{"gene":"AKTIP","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2015,"finding":"AKTIP/Ft1 is a novel shelterin-bound factor that physically interacts with shelterin components TRF1 and TRF2 both in vivo and in vitro, binds telomeric DNA by ChIP, and interacts with PCNA and RPA70. RNAi-mediated depletion causes telomere dysfunction foci (TIFs), S-phase arrest via intra-S checkpoint activation, and (in p53-/- MEFs) multiple telomeric signals (MTS) and sister telomere associations (STAs). Epistasis with TRF1 for MTS formation and ChIP showing reduced TRF1 binding at telomeres in AKTIP-depleted S-phase cells together indicate AKTIP works in concert with TRF1 to facilitate telomeric DNA replication.","method":"Co-IP, pulldown (in vitro), ChIP, RNAi knockdown, immunofluorescence (TIF assay), FACS cell-cycle analysis, genetic epistasis (double mutant MTS quantification)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (in vitro binding, ChIP, TIF assay, epistasis, cell-cycle phenotype) in a single rigorous study","pmids":["26110528"],"is_preprint":false},{"year":2016,"finding":"AKTIP biochemically interacts with A- and B-type lamins (co-IP), localizes at the nuclear rim and nucleoplasm overlapping with lamin B1 and lamin A/C in interphase, and is enriched at spindle poles and the midbody in mitosis. Proper AKTIP localization requires functional lamin A. AKTIP depletion induces senescence-associated markers and a progeroid-like phenotype, and affects lamin A (but not lamin C or B) expression.","method":"Co-IP, double immunostaining/co-localization, siRNA knockdown, senescence marker assays, fractionation","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus direct localization with functional consequence (senescence phenotype) replicated with multiple methods in one study","pmids":["27512140"],"is_preprint":false},{"year":2021,"finding":"During mitosis AKTIP localizes to the midbody and interacts with the ESCRT I subunit VPS28. AKTIP forms a circular supra-structure at the midbody adjacent to ESCRT I (TSG101, VPS28) and ESCRT III subunits (CHMP2A, CHMP4B, IST1). Mechanistically, AKTIP recruitment to the midbody is dependent on MKLP1 and independent of CEP55. AKTIP and TSG101 are jointly required for recruitment of CHMP4B, and act in parallel for IST1 recruitment. AKTIP depletion alone impairs IST1 recruitment and causes multinucleation, establishing AKTIP as an ESCRT I component required for abscission.","method":"Co-IP, super-resolution/confocal immunofluorescence, siRNA knockdown (single and double), multinucleation assay, epistasis analysis of ESCRT subunit recruitment","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal co-IP, super-resolution localization, genetic epistasis of ESCRT subunit recruitment, functional abscission readout; multiple orthogonal methods","pmids":["34449766"],"is_preprint":false},{"year":2021,"finding":"AKTIP is phosphorylated by TLK1 at residues T22 and S237. Phosphorylated AKTIP enhances the association of AKT with PDK1, leading to increased AKT phosphorylation at T308 and S473. TLK1 inhibition reduces AKT phosphorylation, which is potentiated by concurrent AKTIP knockdown, placing AKTIP in a TLK1→AKTIP→AKT signaling axis in prostate cancer cells.","method":"Interactome/phosphoproteomic mass spectrometry, co-IP, siRNA knockdown, phospho-specific western blot, TLK1 inhibitor (J54) treatment","journal":"Pathophysiology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and phospho-western in a single lab; phosphorylation sites identified by MS but functional rescue not fully reconstituted","pmids":["35366279"],"is_preprint":false},{"year":2022,"finding":"AKTIP loss in ERα-positive breast cancer cells stabilizes ERα protein by a mechanism involving CAND1-mediated protection from cullin 2-dependent proteasomal degradation, and concurrently activates JAK2-STAT3 signaling as an alternative survival pathway. AKTIP-depleted cells show resistance to ERα antagonists that can be overcome by co-inhibition of JAK2/STAT3.","method":"siRNA/shRNA knockdown, co-IP, proteasome inhibitor rescue, western blot, ERα reporter assay, patient-derived organoids, pharmacological inhibition","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single study; mechanistic pathway (CAND1/cullin 2/ERα and JAK2-STAT3) supported by biochemical and functional data","pmids":["36516775"],"is_preprint":false},{"year":2022,"finding":"AKTIP co-localizes with lamin A/C at the nuclear rim in HeLa cells; this co-localization