{"gene":"TROAP","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1995,"finding":"Tastin (TROAP) is a cytoplasmic protein necessary for trophinin to function as a cell adhesion molecule; trophinin and tastin associate with the cytoskeleton and mediate divalent cation-independent homophilic cell adhesion between trophoblastic and endometrial epithelial cells at their apical surfaces.","method":"Expression cDNA cloning, cell adhesion assays between HT-H and SNG-M cell lines","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cloning with cell adhesion assays and cytoskeletal association, single lab with two orthogonal methods","pmids":["7758945"],"is_preprint":false},{"year":1998,"finding":"Tastin (TROAP) does not directly bind trophinin; instead, a third cytoplasmic protein, bystin, directly binds both trophinin and tastin, and this binding is enhanced by the presence of cytokeratin 8 and 18 as a third molecule. Tastin co-localizes with trophinin, bystin, and cytokeratins in HT-H cells.","method":"Yeast two-hybrid assays, in vitro protein binding assays (GST pulldown), immunocytochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast two-hybrid and in vitro binding assays with multiple interactors, replicated by co-localization, single lab with multiple orthogonal methods","pmids":["9560222"],"is_preprint":false},{"year":2002,"finding":"Tastin (TROAP) is a microtubule-associated protein; its N-terminal basic region mediates direct microtubule binding. Tastin co-sediments with polymerized microtubules and disperses to the cytoplasm upon nocodazole-induced microtubule depolymerization. Tastin also directly binds Tctex-1, a light chain of cytoplasmic dynein, as confirmed by yeast two-hybrid, co-immunoprecipitation, and in vitro GST-pulldown.","method":"Microtubule sedimentation assay, nocodazole treatment, N- and C-terminal deletion mutant analysis, yeast two-hybrid, co-immunoprecipitation, GST-Tctex-1 pulldown with in vitro translated tastin","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution (in vitro binding), mutagenesis (N-terminal deletion), and multiple orthogonal methods (sedimentation, Co-IP, GST pulldown) in one study","pmids":["12049630"],"is_preprint":false},{"year":2008,"finding":"Tastin (TROAP) is required for bipolar spindle assembly and centrosome integrity during mitosis. Tastin protein levels peak in G2/M phase. Tastin localizes to microtubules, centrosomes, and the mitotic spindle. Tastin interacts with dynein intermediate chain, p150(Glued) (dynactin component), and gamma-tubulin in addition to Tctex-1. Overexpression causes monopolar spindle formation; depletion causes multipolar spindles through fragmentation of pericentrosomal material and centriole splitting, exclusively during mitosis and dependent on microtubule integrity and Eg5 activity. Tastin depletion does not disrupt NuMA or p150(Glued) localization at spindle poles.","method":"siRNA knockdown, overexpression, immunofluorescence microscopy, co-immunoprecipitation, flow cytometry (cell cycle), nocodazole and Eg5-inhibitor treatment","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for multiple interactors, loss- and gain-of-function with defined mitotic phenotypes, multiple orthogonal methods in one study","pmids":["18218922"],"is_preprint":false},{"year":2021,"finding":"TROAP directly binds DYRK1A/B, causing cytoplasmic retention of DYRK1A/B and promoting cell cycle progression via activation of Akt/GSK-3β signaling in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, shRNA knockdown, overexpression, in vitro and in vivo tumor growth assays, western blot for Akt/GSK-3β pathway","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct binding, pathway validation by western blot, loss/gain of function, single lab","pmids":["33500384"],"is_preprint":false},{"year":2021,"finding":"In prostate cancer cells, TROAP functions downstream of EZH2 and activates the TWIST/c-Myc pathway to promote cell proliferation, migration, and invasion; overexpression of TWIST partially rescues the inhibitory effects of TROAP knockdown.","method":"Lentiviral shRNA knockdown, overexpression rescue assay, Transwell assay, flow cytometry, western blot, bioinformatic correlation analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiment, loss-of-function with defined phenotype, single lab","pmids":["33692939"],"is_preprint":false},{"year":2021,"finding":"TROAP activates the Wnt/β-Catenin signaling pathway in glioma cells and promotes cell proliferation, migration, and invasion; silencing β-Catenin or Axin2 reverses the tumor-promoting effects of TROAP overexpression, placing TROAP upstream of Wnt/β-Catenin.","method":"shRNA knockdown, overexpression vector, epistasis rescue (β-Catenin/Axin2 silencing), CCK-8, colony formation, Transwell, flow cytometry, immunofluorescence, western blot, GSEA","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with rescue experiments, multiple functional assays, single lab","pmids":["34077623"],"is_preprint":false},{"year":2022,"finding":"METTL14-mediated m6A RNA methylation promotes TROAP mRNA degradation/instability; loss of METTL14 in