{"gene":"TUFT1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2018,"finding":"TUFT1 physically interacts with RABGAP1 (a Rab GTPase activating protein), thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promotes mTORC1 signaling activation.","method":"Co-immunoprecipitation, cellular fractionation/lysosomal positioning assays, mTORC1 activity assays with TUFT1 knockdown/overexpression","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal physical interaction demonstrated, multiple orthogonal functional readouts (lysosomal positioning, vesicle trafficking, mTORC1 signaling), single lab","pmids":["29423269"],"is_preprint":false},{"year":2018,"finding":"TUFT1 promotes HCC cell growth, metastasis and epithelial-mesenchymal transition via activation of the Ca2+/PI3K/AKT pathway. Hypoxia upregulates TUFT1 through HIF-1α-dependent downregulation of miR-671-5p, which targets the 3'-UTR of TUFT1 mRNA.","method":"MTT, BrdU, Transwell assays, subcutaneous/tail vein xenograft models, chromatin immunoprecipitation (HIF-1α binding to TUFT1 promoter), microRNA array, luciferase reporter (miR-671-5p/TUFT1 3'-UTR), western blot for pathway activation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, luciferase, functional rescue), single lab","pmids":["30250300"],"is_preprint":false},{"year":2016,"finding":"TUFT1 promotes pancreatic cancer EMT by altering expression of Snail and is associated with HIF1 expression and activity, suggesting TUFT1 regulates EMT via a HIF1-Snail signaling axis.","method":"shRNA knockdown and overexpression, migration/invasion assays, in vivo metastasis models, western blot for EMT markers (E-cadherin, vimentin, Snail), HIF1 activity assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function and gain-of-function with defined molecular readouts, single lab, mechanistic link to HIF1-Snail is associative rather than direct reconstitution","pmids":["27566398"],"is_preprint":false},{"year":2022,"finding":"TUFT1 is SUMOylated at lysine 79 by the E3 SUMO ligase TRIM27. TUFT1 binds TRIM27 through its N-terminus. SUMOylation-deficient TUFT1 (K79 mutant) fails to activate AKT/mTOR signaling and impairs gastric cancer cell proliferation, migration, and invasion. SUMOylated TUFT1 also forms a complex with RABGAP1 to promote perinuclear accumulation of mTORC1.","method":"SUMOylation site mutagenesis, Co-IP, functional assays (proliferation, migration, invasion), western blot for AKT/mTOR phosphorylation, TRIM27 knockdown epistasis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of modification site, co-IP for binding partners, multiple functional readouts, single lab","pmids":["36380570"],"is_preprint":false},{"year":2019,"finding":"TUFT1 promotes metastasis and chemoresistance in TNBC by activating Rab5 through binding to p85α, which leads to Tiam1 recruitment and subsequent Rac1 activation, with concurrent downregulation of NF-κB pathway and proapoptotic factors.","method":"Co-immunoprecipitation (TUFT1-p85α interaction), GTP activity assays (Rab5-GTP, Rac1-GTP), shRNA knockdown, nude mouse xenograft metastasis model, Transwell assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct binding, GTP activity assays for downstream effectors, functional rescue experiments, single lab","pmids":["31572059"],"is_preprint":false},{"year":2019,"finding":"TUFT1 promotes TNBC tumor cell metastasis and stemness by upregulating the Rac1/β-catenin pathway, and lack of TUFT1 sensitizes cells to chemotherapy via downregulation of this pathway.","method":"shRNA knockdown, GTP activity assays (Rac1-GTP), migration/invasion assays, sphere formation, apoptosis assay, nude mouse xenograft spontaneous lung metastasis model, western blot","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP activity assay for Rac1 activation, functional rescue, in vivo model, single lab","pmids":["31338333"],"is_preprint":false},{"year":2020,"finding":"BRD9 epigenetically upregulates TUFT1 expression by promoting binding of P300 acetyltransferase to the TUFT1 promoter and increasing H3K27Ac at the promoter, thereby activating AKT signaling in HCC cells.","method":"ChIP-qPCR (P300 and H3K27Ac at TUFT1 promoter), BRD9 knockdown/inhibition, TUFT1 rescue experiments, western blot for AKT phosphorylation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR for direct epigenetic mechanism, functional epistasis rescue, single lab","pmids":["32908135"],"is_preprint":false},{"year":2023,"finding":"Biallelic loss-of-function TUFT1 variants cause woolly hair and superficial skin fragility. Tuftelin-1 is localized to peripheral cell membranes of keratinocytes in normal skin, and loss of TUFT1 leads to desmosomal detachment, acantholysis, widening of intercellular spaces throughout the epidermis, and perinuclear retraction of intermediate filaments.","method":"Whole-genome/exome sequencing, immunofluorescence microscopy (localization in normal vs. patient skin), transmission electron microscopy (desmosomal ultrastructure), haplotype analysis, single-cell RNA sequencing co-expression analysis","journal":"The British journal of dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent families, multiple orthogonal methods (immunofluorescence, TEM, scRNA-seq co-expression), replicated in second study (PMID 37716648)","pmids":["36689522"],"is_preprint":false},{"year":2023,"finding":"TUFT1 is a desmosome-associated protein whose location within the desmosome depends on the presence of the desmoplakin carboxy-terminal tail. Loss of TUFT1 causes acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance in keratinocytes. A Tuft1-knockout mouse model recapitulates skin fragility, woolly hair, and palmoplantar keratoderma.","method":"Immunolabeling (desmosomal localization), transfection studies (desmoplakin carboxy-terminal tail dependence), Tuft1-knockout mouse model, keratinocyte mechanical stress assays, patient skin histology","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model, transfection-based localization dependence, patient-derived keratinocytes, multiple orthogonal methods, independent replication across two labs (PMID 36689522)","pmids":["37716648"],"is_preprint":false},{"year":2017,"finding":"Overexpression of wild-type or mutant TUFT1 in ATDC5 chondrogenic cells inhibits chondrogenic differentiation (decreased marker gene expression, reduced cartilage nodule formation) in calcifying conditions. The T175M