is reduced in MCF7 and A549 tumor cells. AKTIP mislocalizes in HGPS (progerin-expressing) cells but not EDMD2 cells, and exogenous progerin expression in HeLa cells also mislocalizes AKTIP, indicating that nuclear morphology (not lamin expression alone) governs AKTIP positioning.","method":"Super-resolution imaging, quantitative co-localization analysis, exogenous progerin expression, lamin quantification, nuclear morphology analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct super-resolution localization with functional genetic manipulation (progerin); single lab but multiple cell models","pmids":["36096808"],"is_preprint":false},{"year":2023,"finding":"miR-106a-5p directly binds the 3'-UTR of AKTIP mRNA (validated by dual luciferase reporter assay), suppressing AKTIP expression and thereby activating the PI3K/AKT/mTOR pathway to promote laryngeal carcinoma cell proliferation and migration.","method":"Dual luciferase reporter assay, miRNA inhibitor, western blot (pathway readouts), clonogenic and migration assays","journal":"Iranian journal of biotechnology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic depth beyond 3'-UTR binding and pathway activation readout","pmids":["36811106"],"is_preprint":false}],"current_model":"AKTIP is a UEV-domain shelterin-interacting protein that facilitates telomeric DNA replication by cooperating with TRF1, interacts with lamins to maintain nuclear architecture, functions as an ESCRT I component at the midbody by binding VPS28 and orchestrating recruitment of ESCRT III subunits (CHMP4B, IST1) for abscission, and is phosphorylated by TLK1 to promote AKT activation via PDK1; in ERα-positive breast cancer, AKTIP loss stabilizes ERα through a CAND1/cullin 2 axis and activates JAK2-STAT3 as an alternative survival signal."},"narrative":{"teleology":[{"year":2015,"claim":"The question of whether AKTIP has a direct role at telomeres was answered by demonstrating that it physically binds shelterin (TRF1/TRF2), occupies telomeric chromatin, and is required for telomeric DNA replication, establishing it as a novel replication-facilitating telomere factor.","evidence":"Co-IP, in vitro pulldown, ChIP, RNAi, epistasis with TRF1 for MTS formation in MEFs","pmids":["26110528"],"confidence":"High","gaps":["Structural basis of AKTIP–TRF1 interaction unknown","Whether AKTIP participates in telomere replication through its UEV domain or another surface is unresolved","In vivo organismal consequences of telomere-specific AKTIP loss not tested"]},{"year":2016,"claim":"Whether AKTIP connects to nuclear architecture beyond telomeres was resolved by showing it interacts with A- and B-type lamins, localizes to the nuclear rim dependently on lamin A, and its loss induces senescence-associated phenotypes, linking AKTIP to nuclear envelope integrity.","evidence":"Co-IP with lamins, co-localization imaging, siRNA knockdown with senescence marker readouts","pmids":["27512140"],"confidence":"High","gaps":["Whether lamin interaction and telomere function are mechanistically coupled is unclear","Direct binding domain on AKTIP for lamins not mapped","Whether AKTIP loss-induced senescence is telomere-driven or lamin-driven not distinguished"]},{"year":2021,"claim":"The long-standing observation that AKTIP localizes to the midbody was mechanistically resolved: AKTIP acts as an ESCRT I component that binds VPS28, is recruited by MKLP1 independently of CEP55, and cooperates with TSG101 to recruit ESCRT III subunits for cytokinetic abscission.","evidence":"Co-IP, super-resolution imaging, single and double siRNA knockdown with ESCRT subunit recruitment epistasis and multinucleation quantification","pmids":["34449766"],"confidence":"High","gaps":["Whether AKTIP replaces or supplements TSG101-VPS28 in canonical ESCRT I is unresolved","Stoichiometry and structure of AKTIP-containing ESCRT I complex not determined","Relationship between AKTIP's midbody and telomere functions during the cell cycle not tested"]},{"year":2021,"claim":"How AKTIP participates in AKT activation was clarified by identifying TLK1-mediated phosphorylation of AKTIP at T22 and S237, which enhances AKT–PDK1 association and AKT phosphorylation, placing AKTIP as a phospho-regulated scaffold in a TLK1→AKTIP→AKT axis.","evidence":"Phosphoproteomics, co-IP, TLK1 inhibitor and siRNA in prostate cancer cells","pmids":["35366279"],"confidence":"Medium","gaps":["Functional rescue with phospho-mimetic or phospho-dead AKTIP mutants not