ovarian cancer stabilizes TROAP mRNA and increases TROAP protein, promoting cancer cell proliferation.","method":"MeRIP-qPCR, RNA stability assay (actinomycin D), METTL14 overexpression, TROAP siRNA, luciferase reporter assay, cDNA microarray, immunohistochemistry","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-qPCR and RNA stability assay orthogonally establish m6A-dependent mRNA stabilization mechanism, single lab","pmids":["35251990"],"is_preprint":false},{"year":2023,"finding":"TROAP physically interacts with STAT3 in kidney renal clear cell carcinoma cells to promote tumor proliferation, migration, and metastasis; this interaction was identified by co-immunoprecipitation followed by shotgun LC-MS and validated by functional rescue experiments.","method":"Co-immunoprecipitation, shotgun LC-MS/MS, qRT-PCR, western blot, Celigo, MTT, wound healing, flow cytometry, xenograft model, functional rescue assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mass spectrometry identification plus functional rescue, single lab","pmids":["37298609"],"is_preprint":false},{"year":2024,"finding":"The transcription factor E2F1 directly activates TROAP transcription; E2F1 overexpression increases TROAP expression and promotes endometrial cancer cell proliferation, migration, and glycolysis in a TROAP-dependent manner.","method":"Dual luciferase reporter assay, qRT-PCR, western blot, siRNA knockdown, rescue experiments with TROAP knockdown, xenograft mouse model","journal":"Histology and histopathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms direct transcriptional activation, rescue assay confirms TROAP-dependence, single lab","pmids":["39501799"],"is_preprint":false},{"year":2024,"finding":"PCBP2 (an RNA-binding protein) directly binds TROAP mRNA and stabilizes it in gastric cancer cells; PCBP2 depletion reduces TROAP mRNA half-life and suppresses GC cell proliferation, migration, invasion, and promotes ferroptosis.","method":"RIP (RNA immunoprecipitation) assay, actinomycin D RNA stability assay, siRNA knockdown, western blot, functional assays (EdU, wound healing, Transwell), xenograft model","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay and RNA stability assay orthogonally establish post-transcriptional regulation, single lab","pmids":["39586843"],"is_preprint":false},{"year":2025,"finding":"FBXW5 promotes ubiquitination-mediated degradation of KLF13; loss of KLF13 increases TROAP transcription (KLF13 suppresses TROAP promoter activity), thereby facilitating EMT in lung adenocarcinoma. TROAP overexpression reverses KLF13-mediated inhibition of invasion, migration, and EMT.","method":"Co-immunoprecipitation (FBXW5–KLF13 interaction), ChIP assay, dual luciferase reporter gene assay (KLF13 binding to TROAP promoter), overexpression rescue, western blot, Transwell, wound healing, CCK-8, xenograft","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter establish direct transcriptional repression of TROAP by KLF13; Co-IP confirms FBXW5-KLF13 interaction; rescue experiment validates pathway order; single lab","pmids":["40696794"],"is_preprint":false},{"year":2025,"finding":"TROAP promotes chemoresistance in colorectal cancer cells via de novo lipogenesis driven by histone acetylation and PI3K/Akt pathway activation, as evidenced by increased lipid droplet formation and altered PI3K/Akt signaling upon TROAP manipulation.","method":"Nile red staining (lipid droplet), western blot, flow cytometry, CCK-8, Transwell, proteomic and bioinformatics analysis, xenograft model","journal":"Functional & integrative genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — lipid droplet staining and western blot for pathway proteins without direct enzymatic reconstitution or mutagenesis, single lab","pmids":["41350492"],"is_preprint":false}],"current_model":"TROAP (tastin) is a proline-rich cytoplasmic protein that associates with the microtubular cytoskeleton via its N-terminal basic region, binds the dynein light chain Tctex-1 and dynein intermediate chain, and is required for centrosome integrity and bipolar spindle assembly during mitosis; it also serves as an accessory protein enabling trophinin-mediated homophilic cell adhesion through an intermediary complex with bystin and cytokeratins, and in cancer contexts it drives proliferation and invasion by interacting with DYRK1A/B (causing their cytoplasmic retention and activating Akt/GSK-3β), STAT3, and transcriptional programs downstream of EZH2/TWIST and Wnt/β-Catenin, while its own expression is regulated transcriptionally by E2F1 and KLF13 (degraded via FBXW5-mediated ubiquitination of KLF13) and post-transcriptionally by METTL14-mediated m6A methylation and PCBP2-mediated mRNA stabilization."