variant increases extracellular matrix calcium content and reduces proteoglycan content compared to wild-type TUFT1 overexpression.","method":"HEK293 cell transfection (mRNA/protein expression), ATDC5 overexpression in calcifying conditions, chondrogenic marker gene expression, cartilage nodule formation assay, calcium and proteoglycan content measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro assay with wild-type vs. mutant comparison, multiple molecular readouts, single lab","pmids":["28410428"],"is_preprint":false},{"year":2018,"finding":"Tuft1 promotes thyroid carcinoma cell invasion and proliferation and suppresses apoptosis through the Akt-mTOR and Akt-GSK3β signaling pathways. Addition of recombinant Tuft1 protein to TC cells increases phosphorylation of Akt, mTOR, and GSK3β; mTOR inhibitor abrogates Tuft1-induced invasion and proliferation, while GSK3β inhibitor abrogates Tuft1-induced proliferation only.","method":"shRNA knockdown, recombinant protein treatment, mTOR inhibitor (Dactolisib) and GSK3β inhibitor (CHIR-98014) pharmacological epistasis, western blot for pathway phosphorylation, in vivo xenograft","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with two inhibitors defining pathway specificity, recombinant protein gain-of-function, single lab","pmids":["30662679"],"is_preprint":false},{"year":2025,"finding":"TUFT1 is a centrosomal protein that localizes to the proximal ends of parent centrioles. TUFT1 prevents centrosome amplification and mitotic spindle multipolarity by suppressing premature polo-like kinase 1 (PLK1) activation. TUFT1 is phosphorylated by NEK2 kinase, and the phosphorylation status of TUFT1 is essential for coordinating centrosome number and cell proliferation.","method":"Immunofluorescence (centrosomal localization), TUFT1 loss-of-function (centrosome number, spindle multipolarity readouts), PLK1 activity assays, NEK2-mediated phosphorylation assay, western blot, clinical breast cancer sample analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence, kinase-substrate relationship for NEK2-TUFT1, PLK1 activation epistasis, single lab","pmids":["41022752"],"is_preprint":false},{"year":2026,"finding":"TUFT1 is a novel TGF-β receptor II (TβRII) binding protein in hepatic stellate cells (HSCs). TUFT1 interacts with TβRII via its N-terminal fragments (amino acids 1-86 and 87-157), protecting TβRII from lysosomal degradation by competing with caveolin-1 for TβRII binding, diverting TβRII from the lipid rafts/caveolae-mediated degradation pathway into the endosome-mediated trafficking and signaling pathway, thereby facilitating TGF-β signaling and myofibroblastic activation of HSCs.","method":"Immunoprecipitation coupled with mass spectrometry (TβRII-TUFT1 interaction discovery), Co-IP (domain mapping, caveolin-1 competition), lysosomal degradation assays, TUFT1 knockdown with TGF-β signaling readouts, in vivo HSC/CRC co-implantation and portal vein injection mouse models, bulk RNA sequencing","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — IP-MS for unbiased binding partner identification, domain-level binding mapping, mechanistic competition assay with caveolin-1, in vivo functional validation with multiple mouse models, multiple orthogonal methods","pmids":["41593321"],"is_preprint":false},{"year":2025,"finding":"TUFT1 binds to ATF1 (activating transcription factor 1) in cervical cancer cells and positively regulates ATF1 expression. ATF1 overexpression counteracts the effects of TUFT1 silencing on proliferation, migration, invasion, stemness, and EGFR signaling.","method":"Co-IP assay (TUFT1-ATF1 interaction), RT-qPCR and western blot (ATF1 expression after TUFT1 silencing), epistasis rescue (co-transfection of TUFT1 siRNA + ATF1 overexpression), functional assays","journal":"Cell biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for binding, single lab, partial mechanistic follow-up, EGFR pathway link is inferred from western blot without direct biochemical reconstitution","pmids":["39948288"],"is_preprint":false},{"year":2022,"finding":"ATF2 transcription factor directly targets the miR-548p promoter (confirmed by ChIP and luciferase assay), and miR-548p directly binds the 3'-UTR of TUFT1 to suppress its expression, thereby suppressing PI3K/AKT signaling in HCC.","method":"Chromatin immunoprecipitation (ATF2 binding to miR-548p promoter), luciferase reporter assay (miR-548p binding to TUFT1 3'-UTR), western blot for PI3K/AKT signaling, functional assays","journal":"Hepatology research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and luciferase assays confirm the regulatory axis, but mechanistic characterization of TUFT1 itself is indirect (downstream of miR-548p), single lab","pmids":["34904343"],"is_preprint":false}],"current_model":"TUFT1 (tuftelin 1) is a multifunctional protein that localizes to centrosome proximal ends, peripheral keratinocyte cell membranes (within desmosomes), and intracellular vesicular compartments; it promotes mTORC1 signaling by physically interacting with RABGAP1 to modulate lysosomal positioning and vesicle trafficking, activates PI3K/AKT pathways in multiple cancer types, regulates EMT via HIF1-Snail and Rac1/β-catenin axes, maintains desmosomal integrity in skin (loss of function causes skin fragility and woolly hair), controls centrosome number by suppressing premature PLK1 activation (itself phosphorylated by NEK2), is SUMOylated at K79 by TRIM27 (required for its oncogenic activity), stabilizes TGF-β receptor II by competing with caveolin-1 to redirect it from lysosomal degradation into endosomal signaling, and is transcriptionally regulated by BRD9/P300-mediated H3K27 acetylation and post-transcriptionally by multiple miRNAs including miR-671-5p."