performed","Whether TLK1-AKTIP signaling operates in non-cancer contexts is untested","Direct binding interface between AKTIP and AKT/PDK1 not mapped"]},{"year":2022,"claim":"AKTIP's role in cancer cell signaling was expanded by showing that its loss stabilizes ERα through a CAND1/cullin 2-dependent mechanism and activates JAK2-STAT3 as a compensatory survival pathway, conferring ERα-antagonist resistance in breast cancer.","evidence":"siRNA/shRNA, co-IP, proteasome inhibitor rescue, ERα reporter assay, patient-derived organoids, pharmacological JAK2/STAT3 inhibition","pmids":["36516775"],"confidence":"Medium","gaps":["Whether AKTIP directly interacts with cullin 2 or CAND1 is not established","Mechanism by which AKTIP loss activates JAK2-STAT3 is indirect and not fully delineated","Generalizability beyond ERα-positive breast cancer unknown"]},{"year":2022,"claim":"The dependence of AKTIP localization on nuclear lamina integrity was refined by showing that progerin expression, but not EDMD2 lamin A mutations, mislocalizes AKTIP, indicating nuclear morphology rather than lamin expression level dictates AKTIP positioning.","evidence":"Super-resolution imaging and quantitative co-localization in HGPS, EDMD2, tumor, and progerin-transfected cells","pmids":["36096808"],"confidence":"Medium","gaps":["Functional consequence of AKTIP mislocalization on telomere or ESCRT functions in laminopathy cells not tested","Whether AKTIP mislocalization in tumor cells contributes to genome instability is unresolved"]},{"year":null,"claim":"A unified model explaining how AKTIP's telomere replication, nuclear lamina, ESCRT I/abscission, and AKT signaling functions are coordinated across the cell cycle remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for AKTIP in any of its functional complexes","How the UEV domain contributes to each distinct function is not dissected","Whether AKTIP's separate roles are independent or mechanistically linked is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0]}],"complexes":["ESCRT I (midbody)","Shelterin-associated complex"],"partners":["TRF1","TRF2","VPS28","LMNA","LMNB1","TSG101","PCNA","TLK1"],"other_free_text":[]},"mechanistic_narrative":"AKTIP is a UEV-domain protein that operates at the intersection of telomere maintenance, nuclear architecture, cytokinetic abscission, and AKT signaling. At telomeres, AKTIP binds shelterin components TRF1 and TRF2 as well as replication factors PCNA and RPA70, and cooperates with TRF1 to facilitate telomeric DNA replication during S phase; its depletion causes telomere dysfunction foci, replication-associated telomeric aberrations, and intra-S checkpoint activation [PMID:26110528]. AKTIP interacts with A- and B-type lamins at the nuclear envelope, requires functional lamin A for proper localization, and its mislocalization—as seen in progerin-expressing cells—links nuclear lamina integrity to AKTIP positioning [PMID:27512140, PMID:36096808]. During cytokinesis, AKTIP functions as an ESCRT I component at the midbody, where it is recruited in an MKLP1-dependent manner, binds VPS28, and cooperates with TSG101 to recruit ESCRT III subunits CHMP4B and IST1 for abscission; its depletion causes multinucleation [PMID:34449766]."},"prefetch_data":{"uniprot":{"accession":"Q9H8T0","full_name":"AKT-interacting protein","aliases":["Ft1","Fused toes protein homolog"],"length_aa":292,"mass_kda":33.1,"function":"Component of the FTS/Hook/FHIP complex (FHF complex) (PubMed:32073997). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). Regulates apoptosis by enhancing phosphorylation and activation of AKT1. Increases release of TNFSF6 via the AKT1/GSK3B/NFATC1 signaling cascade. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H8T0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKTIP","classification":"Not Classified","n_dependent_lines":85,"n_total_lines":1208,"dependency_fraction":0.07036423841059603},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AKTIP","total_profiled":1310},"omim":[{"mim_id":"620230","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 2B; FHIP2B","url":"https://www.omim.org/entry/620230"},{"mim_id":"620229","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 1B; FHIP1B","url":"https://www.omim.org/entry/620229"},{"mim_id":"617312","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 2A; FHIP2A","url":"https://www.omim.org/entry/617312"},{"mim_id":"608551","title":"VPS18 CORE SUBUNIT OF CORVET AND HOPS COMPLEXES; VPS18","url":"https://www.omim.org/entry/608551"},{"mim_id":"608483","title":"AKT-INTERACTING PROTEIN; AKTIP","url":"https://www.omim.org/entry/608483"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKTIP"},"hgnc":{"alias_symbol":["FLJ13258"],"prev_symbol":["FTS"]},"alphafold":{"accession":"Q9H8T0","domains":[{"cath_id":"3.10.110.10","chopping":"70-230","consensus_level":"high","plddt":95.4756,"start":70,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8T0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8T0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8T0-F1-predicted_aligned_error_v6.png","plddt_mean":77.