},"narrative":{"mechanistic_narrative":"TROAP (tastin) is a proline-rich cytoplasmic protein with two well-supported roles: as an accessory factor in trophinin-mediated cell adhesion and as a microtubule-associated regulator of mitotic spindle architecture [PMID:9560222, PMID:12049630, PMID:18218922]. In adhesion, TROAP does not bind trophinin directly but is bridged to it by bystin, an interaction enhanced by cytokeratins 8 and 18, enabling divalent cation-independent homophilic adhesion between trophoblastic and endometrial epithelial cells [PMID:7758945, PMID:9560222]. TROAP associates with the microtubule cytoskeleton through its N-terminal basic region and directly binds the dynein light chain Tctex-1, co-sedimenting with polymerized microtubules and dispersing upon depolymerization [PMID:12049630]. During mitosis its levels peak in G2/M, when it localizes to centrosomes and the spindle and interacts with dynein intermediate chain, the dynactin component p150(Glued), and gamma-tubulin; depletion produces multipolar spindles through pericentrosomal fragmentation and centriole splitting, while overexpression yields monopolar spindles, establishing TROAP as required for centrosome integrity and bipolar spindle assembly [PMID:18218922]. Across multiple cancers TROAP acts as a proliferation- and invasion-promoting factor, binding DYRK1A/B to drive their cytoplasmic retention and activate Akt/GSK-3β signaling [PMID:33500384], physically associating with STAT3 [PMID:37298609], and operating within EZH2–TWIST/c-Myc [PMID:33692939] and Wnt/β-Catenin [PMID:34077623] programs. Its abundance is set transcriptionally by E2F1 activation [PMID:39501799] and KLF13 repression—the latter relieved by FBXW5-mediated ubiquitination of KLF13 [PMID:40696794]—and post-transcriptionally by METTL14-dependent m6A-driven mRNA destabilization [PMID:35251990] and PCBP2-mediated mRNA stabilization [PMID:39586843].","teleology":[{"year":1995,"claim":"Established TROAP (tastin) as a cytoplasmic factor required for trophinin-mediated cell adhesion, defining its first biological context at the trophoblast-endometrial interface.","evidence":"Expression cDNA cloning and cell adhesion assays between HT-H and SNG-M cell lines","pmids":["7758945"],"confidence":"Medium","gaps":["Did not resolve the molecular nature of the tastin-trophinin link","No structural or domain mapping of tastin's contribution"]},{"year":1998,"claim":"Resolved that tastin connects to trophinin indirectly, identifying bystin as the bridging protein and cytokeratins as a stabilizing component of the adhesion complex.","evidence":"Yeast two-hybrid, GST pulldown, and immunocytochemistry in HT-H cells","pmids":["9560222"],"confidence":"High","gaps":["Did not establish stoichiometry or assembly order of the complex","Functional consequence of the cytokeratin enhancement not quantified in adhesion"]},{"year":2002,"claim":"Defined tastin as a microtubule-associated protein with an N-terminal microtubule-binding region and a direct dynein light chain (Tctex-1) interaction, linking it to the cytoskeletal transport machinery.","evidence":"Microtubule sedimentation, nocodazole treatment, deletion mutagenesis, yeast two-hybrid, Co-IP, GST-Tctex-1 pulldown","pmids":["12049630"],"confidence":"High","gaps":["Cellular function of the Tctex-1 interaction not yet tested","Did not address mitotic role"]},{"year":2008,"claim":"Demonstrated that tastin is required for bipolar spindle assembly and centrosome integrity, connecting its dynein/microtubule associations to a concrete mitotic phenotype.","evidence":"siRNA knockdown, overexpression, immunofluorescence, Co-IP for dynein IC/p150(Glued)/gamma-tubulin, cell-cycle flow cytometry, Eg5 inhibition","pmids":["18218922"],"confidence":"High","gaps":["Mechanism by which tastin maintains pericentrosomal material cohesion not defined","No structural model of the spindle-pole complex it participates in"]},{"year":2021,"claim":"Identified a cancer-promoting mechanism in which TROAP binds DYRK1A/B for cytoplasmic retention and activates Akt/GSK-3β to drive cell-cycle progression in hepatocellular carcinoma.","evidence":"Co-IP, shRNA/overexpression, tumor growth assays, Akt/GSK-3β western blot","pmids":["33500384"],"confidence":"Medium","gaps":["Direct binding interface not mapped","Link to the mitotic centrosomal role unresolved"]},{"year":2021,"claim":"Placed TROAP within oncogenic transcriptional programs by showing it acts downstream of EZH2 to activate TWIST/c-Myc and upstream of Wnt/β-Catenin in distinct tumor types.","evidence":"shRNA knockdown with epistasis rescue (TWIST overexpression; β-Catenin/Axin2 silencing), Transwell, GSEA, western blot in prostate cancer and glioma cells","pmids":["33692939","34077623"],"confidence":"Medium","gaps":["Direct molecular link between cytoplasmic TROAP and nuclear transcriptional output not defined","Effects shown as pathway epistasis rather than physical mechanism"]},{"year":2023,"claim":"Extended TROAP's oncogenic interactome by demonstrating a physical STAT3 interaction driving proliferation and metastasis in renal clear cell carcinoma.","evidence":"Co-IP with shotgun LC-MS/MS, functional rescue, xenograft","pmids":["37298609"],"confidence":"Medium","gaps":["Interaction interface and effect on STAT3 phosphorylation not defined","Whether STAT3 binding is direct vs complex-mediated unresolved"]},{"year":2024,"claim":"Established multilayered regulation of TROAP abundance, identifying E2F1 as a direct transcriptional activator and PCBP2 as an mRNA-stabilizing