},"narrative":{"mechanistic_narrative":"TUFT1 (tuftelin 1) is a multifunctional scaffolding protein that operates in two broad arenas: maintenance of epidermal desmosomal integrity and promotion of growth-signaling, vesicular-trafficking, and centrosomal homeostasis in proliferating and malignant cells [PMID:29423269, PMID:36689522, PMID:41022752]. In skin, TUFT1 localizes to peripheral keratinocyte cell membranes within desmosomes in a manner dependent on the desmoplakin carboxy-terminal tail, and biallelic loss-of-function variants cause woolly hair and superficial skin fragility characterized by desmosomal detachment, acantholysis, and perinuclear retraction of intermediate filaments, a phenotype recapitulated in Tuft1-knockout mice [PMID:36689522, PMID:37716648]. In its trafficking/signaling role, TUFT1 physically interacts with the Rab GTPase-activating protein RABGAP1 to control lysosomal positioning and vesicle trafficking and to promote mTORC1 activation [PMID:29423269]. Across multiple cancers it activates PI3K/AKT-mTOR signaling and drives proliferation, invasion, and epithelial-mesenchymal transition, acting through a HIF1-Snail axis, a p85α/Rab5/Tiam1/Rac1 and Rac1/β-catenin cascade, and Akt-mTOR/Akt-GSK3β pathways [PMID:30250300, PMID:27566398, PMID:31572059, PMID:31338333, PMID:30662679]. Its oncogenic activity is gated by post-translational SUMOylation at K79 by TRIM27, which is required for AKT/mTOR activation and for forming a perinuclear mTORC1-promoting complex with RABGAP1 [PMID:36380570]. TUFT1 also stabilizes TGF-β receptor II by binding it through its N-terminus and competing with caveolin-1, redirecting the receptor away from lysosomal degradation toward endosomal signaling to drive myofibroblastic activation of hepatic stellate cells [PMID:41593321]. At the centrosome, TUFT1 localizes to proximal ends of parent centrioles and prevents centrosome amplification and spindle multipolarity by suppressing premature PLK1 activation, with its function regulated by NEK2-mediated phosphorylation [PMID:41022752]. Its expression is controlled epigenetically by BRD9/P300-driven H3K27 acetylation and post-transcriptionally by miRNAs targeting its 3'-UTR [PMID:30250300, PMID:32908135].","teleology":[{"year":2016,"claim":"Established TUFT1 as a driver of epithelial-mesenchymal transition in cancer, linking it to a transcriptional EMT program for the first time.","evidence":"shRNA knockdown/overexpression with migration, invasion, and metastasis readouts plus EMT marker and HIF1 activity analysis in pancreatic cancer","pmids":["27566398"],"confidence":"Medium","gaps":["HIF1-Snail link is associative, not reconstituted","no direct binding partner identified","molecular mechanism by which TUFT1 alters Snail unknown"]},{"year":2018,"claim":"Identified the first direct physical partner of TUFT1 (RABGAP1) and connected it to lysosomal positioning, vesicle trafficking, and mTORC1 activation, defining a core trafficking/signaling function.","evidence":"Co-IP, cellular fractionation/lysosomal positioning assays, and mTORC1 activity assays with TUFT1 perturbation","pmids":["29423269"],"confidence":"High","gaps":["structural basis of TUFT1-RABGAP1 interaction unresolved","how TUFT1 modulates RABGAP1 GAP activity not defined","link between trafficking role and skin/centrosome functions unexplored"]},{"year":2018,"claim":"Defined an upstream regulatory and downstream signaling axis showing hypoxia drives TUFT1 via HIF-1α/miR-671-5p and TUFT1 activates Ca2+/PI3K/AKT to promote HCC growth and metastasis.","evidence":"ChIP, microRNA array, luciferase 3'-UTR reporter, functional rescue, and xenograft models","pmids":["30250300"],"confidence":"Medium","gaps":["mechanism linking TUFT1 to Ca2+/PI3K/AKT not biochemically reconstituted","single tumor type"]},{"year":2018,"claim":"Showed TUFT1 acts as a secreted/recombinant-active factor signaling through Akt-mTOR and Akt-GSK3β, with pharmacological epistasis dissecting distinct contributions to invasion versus proliferation.","evidence":"Recombinant protein treatment plus mTOR and GSK3β inhibitor epistasis and xenograft in thyroid carcinoma","pmids":["30662679"],"confidence":"Medium","gaps":["receptor mediating recombinant TUFT1 effects unidentified","single lab"]},{"year":2019,"claim":"Mapped a TUFT1-driven small-GTPase cascade in TNBC, identifying p85α binding leading to Rab5, Tiam1, and Rac1 activation alongside Rac1/β-catenin-mediated stemness and chemoresistance.","evidence":"Co-IP for p85α binding, Rab5-GTP/Rac1-GTP activity assays, sphere formation, and xenograft metastasis models","pmids":["31572059","31338333"],"confidence":"Medium","gaps":["direct versus indirect nature of p85α binding not fully resolved","how one scaffold coordinates multiple GTPases unclear"]},{"year":2020,"claim":"Revealed the epigenetic control of TUFT1, showing BRD9 recruits P300 to deposit H3K27Ac at the TUFT1 promoter to activate AKT signaling.","evidence":"ChIP-qPCR for P300/H3K27Ac, BRD9 knockdown/inhibition, and TUFT1 rescue in HCC","pmids":["32908135"],"confidence":"Medium","gaps":["whether BRD9 binds the promoter directly not established","single tumor context"]},{"year":2022,"claim":"Identified SUMOylation at K79 by TRIM27 as a post-translational switch required for TUFT1 oncogenic AKT/mTOR activation and RABGAP1-dependent perinuclear mTORC1 accumulation.","evidence":"Site-directed mutagenesis (K79), Co-IP, TRIM27 knockdown epistasis, and functional assays in gastric cancer","pmids":["36380570"],"confidence":"Medium","gaps":["how SUMOylation alters TUFT1 conformation/partner binding unknown","deSUMOylation enzymes not identified"]},{"year":2023,"claim":"Established TUFT1 as a desmosome-associated protein essential for epidermal integrity, with biallelic loss causing woolly hair and skin fragility, defining its first Mendelian disease role.","evidence":"Exome/genome sequencing across families, immunofluorescence, TEM, scRNA-seq, desmoplakin tail-dependent transfection, and Tuft1-knockout mouse","pmids":["36689522","37716648"],"confidence":"High","gaps":["molecular interaction of TUFT1 with desmosomal components beyond desmoplakin-tail dependence undefined","how the same protein serves desmosomal and cytoplasmic signaling roles unresolved"]},{"year":2025,"claim":"Placed TUFT1 at the centrosome as a regulator of centriole number and spindle bipolarity by restraining premature PLK1 activation, under control of NEK2 phosphorylation.","evidence":"Immunofluorescence localization, loss-of-function centrosome/spindle readouts, PLK1 activity epistasis, and NEK2 phosphorylation assays","pmids":["41022752"],"confidence":"Medium","gaps":["mechanism by which TUFT1 suppresses PLK1 activation undefined","functional phospho-sites on TUFT1 not mapped","relationship to its trafficking/signaling roles unclear"]},{"year":2026,"claim":"Demonstrated a receptor-stabilization mechanism in which TUFT1 binds TβRII via its N-terminus and competes with caveolin-1 to divert TβRII from lysosomal degradation into endosomal signaling, driving hepatic