2 fusion acting through EphA2/AKT/MMP2 signaling and vascular mimicry, distinct from wild-type TACC2 function.\",\n      \"evidence\": \"RNA-seq fusion identification, vascular mimicry assays, ubiquitylation assay, Trp53-deletion transgenic mouse, EphA2 inhibitor in vivo\",\n      \"pmids\": [\"40615663\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Contribution of the TACC2 portion vs PLEKHA1 portion not dissected\", \"Relationship to native TACC2 activity unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined upstream epigenetic control of TACC2, showing SUV39H1-mediated H3K9me3 represses its promoter to license fibroblast-to-myofibroblast transition in cardiac fibrosis.\",\n      \"evidence\": \"CUT&Tag-seq, RNA-seq, gain/loss of function epistasis, two conditional KO mouse models, transverse aortic constriction\",\n      \"pmids\": [\"41861065\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether co-repressor sequestration underlies the fibrosis phenotype not tested\", \"Mechanism linking TACC2 level to myofibroblast program unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TACC2's microtubule plus-end-tracking activity is mechanistically integrated with its cytoplasmic sequestration of NuRD/CoREST co-repressors remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unified structural model linking cytoskeletal and chromatin functions\", \"Determinants of cytoplasmic vs centrosomal partitioning unknown\", \"Paralog redundancy with TACC1/TACC3 not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTA1\", \"MBD3\", \"HMG20B\", \"GAS41\", \"TTK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}