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKTIP","jax_strain_url":"https://www.jax.org/strain/search?query=AKTIP"},"sequence":{"accession":"Q9H8T0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H8T0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H8T0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8T0"}},"corpus_meta":[{"pmid":"8682793","id":"PMC_8682793","title":"FtsZ ring formation in fts mutants.","date":"1996","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8682793","citation_count":256,"is_preprint":false},{"pmid":"6991482","id":"PMC_6991482","title":"Organization of genes in the ftsA-envA region of the Escherichia coli genetic map and identification of a new fts locus (ftsZ).","date":"1980","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6991482","citation_count":156,"is_preprint":false},{"pmid":"18799622","id":"PMC_18799622","title":"An FTS/Hook/p107(FHIP) complex interacts with and promotes endosomal clustering by the homotypic vacuolar protein sorting complex.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18799622","citation_count":95,"is_preprint":false},{"pmid":"22547163","id":"PMC_22547163","title":"Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer.","date":"2012","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/22547163","citation_count":82,"is_preprint":false},{"pmid":"7011612","id":"PMC_7011612","title":"Characterization of facteur thymique sérique (FTS) in the thymus. 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Fixation of anti-FTS antibodies on thymic reticulo-epithelial cells.","date":"1980","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7011612","citation_count":80,"is_preprint":false},{"pmid":"2676977","id":"PMC_2676977","title":"New mutations fts-36, lts-33, and ftsW clustered in the mra region of the Escherichia coli chromosome induce thermosensitive cell growth and division.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2676977","citation_count":66,"is_preprint":false},{"pmid":"6969145","id":"PMC_6969145","title":"Induction of differentiation in human marrow T cell precursors by the synthetic serum thymic factor, FTS.","date":"1980","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6969145","citation_count":65,"is_preprint":false},{"pmid":"6360436","id":"PMC_6360436","title":"Marked reduction of DNA antibody production and glomerulopathy in thymulin (FTS-Zn) or cyclosporin A treated (NZB X NZW) F1 mice.","date":"1983","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6360436","citation_count":61,"is_preprint":false},{"pmid":"17909812","id":"PMC_17909812","title":"Orally administered FTS (salirasib) inhibits human pancreatic tumor growth in nude mice.","date":"2007","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17909812","citation_count":57,"is_preprint":false},{"pmid":"6124716","id":"PMC_6124716","title":"Improvement of cellular immunity and IgA production in immunodeficient children after treatment with synthetic serum thymic factor (FTS).","date":"1982","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/6124716","citation_count":55,"is_preprint":false},{"pmid":"6248873","id":"PMC_6248873","title":"Specific receptors for the serum thymic factor (FTS) in lymphoblastoid cultured cell lines.","date":"1980","source":"Proceedings of the National 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Aspergillus.