RNA-binding protein.","evidence":"Dual luciferase reporter, RIP, actinomycin D stability assays, siRNA, rescue, xenografts in endometrial and gastric cancer","pmids":["39501799","39586843"],"confidence":"Medium","gaps":["How these inputs are integrated in normal vs tumor cells unknown","PCBP2 binding site on TROAP mRNA not mapped"]},{"year":2025,"claim":"Defined additional regulatory and effector arms: KLF13 directly represses the TROAP promoter (relieved by FBXW5-driven KLF13 degradation), and TROAP promotes chemoresistance via de novo lipogenesis.","evidence":"ChIP, dual luciferase reporter, Co-IP, rescue, xenograft (KLF13/FBXW5); Nile red lipid staining and PI3K/Akt western blot (lipogenesis)","pmids":["40696794","41350492"],"confidence":"Medium","gaps":["Lipogenesis link rests on staining and pathway blots without enzymatic reconstitution (Low confidence)","Whether the FBXW5-KLF13-TROAP axis operates outside lung adenocarcinoma untested"]},{"year":null,"claim":"How TROAP's foundational microtubule/centrosome function mechanistically connects to its many cancer signaling and transcriptional roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TROAP or its complexes","Unclear whether spindle/centrosome activity underlies the proliferative oncogenic phenotypes or is independent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]}],"complexes":["trophinin-bystin-tastin adhesion complex"],"partners":["TROFININ","BYSTIN","DYNLT1","DYRK1A","DYRK1B","STAT3","PCBP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12815","full_name":"Tastin","aliases":["Trophinin-assisting protein","Trophinin-associated protein"],"length_aa":778,"mass_kda":83.9,"function":"Could be involved with bystin and trophinin in a cell adhesion molecule complex that mediates an initial attachment of the blastocyst to uterine epithelial cells at the time of the embryo implantation","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q12815/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TROAP","classification":"Not Classified","n_dependent_lines":184,"n_total_lines":1208,"dependency_fraction":0.152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TROAP","total_profiled":1310},"omim":[{"mim_id":"603872","title":"TROPHININ-ASSOCIATED PROTEIN; TROAP","url":"https://www.omim.org/entry/603872"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":48.3},{"tissue":"lymphoid tissue","ntpm":34.3},{"tissue":"testis","ntpm":27.2}],"url":"https://www.proteinatlas.org/search/TROAP"},"hgnc":{"alias_symbol":["TASTIN"],"prev_symbol":[]},"alphafold":{"accession":"Q12815","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12815","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12815-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12815-F1-predicted_aligned_error_v6.png","plddt_mean":46.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TROAP","jax_strain_url":"https://www.jax.org/strain/search?query=TROAP"},"sequence":{"accession":"Q12815","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12815.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12815/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12815"}},"corpus_meta":[{"pmid":"7758945","id":"PMC_7758945","title":"Trophinin and tastin, a novel cell adhesion molecule complex with potential involvement in embryo implantation.","date":"1995","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7758945","citation_count":156,"is_preprint":false},{"pmid":"9560222","id":"PMC_9560222","title":"A cytoplasmic protein, bystin, interacts with trophinin, tastin, and cytokeratin and may be involved in trophinin-mediated cell adhesion between trophoblast and endometrial epithelial cells.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9560222","citation_count":89,"is_preprint":false},{"pmid":"10026108","id":"PMC_10026108","title":"Expression of trophinin, tastin, and bystin by trophoblast and endometrial cells in human placenta.","date":"1999","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/10026108","citation_count":62,"is_preprint":false},{"pmid":"10797941","id":"PMC_10797941","title":"Trophinin, tastin, and bystin: a complex mediating unique attachment between trophoblastic and endometrial epithelial cells at their respective apical cell membranes.","date":"1999","source":"Seminars in reproductive endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10797941","citation_count":56,"is_preprint":false},{"pmid":"12049630","id":"PMC_12049630","title":"Human tastin, a proline-rich cytoplasmic protein, associates with the microtubular cytoskeleton.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12049630","citation_count":51,"is_preprint":false},{"pmid":"30021381","id":"PMC_30021381","title":"MicroRNA-519d-3p inhibits cell proliferation and migration by targeting TROAP in colorectal cancer.