stellate cell activation.","evidence":"IP-MS partner discovery, domain-mapping Co-IP, caveolin-1 competition and lysosomal degradation assays, and in vivo HSC/CRC mouse models","pmids":["41593321"],"confidence":"High","gaps":["whether this TGF-β mechanism operates in epithelial/cancer contexts not tested","structural detail of TUFT1/caveolin-1 competition unknown"]},{"year":null,"claim":"How a single protein integrates its desmosomal-structural, centrosomal, vesicular-trafficking, and growth-signaling functions — and which post-translational modifications and partners govern the switch between them — remains unresolved.","evidence":"No single study reconciles the distinct cellular roles across tissues","pmids":[],"confidence":"Low","gaps":["no unifying structural model","domain architecture mapped only piecemeal","context-determining factors between roles unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,11,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8]}],"complexes":["desmosome"],"partners":["RABGAP1","TRIM27","PIK3R1","TGFBR2","CAV1","NEK2","DSP","ATF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NNX1","full_name":"Tuftelin","aliases":[],"length_aa":390,"mass_kda":44.3,"function":"Involved in the structural organization of the epidermis (PubMed:36689522). Involved in the mineralization and structural organization of enamel","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NNX1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TUFT1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TUFT1","total_profiled":1310},"omim":[{"mim_id":"620415","title":"WOOLLY HAIR-SKIN FRAGILITY SYNDROME; WHSF","url":"https://www.omim.org/entry/620415"},{"mim_id":"614843","title":"ODONTOGENIC AMELOBLAST-ASSOCIATED PROTEIN; ODAM","url":"https://www.omim.org/entry/614843"},{"mim_id":"612747","title":"TUFTELIN-INTERACTING PROTEIN 11; TFIP11","url":"https://www.omim.org/entry/612747"},{"mim_id":"606585","title":"ENAMELIN; ENAM","url":"https://www.omim.org/entry/606585"},{"mim_id":"600087","title":"TUFTELIN; TUFT1","url":"https://www.omim.org/entry/600087"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skin 1","ntpm":105.2}],"url":"https://www.proteinatlas.org/search/TUFT1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NNX1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NNX1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NNX1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NNX1-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TUFT1","jax_strain_url":"https://www.jax.org/strain/search?query=TUFT1"},"sequence":{"accession":"Q9NNX1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NNX1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NNX1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NNX1"}},"corpus_meta":[{"pmid":"30250300","id":"PMC_30250300","title":"Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca2+/PI3K/AKT pathway.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30250300","citation_count":105,"is_preprint":false},{"pmid":"31827397","id":"PMC_31827397","title":"Exosomal lncRNA HNF1A-AS1 affects cisplatin resistance in cervical cancer cells through regulating microRNA-34b/TUFT1 axis.","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31827397","citation_count":74,"is_preprint":false},{"pmid":"27566398","id":"PMC_27566398","title":"TUFT1 regulates metastasis of pancreatic cancer through HIF1-Snail pathway induced epithelial-mesenchymal transition.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27566398","citation_count":47,"is_preprint":false},{"pmid":"29423269","id":"PMC_29423269","title":"TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling.","date":"2018","source":"Cell 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cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33058834","citation_count":33,"is_preprint":false},{"pmid":"31338333","id":"PMC_31338333","title":"TUFT1 Promotes Triple Negative Breast Cancer Metastasis, Stemness, and Chemoresistance by Up-Regulating the Rac1/β-Catenin Pathway.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31338333","citation_count":32,"is_preprint":false},{"pmid":"28410428","id":"PMC_28410428","title":"TUFT1, a novel candidate gene for metatarsophalangeal osteoarthritis, plays a role in chondrogenesis on a calcium-related pathway.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28410428","citation_count":25,"is_preprint":false},{"pmid":"37986103","id":"PMC_37986103","title":"m6A modified BACE1-AS contributes to liver metastasis and stemness-like properties in colorectal cancer through TUFT1 dependent activation of Wnt signaling.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37986103","citation_count":24,"is_preprint":false},{"pmid":"29088838","id":"PMC_29088838","title":"TUFT1 is expressed in breast cancer and involved in cancer cell proliferation and survival.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29088838","citation_count":22,"is_preprint":false},{"pmid":"35075616","id":"PMC_35075616","title":"Hsa_circ_0074269-mediated Upregulation of TUFT1 Through miR-485-5p Increases Cisplatin Resistance in Cervical Cancer.","date":"2022","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/35075616","citation_count":20,"is_preprint":false},{"pmid":"31572059","id":"PMC_31572059","title":"TUFT1 promotes metastasis and chemoresistance in triple negative breast cancer through the TUFT1/Rab5/Rac1 pathway.","date":"2019","source":"Cancer cell 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research","url":"https://pubmed.ncbi.nlm.nih.gov/30662679","citation_count":17,"is_preprint":false},{"pmid":"32115852","id":"PMC_32115852","title":"MiR-671-5p plays a promising role in restraining osteosarcoma cell characteristics through targeting TUFT1.","date":"2020","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32115852","citation_count":16,"is_preprint":false},{"pmid":"36149758","id":"PMC_36149758","title":"LINC00960 regulates cell proliferation and glycolysis in pancreatic cancer through the miR-326-3p/TUFT1/AKT-mTOR axis.","date":"2022","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36149758","citation_count":12,"is_preprint":false},{"pmid":"33634374","id":"PMC_33634374","title":"TUFT1 Facilitates Metastasis, Stemness, and Vincristine Resistance in Colorectal Cancer via Activation of PI3K/AKT Pathway.","date":"2021","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33634374","citation_count":11,"is_preprint":false},{"pmid":"36380570","id":"PMC_36380570","title":"SUMOylation of TUFT1 is essential for gastric cancer progression through AKT/mTOR signaling pathway activation.