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24870033","citation_count":48,"is_preprint":false},{"pmid":"7037626","id":"PMC_7037626","title":"Monoclonal antibody against the serum thymic factor (FTS).","date":"1982","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/7037626","citation_count":48,"is_preprint":false},{"pmid":"10604579","id":"PMC_10604579","title":"The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats.","date":"1999","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/10604579","citation_count":47,"is_preprint":false},{"pmid":"11737078","id":"PMC_11737078","title":"Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS).","date":"2001","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11737078","citation_count":42,"is_preprint":false},{"pmid":"22419113","id":"PMC_22419113","title":"FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice.","date":"2012","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/22419113","citation_count":39,"is_preprint":false},{"pmid":"6200531","id":"PMC_6200531","title":"Production of anti-thymulin (FTS) monoclonal antibodies by immunization against human thymic epithelial cells.","date":"1984","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/6200531","citation_count":39,"is_preprint":false},{"pmid":"26110528","id":"PMC_26110528","title":"AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.","date":"2015","source":"PLoS 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JASN","url":"https://pubmed.ncbi.nlm.nih.gov/12660318","citation_count":34,"is_preprint":false},{"pmid":"6890728","id":"PMC_6890728","title":"Location of FTS (facteur thymique sérique) in the thymus of normal and auto-immune mice.","date":"1982","source":"Thymus","url":"https://pubmed.ncbi.nlm.nih.gov/6890728","citation_count":31,"is_preprint":false},{"pmid":"24971934","id":"PMC_24971934","title":"EGF-induced expression of Fused Toes Homolog (FTS) facilitates epithelial-mesenchymal transition and promotes cell migration in ME180 cervical cancer cells.","date":"2014","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/24971934","citation_count":28,"is_preprint":false},{"pmid":"32073997","id":"PMC_32073997","title":"The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A.","date":"2020","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/32073997","citation_count":27,"is_preprint":false},{"pmid":"27512140","id":"PMC_27512140","title":"The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence.","date":"2016","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/27512140","citation_count":26,"is_preprint":false},{"pmid":"1379670","id":"PMC_1379670","title":"Localised mutagenesis of the fts YEX operon: conditionally lethal missense substitutions in the FtsE cell division protein of Escherichia coli are similar to those found in the cystic fibrosis transmembrane conductance regulator protein (CFTR) of human patients.","date":"1992","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/1379670","citation_count":25,"is_preprint":false},{"pmid":"30244128","id":"PMC_30244128","title":"Silencing of FTS increases radiosensitivity by blocking radiation-induced Notch1 activation and spheroid formation in cervical cancer cells.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30244128","citation_count":22,"is_preprint":false},{"pmid":"33676427","id":"PMC_33676427","title":"Inhibition of ERAD synergizes with FTS to eradicate pancreatic cancer cells.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33676427","citation_count":21,"is_preprint":false},{"pmid":"24706375","id":"PMC_24706375","title":"Targeted delivery of curcumin to tumors via PEG-derivatized FTS-based micellar system.","date":"2014","source":"The AAPS journal","url":"https://pubmed.ncbi.nlm.nih.gov/24706375","citation_count":21,"is_preprint":false},{"pmid":"24022875","id":"PMC_24022875","title":"Genetic variant of AKT1 and AKTIP associated with late-onset depression in a Brazilian population.","date":"2013","source":"International journal of geriatric 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RNAi-mediated depletion causes telomere dysfunction foci (TIFs), S-phase arrest via intra-S checkpoint activation, and (in p53-/- MEFs) multiple telomeric signals (MTS) and sister telomere associations (STAs). Epistasis with TRF1 for MTS formation and ChIP showing reduced TRF1 binding at telomeres in AKTIP-depleted S-phase cells together indicate AKTIP works in concert with TRF1 to facilitate telomeric DNA replication.\",\n      \"method\": \"Co-IP, pulldown (in vitro), ChIP, RNAi knockdown, immunofluorescence (TIF assay), FACS cell-cycle analysis, genetic epistasis (double mutant MTS quantification)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (in vitro binding, ChIP, TIF assay, epistasis, cell-cycle phenotype) in a single rigorous study\",\n      \"pmids\": [\"26110528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AKTIP biochemically interacts with A- and B-type lamins (co-IP), localizes at the nuclear rim and nucleoplasm overlapping with lamin B1 and lamin A/C in interphase, and is enriched at spindle poles and the midbody in mitosis. Proper AKTIP localization requires functional lamin A. AKTIP depletion induces senescence-associated markers and a progeroid-like phenotype, and affects lamin A (but not lamin C or B) expression.