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30021381","citation_count":49,"is_preprint":false},{"pmid":"18218922","id":"PMC_18218922","title":"Tastin is required for bipolar spindle assembly and centrosome integrity during mitosis.","date":"2008","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/18218922","citation_count":43,"is_preprint":false},{"pmid":"33500384","id":"PMC_33500384","title":"TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33500384","citation_count":31,"is_preprint":false},{"pmid":"31198787","id":"PMC_31198787","title":"TROAP Promotes Breast Cancer Proliferation and Metastasis.","date":"2019","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/31198787","citation_count":28,"is_preprint":false},{"pmid":"29956806","id":"PMC_29956806","title":"Decreased expression of TROAP suppresses cellular proliferation, migration and invasion in gastric cancer.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29956806","citation_count":28,"is_preprint":false},{"pmid":"30431120","id":"PMC_30431120","title":"TROAP regulates prostate cancer progression via the WNT3/survivin signalling pathways.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30431120","citation_count":27,"is_preprint":false},{"pmid":"34077623","id":"PMC_34077623","title":"TROAP regulates cell cycle and promotes tumor progression through Wnt/β-Catenin signaling pathway in glioma cells.","date":"2021","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34077623","citation_count":25,"is_preprint":false},{"pmid":"11299965","id":"PMC_11299965","title":"Recent molecular approaches to elucidate the mechanism of embryo implantation: trophinin, bystin, and tastin as molecules involved in the initial attachment of blastocysts to the uterus in humans.","date":"2000","source":"Seminars in reproductive 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/37608033","citation_count":8,"is_preprint":false},{"pmid":"37731946","id":"PMC_37731946","title":"Integrative analysis of TROAP with molecular features, carcinogenesis, and related immune and pharmacogenomic characteristics in soft tissue sarcoma.","date":"2023","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/37731946","citation_count":8,"is_preprint":false},{"pmid":"39501799","id":"PMC_39501799","title":"E2F1-induced upregulation of TROAP contributes to endometrial cancer progression.","date":"2024","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/39501799","citation_count":4,"is_preprint":false},{"pmid":"41350492","id":"PMC_41350492","title":"TROAP aggravates chemoresistance of colorectal cancer cells via lipogenesis by PI3K/Akt pathway and histone acetylation.","date":"2025","source":"Functional & integrative 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40252097","citation_count":0,"is_preprint":false},{"pmid":"39148975","id":"PMC_39148975","title":"LncRNA ERICD interacts with TROAP to regulate TGF-β signaling in hepatocellular carcinoma.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39148975","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14594,"output_tokens":3492,"usd":0.048081,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11075,"output_tokens":3429,"usd":0.07055,"stage2_stop_reason":"end_turn"},"total_usd":0.118631,"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\": 1995,\n      \"finding\": \"Tastin (TROAP) is a cytoplasmic protein necessary for trophinin to function as a cell adhesion molecule; trophinin and tastin associate with the cytoskeleton and mediate divalent cation-independent homophilic cell adhesion between trophoblastic and endometrial epithelial cells at their apical surfaces.\",\n      \"method\": \"Expression cDNA cloning, cell adhesion assays between HT-H and SNG-M cell lines\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cloning with cell adhesion assays and cytoskeletal association, single lab with two orthogonal methods\",\n      \"pmids\": [\"7758945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tastin (TROAP) does not directly bind trophinin; instead, a third cytoplasmic protein, bystin, directly binds both trophinin and tastin, and this binding is enhanced by the presence of cytokeratin 8 and 18 as a third molecule. Tastin co-localizes with trophinin, bystin, and cytokeratins in HT-H cells.\",\n      \"method\": \"Yeast two-hybrid assays, in vitro protein binding assays (GST pulldown), immunocytochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast two-hybrid and in vitro binding assays with multiple interactors, replicated by co-localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9560222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tastin (TROAP) is a microtubule-associated protein; its N-terminal basic region mediates direct microtubule binding. Tastin co-sediments with polymerized microtubules and disperses to the cytoplasm upon nocodazole-induced microtubule depolymerization. Tastin also directly binds Tctex-1, a light chain of cytoplasmic dynein, as confirmed by yeast two-hybrid, co-immunoprecipitation, and in vitro GST-pulldown.