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36380570","citation_count":11,"is_preprint":false},{"pmid":"36689522","id":"PMC_36689522","title":"Biallelic TUFT1 variants cause woolly hair, superficial skin fragility and desmosomal defects.","date":"2023","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/36689522","citation_count":9,"is_preprint":false},{"pmid":"36797791","id":"PMC_36797791","title":"microRNA-128-3p inhibits proliferation and accelerates apoptosis of gastric cancer cells via inhibition of TUFT1.","date":"2023","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36797791","citation_count":8,"is_preprint":false},{"pmid":"36389808","id":"PMC_36389808","title":"Construction and protective efficacy of a novel Streptococcus pneumoniae fusion protein vaccine NanAT1-TufT1-PlyD4.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36389808","citation_count":8,"is_preprint":false},{"pmid":"37801178","id":"PMC_37801178","title":"In silico screening of non-synonymous SNPs in human TUFT1 gene.","date":"2023","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37801178","citation_count":6,"is_preprint":false},{"pmid":"37716648","id":"PMC_37716648","title":"Disruption of TUFT1, a Desmosome-Associated Protein, Causes Skin Fragility, Woolly Hair, and Palmoplantar Keratoderma.","date":"2023","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/37716648","citation_count":3,"is_preprint":false},{"pmid":"34904343","id":"PMC_34904343","title":"ATF2 accelerates the invasion and metastasis of hepatocellular carcinoma through targeting the miR-548p/TUFT1 axis.","date":"2022","source":"Hepatology research : the official journal of the Japan Society of Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/34904343","citation_count":3,"is_preprint":false},{"pmid":"35616620","id":"PMC_35616620","title":"MicroRNA-145 regulates the proliferation of the human gastric cancer cells by targeting tuftelin 1 (TUFT1).","date":"2022","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/35616620","citation_count":2,"is_preprint":false},{"pmid":"34239359","id":"PMC_34239359","title":"Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34239359","citation_count":2,"is_preprint":false},{"pmid":"39948288","id":"PMC_39948288","title":"TUFT1 Modulates Cell Proliferation, Migration, Invasion, Stemness and EGFR Signaling in Cervical Cancer through Interacting with and Targeting ATF1.","date":"2025","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39948288","citation_count":1,"is_preprint":false},{"pmid":"33994858","id":"PMC_33994858","title":"Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33994858","citation_count":1,"is_preprint":false},{"pmid":"41022752","id":"PMC_41022752","title":"TUFT1 regulates cancer progression by suppressing centrosome amplification and mitotic spindle multipolarity.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41022752","citation_count":0,"is_preprint":false},{"pmid":"39859478","id":"PMC_39859478","title":"Expression of AMELX, AMBN, ENAM, TUFT1, FAM83H and MMP20 Genes in Buccal Epithelial Cells from Patients with Molar Incisor Hypomineralization (MIH)-A Pilot Study.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39859478","citation_count":0,"is_preprint":false},{"pmid":"41593321","id":"PMC_41593321","title":"TUFT1 stabilizes TGF-β receptor II protein and facilitates activation of hepatic stellate cells into metastasis-promoting myofibroblasts.","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41593321","citation_count":0,"is_preprint":false},{"pmid":"38478261","id":"PMC_38478261","title":"Assessment of TUFT1 and Rac1-GTP levels in triple-negative breast cancer patients: clinical and pathological correlations.","date":"2024","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/38478261","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20194,"output_tokens":4335,"usd":0.062803,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12261,"output_tokens":4067,"usd":0.08149,"stage2_stop_reason":"end_turn"},"total_usd":0.144293,"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\": 2018,\n      \"finding\": \"TUFT1 physically interacts with RABGAP1 (a Rab GTPase activating protein), thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promotes mTORC1 signaling activation.\",\n      \"method\": \"Co-immunoprecipitation, cellular fractionation/lysosomal positioning assays, mTORC1 activity assays with TUFT1 knockdown/overexpression\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal physical interaction demonstrated, multiple orthogonal functional readouts (lysosomal positioning, vesicle trafficking, mTORC1 signaling), single lab\",\n      \"pmids\": [\"29423269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TUFT1 promotes HCC cell growth, metastasis and epithelial-mesenchymal transition via activation of the Ca2+/PI3K/AKT pathway. Hypoxia upregulates TUFT1 through HIF-1α-dependent downregulation of miR-671-5p, which targets the 3'-UTR of TUFT1 mRNA.\",\n      \"method\": \"MTT, BrdU, Transwell assays, subcutaneous/tail vein xenograft models, chromatin immunoprecipitation (HIF-1α binding to TUFT1 promoter), microRNA array, luciferase reporter (miR-671-5p/TUFT1 3'-UTR), western blot for pathway activation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, luciferase, functional rescue), single lab\",\n      \"pmids\": [\"30250300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TUFT1 promotes pancreatic cancer EMT by altering expression of Snail and is associated with HIF1 expression and activity, suggesting TUFT1 regulates EMT via a HIF1-Snail signaling axis.\",\n      \"method\": \"shRNA knockdown and overexpression, migration/invasion assays, in vivo metastasis models, western blot for EMT markers (E-cadherin, vimentin, Snail), HIF1 activity assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function and gain-of-function with defined molecular readouts, single lab, mechanistic link to HIF1-Snail is associative rather than direct reconstitution\",\n      \"pmids\": [\"27566398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TUFT1 is SUMOylated at lysine 79 by the E3 SUMO ligase TRIM27. TUFT1 binds TRIM27 through its N-terminus. SUMOylation-deficient TUFT1 (K79 mutant) fails to activate AKT/mTOR signaling and impairs gastric cancer cell proliferation, migration, and invasion. SUMOylated TUFT1 also forms a complex with RABGAP1 to promote perinuclear accumulation of mTORC1.