\",\n      \"method\": \"Co-IP, double immunostaining/co-localization, siRNA knockdown, senescence marker assays, fractionation\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus direct localization with functional consequence (senescence phenotype) replicated with multiple methods in one study\",\n      \"pmids\": [\"27512140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During mitosis AKTIP localizes to the midbody and interacts with the ESCRT I subunit VPS28. AKTIP forms a circular supra-structure at the midbody adjacent to ESCRT I (TSG101, VPS28) and ESCRT III subunits (CHMP2A, CHMP4B, IST1). Mechanistically, AKTIP recruitment to the midbody is dependent on MKLP1 and independent of CEP55. AKTIP and TSG101 are jointly required for recruitment of CHMP4B, and act in parallel for IST1 recruitment. AKTIP depletion alone impairs IST1 recruitment and causes multinucleation, establishing AKTIP as an ESCRT I component required for abscission.\",\n      \"method\": \"Co-IP, super-resolution/confocal immunofluorescence, siRNA knockdown (single and double), multinucleation assay, epistasis analysis of ESCRT subunit recruitment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal co-IP, super-resolution localization, genetic epistasis of ESCRT subunit recruitment, functional abscission readout; multiple orthogonal methods\",\n      \"pmids\": [\"34449766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AKTIP is phosphorylated by TLK1 at residues T22 and S237. Phosphorylated AKTIP enhances the association of AKT with PDK1, leading to increased AKT phosphorylation at T308 and S473. TLK1 inhibition reduces AKT phosphorylation, which is potentiated by concurrent AKTIP knockdown, placing AKTIP in a TLK1→AKTIP→AKT signaling axis in prostate cancer cells.\",\n      \"method\": \"Interactome/phosphoproteomic mass spectrometry, co-IP, siRNA knockdown, phospho-specific western blot, TLK1 inhibitor (J54) treatment\",\n      \"journal\": \"Pathophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and phospho-western in a single lab; phosphorylation sites identified by MS but functional rescue not fully reconstituted\",\n      \"pmids\": [\"35366279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AKTIP loss in ERα-positive breast cancer cells stabilizes ERα protein by a mechanism involving CAND1-mediated protection from cullin 2-dependent proteasomal degradation, and concurrently activates JAK2-STAT3 signaling as an alternative survival pathway. AKTIP-depleted cells show resistance to ERα antagonists that can be overcome by co-inhibition of JAK2/STAT3.\",\n      \"method\": \"siRNA/shRNA knockdown, co-IP, proteasome inhibitor rescue, western blot, ERα reporter assay, patient-derived organoids, pharmacological inhibition\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study; mechanistic pathway (CAND1/cullin 2/ERα and JAK2-STAT3) supported by biochemical and functional data\",\n      \"pmids\": [\"36516775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AKTIP co-localizes with lamin A/C at the nuclear rim in HeLa cells; this co-localization is reduced in MCF7 and A549 tumor cells. AKTIP mislocalizes in HGPS (progerin-expressing) cells but not EDMD2 cells, and exogenous progerin expression in HeLa cells also mislocalizes AKTIP, indicating that nuclear morphology (not lamin expression alone) governs AKTIP positioning.\",\n      \"method\": \"Super-resolution imaging, quantitative co-localization analysis, exogenous progerin expression, lamin quantification, nuclear morphology analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct super-resolution localization with functional genetic manipulation (progerin); single lab but multiple cell models\",\n      \"pmids\": [\"36096808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-106a-5p directly binds the 3'-UTR of AKTIP mRNA (validated by dual luciferase reporter assay), suppressing AKTIP expression and thereby activating the PI3K/AKT/mTOR pathway to promote laryngeal carcinoma cell proliferation and migration.