\",\n      \"method\": \"Microtubule sedimentation assay, nocodazole treatment, N- and C-terminal deletion mutant analysis, yeast two-hybrid, co-immunoprecipitation, GST-Tctex-1 pulldown with in vitro translated tastin\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution (in vitro binding), mutagenesis (N-terminal deletion), and multiple orthogonal methods (sedimentation, Co-IP, GST pulldown) in one study\",\n      \"pmids\": [\"12049630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tastin (TROAP) is required for bipolar spindle assembly and centrosome integrity during mitosis. Tastin protein levels peak in G2/M phase. Tastin localizes to microtubules, centrosomes, and the mitotic spindle. Tastin interacts with dynein intermediate chain, p150(Glued) (dynactin component), and gamma-tubulin in addition to Tctex-1. Overexpression causes monopolar spindle formation; depletion causes multipolar spindles through fragmentation of pericentrosomal material and centriole splitting, exclusively during mitosis and dependent on microtubule integrity and Eg5 activity. Tastin depletion does not disrupt NuMA or p150(Glued) localization at spindle poles.\",\n      \"method\": \"siRNA knockdown, overexpression, immunofluorescence microscopy, co-immunoprecipitation, flow cytometry (cell cycle), nocodazole and Eg5-inhibitor treatment\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for multiple interactors, loss- and gain-of-function with defined mitotic phenotypes, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18218922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TROAP directly binds DYRK1A/B, causing cytoplasmic retention of DYRK1A/B and promoting cell cycle progression via activation of Akt/GSK-3β signaling in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, overexpression, in vitro and in vivo tumor growth assays, western blot for Akt/GSK-3β pathway\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct binding, pathway validation by western blot, loss/gain of function, single lab\",\n      \"pmids\": [\"33500384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In prostate cancer cells, TROAP functions downstream of EZH2 and activates the TWIST/c-Myc pathway to promote cell proliferation, migration, and invasion; overexpression of TWIST partially rescues the inhibitory effects of TROAP knockdown.\",\n      \"method\": \"Lentiviral shRNA knockdown, overexpression rescue assay, Transwell assay, flow cytometry, western blot, bioinformatic correlation analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiment, loss-of-function with defined phenotype, single lab\",\n      \"pmids\": [\"33692939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TROAP activates the Wnt/β-Catenin signaling pathway in glioma cells and promotes cell proliferation, migration, and invasion; silencing β-Catenin or Axin2 reverses the tumor-promoting effects of TROAP overexpression, placing TROAP upstream of Wnt/β-Catenin.\",\n      \"method\": \"shRNA knockdown, overexpression vector, epistasis rescue (β-Catenin/Axin2 silencing), CCK-8, colony formation, Transwell, flow cytometry, immunofluorescence, western blot, GSEA\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with rescue experiments, multiple functional assays, single lab\",\n      \"pmids\": [\"34077623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14-mediated m6A RNA methylation promotes TROAP mRNA degradation/instability; loss of METTL14 in ovarian cancer stabilizes TROAP mRNA and increases TROAP protein, promoting cancer cell proliferation.\",\n      \"method\": \"MeRIP-qPCR, RNA stability assay (actinomycin D), METTL14 overexpression, TROAP siRNA, luciferase reporter assay, cDNA microarray, immunohistochemistry\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-qPCR and RNA stability assay orthogonally establish m6A-dependent mRNA stabilization mechanism, single lab\",\n      \"pmids\": [\"35251990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TROAP physically interacts with STAT3 in kidney renal clear cell carcinoma cells to promote tumor proliferation, migration, and metastasis; this interaction was identified by co-immunoprecipitation followed by shotgun LC-MS and validated by functional rescue experiments.\",\n      \"method\": \"Co-immunoprecipitation, shotgun LC-MS/MS, qRT-PCR, western blot, Celigo, MTT, wound healing, flow cytometry, xenograft model, functional rescue assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mass spectrometry identification plus functional rescue, single lab\",\n      \"pmids\": [\"37298609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The transcription factor E2F1 directly activates TROAP transcription; E2F1 overexpression increases TROAP expression and promotes endometrial cancer cell proliferation, migration, and glycolysis in a TROAP-dependent manner.\",\n      \"method\": \"Dual luciferase reporter assay, qRT-PCR, western blot, siRNA knockdown, rescue experiments with TROAP knockdown, xenograft mouse model\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms direct transcriptional activation, rescue assay confirms TROAP-dependence, single lab\",\n      \"pmids\": [\"39501799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PCBP2 (an RNA-binding protein) directly binds TROAP mRNA and stabilizes it in gastric cancer cells; PCBP2 depletion reduces TROAP mRNA half-life and suppresses GC cell proliferation, migration, invasion, and promotes ferroptosis.