\",\n      \"method\": \"SUMOylation site mutagenesis, Co-IP, functional assays (proliferation, migration, invasion), western blot for AKT/mTOR phosphorylation, TRIM27 knockdown epistasis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of modification site, co-IP for binding partners, multiple functional readouts, single lab\",\n      \"pmids\": [\"36380570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TUFT1 promotes metastasis and chemoresistance in TNBC by activating Rab5 through binding to p85α, which leads to Tiam1 recruitment and subsequent Rac1 activation, with concurrent downregulation of NF-κB pathway and proapoptotic factors.\",\n      \"method\": \"Co-immunoprecipitation (TUFT1-p85α interaction), GTP activity assays (Rab5-GTP, Rac1-GTP), shRNA knockdown, nude mouse xenograft metastasis model, Transwell assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct binding, GTP activity assays for downstream effectors, functional rescue experiments, single lab\",\n      \"pmids\": [\"31572059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TUFT1 promotes TNBC tumor cell metastasis and stemness by upregulating the Rac1/β-catenin pathway, and lack of TUFT1 sensitizes cells to chemotherapy via downregulation of this pathway.\",\n      \"method\": \"shRNA knockdown, GTP activity assays (Rac1-GTP), migration/invasion assays, sphere formation, apoptosis assay, nude mouse xenograft spontaneous lung metastasis model, western blot\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP activity assay for Rac1 activation, functional rescue, in vivo model, single lab\",\n      \"pmids\": [\"31338333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRD9 epigenetically upregulates TUFT1 expression by promoting binding of P300 acetyltransferase to the TUFT1 promoter and increasing H3K27Ac at the promoter, thereby activating AKT signaling in HCC cells.\",\n      \"method\": \"ChIP-qPCR (P300 and H3K27Ac at TUFT1 promoter), BRD9 knockdown/inhibition, TUFT1 rescue experiments, western blot for AKT phosphorylation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR for direct epigenetic mechanism, functional epistasis rescue, single lab\",\n      \"pmids\": [\"32908135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Biallelic loss-of-function TUFT1 variants cause woolly hair and superficial skin fragility. Tuftelin-1 is localized to peripheral cell membranes of keratinocytes in normal skin, and loss of TUFT1 leads to desmosomal detachment, acantholysis, widening of intercellular spaces throughout the epidermis, and perinuclear retraction of intermediate filaments.\",\n      \"method\": \"Whole-genome/exome sequencing, immunofluorescence microscopy (localization in normal vs. patient skin), transmission electron microscopy (desmosomal ultrastructure), haplotype analysis, single-cell RNA sequencing co-expression analysis\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent families, multiple orthogonal methods (immunofluorescence, TEM, scRNA-seq co-expression), replicated in second study (PMID 37716648)\",\n      \"pmids\": [\"36689522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TUFT1 is a desmosome-associated protein whose location within the desmosome depends on the presence of the desmoplakin carboxy-terminal tail. Loss of TUFT1 causes acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance in keratinocytes. A Tuft1-knockout mouse model recapitulates skin fragility, woolly hair, and palmoplantar keratoderma.\",\n      \"method\": \"Immunolabeling (desmosomal localization), transfection studies (desmoplakin carboxy-terminal tail dependence), Tuft1-knockout mouse model, keratinocyte mechanical stress assays, patient skin histology\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model, transfection-based localization dependence, patient-derived keratinocytes, multiple orthogonal methods, independent replication across two labs (PMID 36689522)\",\n      \"pmids\": [\"37716648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of wild-type or mutant TUFT1 in ATDC5 chondrogenic cells inhibits chondrogenic differentiation (decreased marker gene expression, reduced cartilage nodule formation) in calcifying conditions. The T175M variant increases extracellular matrix calcium content and reduces proteoglycan content compared to wild-type TUFT1 overexpression.\",\n      \"method\": \"HEK293 cell transfection (mRNA/protein expression), ATDC5 overexpression in calcifying conditions, chondrogenic marker gene expression, cartilage nodule formation assay, calcium and proteoglycan content measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro assay with wild-type vs. mutant comparison, multiple molecular readouts, single lab\",\n      \"pmids\": [\"28410428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tuft1 promotes thyroid carcinoma cell invasion and proliferation and suppresses apoptosis through the Akt-mTOR and Akt-GSK3β signaling pathways. Addition of recombinant Tuft1 protein to TC cells increases phosphorylation of Akt, mTOR, and GSK3β; mTOR inhibitor abrogates Tuft1-induced invasion and proliferation, while GSK3β inhibitor abrogates Tuft1-induced proliferation only.\",\n      \"method\": \"shRNA knockdown, recombinant protein treatment, mTOR inhibitor (Dactolisib) and GSK3β inhibitor (CHIR-98014) pharmacological epistasis, western blot for pathway phosphorylation, in vivo xenograft\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with two inhibitors defining pathway specificity, recombinant protein gain-of-function, single lab\",\n      \"pmids\": [\"30662679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TUFT1 is a centrosomal protein that localizes to the proximal ends of parent centrioles. TUFT1 prevents centrosome amplification and mitotic spindle multipolarity by suppressing premature polo-like kinase 1 (PLK1) activation. TUFT1 is phosphorylated by NEK2 kinase, and the phosphorylation status of TUFT1 is essential for coordinating centrosome number and cell proliferation.\",\n      \"method\": \"Immunofluorescence (centrosomal localization), TUFT1 loss-of-function (centrosome number, spindle multipolarity readouts), PLK1 activity assays, NEK2-mediated phosphorylation assay, western blot, clinical breast cancer sample analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence, kinase-substrate relationship for NEK2-TUFT1, PLK1 activation epistasis, single lab\",\n      \"pmids\": [\"41022752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TUFT1 is a novel TGF-β receptor II (TβRII) binding protein in hepatic stellate cells (HSCs). TUFT1 interacts with TβRII via its N-terminal fragments (amino acids 1-86 and 87-157), protecting TβRII from lysosomal degradation by competing with caveolin-1 for TβRII binding, diverting TβRII from the lipid rafts/caveolae-mediated degradation pathway into the endosome-mediated trafficking and signaling pathway, thereby facilitating TGF-β signaling and myofibroblastic activation of HSCs.\",\n      \"method\": \"Immunoprecipitation coupled with mass spectrometry (TβRII-TUFT1 interaction discovery), Co-IP (domain mapping, caveolin-1 competition), lysosomal degradation assays, TUFT1 knockdown with TGF-β signaling readouts, in vivo HSC/CRC co-implantation and portal vein injection mouse models, bulk RNA sequencing\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — IP-MS for unbiased binding partner identification, domain-level binding mapping, mechanistic competition assay with caveolin-1, in vivo functional validation with multiple mouse models, multiple orthogonal methods\",\n      \"pmids\": [\"41593321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TUFT1 binds to ATF1 (activating transcription factor 1) in cervical cancer cells and positively regulates ATF1 expression. ATF1 overexpression counteracts the effects of TUFT1 silencing on proliferation, migration, invasion, stemness, and EGFR signaling.\",\n      \"method\": \"Co-IP assay (TUFT1-ATF1 interaction), RT-qPCR and western blot (ATF1 expression after TUFT1 silencing), epistasis rescue (co-transfection of TUFT1 siRNA + ATF1 overexpression), functional assays\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for binding, single lab, partial mechanistic follow-up, EGFR pathway link is inferred from western blot without direct biochemical reconstitution\",\n      \"pmids\": [\"39948288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF2 transcription factor directly targets the miR-548p promoter (confirmed by ChIP and luciferase assay), and miR-548p directly binds the 3'-UTR of TUFT1 to suppress its expression, thereby suppressing PI3K/AKT signaling in HCC.\",\n      \"method\": \"Chromatin immunoprecipitation (ATF2 binding to miR-548p promoter), luciferase reporter assay (miR-548p binding to TUFT1 3'-UTR), western blot for PI3K/AKT signaling, functional assays\",\n      \"journal\": \"Hepatology research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and luciferase assays confirm the regulatory axis, but mechanistic characterization of TUFT1 itself is indirect (downstream of miR-548p), single lab\",\n      \"pmids\": [\"34904343\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TUFT1 (tuftelin 1) is a multifunctional protein that localizes to centrosome proximal ends, peripheral keratinocyte cell membranes (within desmosomes), and intracellular vesicular compartments; it promotes mTORC1 signaling by physically interacting with RABGAP1 to modulate lysosomal positioning and vesicle trafficking, activates PI3K/AKT pathways in multiple cancer types, regulates EMT via HIF1-Snail and Rac1/β-catenin axes, maintains desmosomal integrity in skin (loss of function causes skin fragility and woolly hair), controls centrosome number by suppressing premature PLK1 activation (itself phosphorylated by NEK2), is SUMOylated at K79 by TRIM27 (required for its oncogenic activity), stabilizes TGF-β receptor II by competing with caveolin-1 to redirect it from lysosomal degradation into endosomal signaling, and is transcriptionally regulated by BRD9/P300-mediated H3K27 acetylation and post-transcriptionally by multiple miRNAs including miR-671-5p.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TUFT1 (tuftelin 1) is a multifunctional scaffolding protein that operates in two broad arenas: maintenance of epidermal desmosomal integrity and promotion of growth-signaling, vesicular-trafficking, and centrosomal homeostasis in proliferating and malignant cells [#0, #7, #11]. In skin, TUFT1 localizes to peripheral keratinocyte cell membranes within desmosomes in a manner dependent on the desmoplakin carboxy-terminal tail, and biallelic loss-of-function variants cause woolly hair and superficial skin fragility characterized by desmosomal detachment, acantholysis, and perinuclear retraction of intermediate filaments, a phenotype recapitulated in Tuft1-knockout mice [#7, #8]. In its trafficking/signaling role, TUFT1 physically interacts with the Rab GTPase-activating protein RABGAP1 to control lysosomal positioning and vesicle trafficking and to promote mTORC1 activation [#0]. Across multiple cancers it activates PI3K/AKT-mTOR signaling and drives proliferation, invasion, and epithelial-mesenchymal transition, acting through a HIF1-Snail axis, a p85\\u03b1/Rab5/Tiam1/Rac1 and Rac1/\\u03b2-catenin cascade, and Akt-mTOR/Akt-GSK3\\u03b2 pathways [#1, #2, #4, #5, #10]. Its oncogenic activity is gated by post-translational SUMOylation at K79 by TRIM27, which is required for AKT/mTOR activation and for forming a perinuclear mTORC1-promoting complex with RABGAP1 [#3]. TUFT1 also stabilizes TGF-\\u03b2 receptor II by binding it through its N-terminus and competing with caveolin-1, redirecting the receptor away from lysosomal degradation toward endosomal signaling to drive myofibroblastic activation of hepatic stellate cells [#12]. At the centrosome, TUFT1 localizes to proximal ends of parent centrioles and prevents centrosome amplification and spindle multipolarity by suppressing premature PLK1 activation, with its function regulated by NEK2-mediated phosphorylation [#11]. Its expression is controlled epigenetically by BRD9/P300-driven H3K27 acetylation and post-transcriptionally by miRNAs targeting its 3'-UTR [#1, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established TUFT1 as a driver of epithelial-mesenchymal transition in cancer, linking it to a transcriptional EMT program for the first time.