\",\n      \"method\": \"RIP (RNA immunoprecipitation) assay, actinomycin D RNA stability assay, siRNA knockdown, western blot, functional assays (EdU, wound healing, Transwell), xenograft model\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay and RNA stability assay orthogonally establish post-transcriptional regulation, single lab\",\n      \"pmids\": [\"39586843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW5 promotes ubiquitination-mediated degradation of KLF13; loss of KLF13 increases TROAP transcription (KLF13 suppresses TROAP promoter activity), thereby facilitating EMT in lung adenocarcinoma. TROAP overexpression reverses KLF13-mediated inhibition of invasion, migration, and EMT.\",\n      \"method\": \"Co-immunoprecipitation (FBXW5–KLF13 interaction), ChIP assay, dual luciferase reporter gene assay (KLF13 binding to TROAP promoter), overexpression rescue, western blot, Transwell, wound healing, CCK-8, xenograft\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter establish direct transcriptional repression of TROAP by KLF13; Co-IP confirms FBXW5-KLF13 interaction; rescue experiment validates pathway order; single lab\",\n      \"pmids\": [\"40696794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TROAP promotes chemoresistance in colorectal cancer cells via de novo lipogenesis driven by histone acetylation and PI3K/Akt pathway activation, as evidenced by increased lipid droplet formation and altered PI3K/Akt signaling upon TROAP manipulation.\",\n      \"method\": \"Nile red staining (lipid droplet), western blot, flow cytometry, CCK-8, Transwell, proteomic and bioinformatics analysis, xenograft model\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — lipid droplet staining and western blot for pathway proteins without direct enzymatic reconstitution or mutagenesis, single lab\",\n      \"pmids\": [\"41350492\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TROAP (tastin) is a proline-rich cytoplasmic protein that associates with the microtubular cytoskeleton via its N-terminal basic region, binds the dynein light chain Tctex-1 and dynein intermediate chain, and is required for centrosome integrity and bipolar spindle assembly during mitosis; it also serves as an accessory protein enabling trophinin-mediated homophilic cell adhesion through an intermediary complex with bystin and cytokeratins, and in cancer contexts it drives proliferation and invasion by interacting with DYRK1A/B (causing their cytoplasmic retention and activating Akt/GSK-3β), STAT3, and transcriptional programs downstream of EZH2/TWIST and Wnt/β-Catenin, while its own expression is regulated transcriptionally by E2F1 and KLF13 (degraded via FBXW5-mediated ubiquitination of KLF13) and post-transcriptionally by METTL14-mediated m6A methylation and PCBP2-mediated mRNA stabilization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TROAP (tastin) is a proline-rich cytoplasmic protein with two well-supported roles: as an accessory factor in trophinin-mediated cell adhesion and as a microtubule-associated regulator of mitotic spindle architecture [#1, #2, #3]. In adhesion, TROAP does not bind trophinin directly but is bridged to it by bystin, an interaction enhanced by cytokeratins 8 and 18, enabling divalent cation-independent homophilic adhesion between trophoblastic and endometrial epithelial cells [#0, #1]. TROAP associates with the microtubule cytoskeleton through its N-terminal basic region and directly binds the dynein light chain Tctex-1, co-sedimenting with polymerized microtubules and dispersing upon depolymerization [#2]. During mitosis its levels peak in G2/M, when it localizes to centrosomes and the spindle and interacts with dynein intermediate chain, the dynactin component p150(Glued), and gamma-tubulin; depletion produces multipolar spindles through pericentrosomal fragmentation and centriole splitting, while overexpression yields monopolar spindles, establishing TROAP as required for centrosome integrity and bipolar spindle assembly [#3]. Across multiple cancers TROAP acts as a proliferation- and invasion-promoting factor, binding DYRK1A/B to drive their cytoplasmic retention and activate Akt/GSK-3\\u03b2 signaling [#4], physically associating with STAT3 [#8], and operating within EZH2\\u2013TWIST/c-Myc [#5] and Wnt/\\u03b2-Catenin [#6] programs. Its abundance is set transcriptionally by E2F1 activation [#9] and KLF13 repression\\u2014the latter relieved by FBXW5-mediated ubiquitination of KLF13 [#11]\\u2014and post-transcriptionally by METTL14-dependent m6A-driven mRNA destabilization [#7] and PCBP2-mediated mRNA stabilization [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established TROAP (tastin) as a cytoplasmic factor required for trophinin-mediated cell adhesion, defining its first biological context at the trophoblast-endometrial interface.\",\n      \"evidence\": \"Expression cDNA cloning and cell adhesion assays between HT-H and SNG-M cell lines\",\n      \"pmids\": [\"7758945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the molecular nature of the tastin-trophinin link\", \"No structural or domain mapping of tastin's contribution\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved that tastin connects to trophinin indirectly, identifying bystin as the bridging protein and cytokeratins as a stabilizing component of the adhesion complex.