\",\n      \"evidence\": \"shRNA knockdown/overexpression with migration, invasion, and metastasis readouts plus EMT marker and HIF1 activity analysis in pancreatic cancer\",\n      \"pmids\": [\"27566398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HIF1-Snail link is associative, not reconstituted\", \"no direct binding partner identified\", \"molecular mechanism by which TUFT1 alters Snail unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the first direct physical partner of TUFT1 (RABGAP1) and connected it to lysosomal positioning, vesicle trafficking, and mTORC1 activation, defining a core trafficking/signaling function.\",\n      \"evidence\": \"Co-IP, cellular fractionation/lysosomal positioning assays, and mTORC1 activity assays with TUFT1 perturbation\",\n      \"pmids\": [\"29423269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of TUFT1-RABGAP1 interaction unresolved\", \"how TUFT1 modulates RABGAP1 GAP activity not defined\", \"link between trafficking role and skin/centrosome functions unexplored\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined an upstream regulatory and downstream signaling axis showing hypoxia drives TUFT1 via HIF-1\\u03b1/miR-671-5p and TUFT1 activates Ca2+/PI3K/AKT to promote HCC growth and metastasis.\",\n      \"evidence\": \"ChIP, microRNA array, luciferase 3'-UTR reporter, functional rescue, and xenograft models\",\n      \"pmids\": [\"30250300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking TUFT1 to Ca2+/PI3K/AKT not biochemically reconstituted\", \"single tumor type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed TUFT1 acts as a secreted/recombinant-active factor signaling through Akt-mTOR and Akt-GSK3\\u03b2, with pharmacological epistasis dissecting distinct contributions to invasion versus proliferation.\",\n      \"evidence\": \"Recombinant protein treatment plus mTOR and GSK3\\u03b2 inhibitor epistasis and xenograft in thyroid carcinoma\",\n      \"pmids\": [\"30662679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"receptor mediating recombinant TUFT1 effects unidentified\", \"single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped a TUFT1-driven small-GTPase cascade in TNBC, identifying p85\\u03b1 binding leading to Rab5, Tiam1, and Rac1 activation alongside Rac1/\\u03b2-catenin-mediated stemness and chemoresistance.\",\n      \"evidence\": \"Co-IP for p85\\u03b1 binding, Rab5-GTP/Rac1-GTP activity assays, sphere formation, and xenograft metastasis models\",\n      \"pmids\": [\"31572059\", \"31338333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct versus indirect nature of p85\\u03b1 binding not fully resolved\", \"how one scaffold coordinates multiple GTPases unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed the epigenetic control of TUFT1, showing BRD9 recruits P300 to deposit H3K27Ac at the TUFT1 promoter to activate AKT signaling.\",\n      \"evidence\": \"ChIP-qPCR for P300/H3K27Ac, BRD9 knockdown/inhibition, and TUFT1 rescue in HCC\",\n      \"pmids\": [\"32908135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether BRD9 binds the promoter directly not established\", \"single tumor context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SUMOylation at K79 by TRIM27 as a post-translational switch required for TUFT1 oncogenic AKT/mTOR activation and RABGAP1-dependent perinuclear mTORC1 accumulation.\",\n      \"evidence\": \"Site-directed mutagenesis (K79), Co-IP, TRIM27 knockdown epistasis, and functional assays in gastric cancer\",\n      \"pmids\": [\"36380570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how SUMOylation alters TUFT1 conformation/partner binding unknown\", \"deSUMOylation enzymes not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established TUFT1 as a desmosome-associated protein essential for epidermal integrity, with biallelic loss causing woolly hair and skin fragility, defining its first Mendelian disease role.\",\n      \"evidence\": \"Exome/genome sequencing across families, immunofluorescence, TEM, scRNA-seq, desmoplakin tail-dependent transfection, and Tuft1-knockout mouse\",\n      \"pmids\": [\"36689522\", \"37716648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular interaction of TUFT1 with desmosomal components beyond desmoplakin-tail dependence undefined\", \"how the same protein serves desmosomal and cytoplasmic signaling roles unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed TUFT1 at the centrosome as a regulator of centriole number and spindle bipolarity by restraining premature PLK1 activation, under control of NEK2 phosphorylation.\",\n      \"evidence\": \"Immunofluorescence localization, loss-of-function centrosome/spindle readouts, PLK1 activity epistasis, and NEK2 phosphorylation assays\",\n      \"pmids\": [\"41022752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism by which TUFT1 suppresses PLK1 activation undefined\", \"functional phospho-sites on TUFT1 not mapped\", \"relationship to its trafficking/signaling roles unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a receptor-stabilization mechanism in which TUFT1 binds T\\u03b2RII via its N-terminus and competes with caveolin-1 to divert T\\u03b2RII from lysosomal degradation into endosomal signaling, driving hepatic stellate cell activation.\",\n      \"evidence\": \"IP-MS partner discovery, domain-mapping Co-IP, caveolin-1 competition and lysosomal degradation assays, and in vivo HSC/CRC mouse models\",\n      \"pmids\": [\"41593321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether this TGF-\\u03b2 mechanism operates in epithelial/cancer contexts not tested\", \"structural detail of TUFT1/caveolin-1 competition unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single protein integrates its desmosomal-structural, centrosomal, vesicular-trafficking, and growth-signaling functions \\u2014 and which post-translational modifications and partners govern the switch between them \\u2014 remains unresolved.\",\n      \"evidence\": \"No single study reconciles the distinct cellular roles across tissues\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no unifying structural model\", \"domain architecture mapped only piecemeal\", \"context-determining factors between roles unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 11, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"desmosome\"],\n    \"partners\": [\"RABGAP1\", \"TRIM27\", \"PIK3R1\", \"TGFBR2\", \"CAV1\", \"NEK2\", \"DSP\", \"ATF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}