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, and immunocytochemistry in HT-H cells\",\n      \"pmids\": [\"9560222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish stoichiometry or assembly order of the complex\", \"Functional consequence of the cytokeratin enhancement not quantified in adhesion\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined tastin as a microtubule-associated protein with an N-terminal microtubule-binding region and a direct dynein light chain (Tctex-1) interaction, linking it to the cytoskeletal transport machinery.\",\n      \"evidence\": \"Microtubule sedimentation, nocodazole treatment, deletion mutagenesis, yeast two-hybrid, Co-IP, GST-Tctex-1 pulldown\",\n      \"pmids\": [\"12049630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular function of the Tctex-1 interaction not yet tested\", \"Did not address mitotic role\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that tastin is required for bipolar spindle assembly and centrosome integrity, connecting its dynein/microtubule associations to a concrete mitotic phenotype.\",\n      \"evidence\": \"siRNA knockdown, overexpression, immunofluorescence, Co-IP for dynein IC/p150(Glued)/gamma-tubulin, cell-cycle flow cytometry, Eg5 inhibition\",\n      \"pmids\": [\"18218922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which tastin maintains pericentrosomal material cohesion not defined\", \"No structural model of the spindle-pole complex it participates in\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a cancer-promoting mechanism in which TROAP binds DYRK1A/B for cytoplasmic retention and activates Akt/GSK-3\\u03b2 to drive cell-cycle progression in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, shRNA/overexpression, tumor growth assays, Akt/GSK-3\\u03b2 western blot\",\n      \"pmids\": [\"33500384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Link to the mitotic centrosomal role unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed TROAP within oncogenic transcriptional programs by showing it acts downstream of EZH2 to activate TWIST/c-Myc and upstream of Wnt/\\u03b2-Catenin in distinct tumor types.\",\n      \"evidence\": \"shRNA knockdown with epistasis rescue (TWIST overexpression; \\u03b2-Catenin/Axin2 silencing), Transwell, GSEA, western blot in prostate cancer and glioma cells\",\n      \"pmids\": [\"33692939\", \"34077623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between cytoplasmic TROAP and nuclear transcriptional output not defined\", \"Effects shown as pathway epistasis rather than physical mechanism\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended TROAP's oncogenic interactome by demonstrating a physical STAT3 interaction driving proliferation and metastasis in renal clear cell carcinoma.\",\n      \"evidence\": \"Co-IP with shotgun LC-MS/MS, functional rescue, xenograft\",\n      \"pmids\": [\"37298609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction interface and effect on STAT3 phosphorylation not defined\", \"Whether STAT3 binding is direct vs complex-mediated unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established multilayered regulation of TROAP abundance, identifying E2F1 as a direct transcriptional activator and PCBP2 as an mRNA-stabilizing RNA-binding protein.\",\n      \"evidence\": \"Dual luciferase reporter, RIP, actinomycin D stability assays, siRNA, rescue, xenografts in endometrial and gastric cancer\",\n      \"pmids\": [\"39501799\", \"39586843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How these inputs are integrated in normal vs tumor cells unknown\", \"PCBP2 binding site on TROAP mRNA not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined additional regulatory and effector arms: KLF13 directly represses the TROAP promoter (relieved by FBXW5-driven KLF13 degradation), and TROAP promotes chemoresistance via de novo lipogenesis.\",\n      \"evidence\": \"ChIP, dual luciferase reporter, Co-IP, rescue, xenograft (KLF13/FBXW5); Nile red lipid staining and PI3K/Akt western blot (lipogenesis)\",\n      \"pmids\": [\"40696794\", \"41350492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipogenesis link rests on staining and pathway blots without enzymatic reconstitution (Low confidence)\", \"Whether the FBXW5-KLF13-TROAP axis operates outside lung adenocarcinoma untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TROAP's foundational microtubule/centrosome function mechanistically connects to its many cancer signaling and transcriptional roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TROAP or its complexes\", \"Unclear whether spindle/centrosome activity underlies the proliferative oncogenic phenotypes or is independent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\"trophinin-bystin-tastin adhesion complex\"],\n    \"partners\": [\"TROFININ\", \"BYSTIN\", \"DYNLT1\", \"DYRK1A\", \"DYRK1B\", \"STAT3\", \"PCBP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}