\",\n      \"method\": \"Dual luciferase reporter assay, miRNA inhibitor, western blot (pathway readouts), clonogenic and migration assays\",\n      \"journal\": \"Iranian journal of biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic depth beyond 3'-UTR binding and pathway activation readout\",\n      \"pmids\": [\"36811106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKTIP is a UEV-domain shelterin-interacting protein that facilitates telomeric DNA replication by cooperating with TRF1, interacts with lamins to maintain nuclear architecture, functions as an ESCRT I component at the midbody by binding VPS28 and orchestrating recruitment of ESCRT III subunits (CHMP4B, IST1) for abscission, and is phosphorylated by TLK1 to promote AKT activation via PDK1; in ERα-positive breast cancer, AKTIP loss stabilizes ERα through a CAND1/cullin 2 axis and activates JAK2-STAT3 as an alternative survival signal.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AKTIP is a UEV-domain protein that operates at the intersection of telomere maintenance, nuclear architecture, cytokinetic abscission, and AKT signaling. At telomeres, AKTIP binds shelterin components TRF1 and TRF2 as well as replication factors PCNA and RPA70, and cooperates with TRF1 to facilitate telomeric DNA replication during S phase; its depletion causes telomere dysfunction foci, replication-associated telomeric aberrations, and intra-S checkpoint activation [PMID:26110528]. AKTIP interacts with A- and B-type lamins at the nuclear envelope, requires functional lamin A for proper localization, and its mislocalization—as seen in progerin-expressing cells—links nuclear lamina integrity to AKTIP positioning [PMID:27512140, PMID:36096808]. During cytokinesis, AKTIP functions as an ESCRT I component at the midbody, where it is recruited in an MKLP1-dependent manner, binds VPS28, and cooperates with TSG101 to recruit ESCRT III subunits CHMP4B and IST1 for abscission; its depletion causes multinucleation [PMID:34449766].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"The question of whether AKTIP has a direct role at telomeres was answered by demonstrating that it physically binds shelterin (TRF1/TRF2), occupies telomeric chromatin, and is required for telomeric DNA replication, establishing it as a novel replication-facilitating telomere factor.\",\n      \"evidence\": \"Co-IP, in vitro pulldown, ChIP, RNAi, epistasis with TRF1 for MTS formation in MEFs\",\n      \"pmids\": [\"26110528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of AKTIP–TRF1 interaction unknown\",\n        \"Whether AKTIP participates in telomere replication through its UEV domain or another surface is unresolved\",\n        \"In vivo organismal consequences of telomere-specific AKTIP loss not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether AKTIP connects to nuclear architecture beyond telomeres was resolved by showing it interacts with A- and B-type lamins, localizes to the nuclear rim dependently on lamin A, and its loss induces senescence-associated phenotypes, linking AKTIP to nuclear envelope integrity.\",\n      \"evidence\": \"Co-IP with lamins, co-localization imaging, siRNA knockdown with senescence marker readouts\",\n      \"pmids\": [\"27512140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether lamin interaction and telomere function are mechanistically coupled is unclear\",\n        \"Direct binding domain on AKTIP for lamins not mapped\",\n        \"Whether AKTIP loss-induced senescence is telomere-driven or lamin-driven not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The long-standing observation that AKTIP localizes to the midbody was mechanistically resolved: AKTIP acts as an ESCRT I component that binds VPS28, is recruited by MKLP1 independently of CEP55, and cooperates with TSG101 to recruit ESCRT III subunits for cytokinetic abscission.\",\n      \"evidence\": \"Co-IP, super-resolution imaging, single and double siRNA knockdown with ESCRT subunit recruitment epistasis and multinucleation quantification\",\n      \"pmids\": [\"34449766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AKTIP replaces or supplements TSG101-VPS28 in canonical ESCRT I is unresolved\",\n        \"Stoichiometry and structure of AKTIP-containing ESCRT I complex not determined\",\n        \"Relationship between AKTIP's midbody and telomere functions during the cell cycle not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How AKTIP participates in AKT activation was clarified by identifying TLK1-mediated phosphorylation of AKTIP at T22 and S237, which enhances AKT–PDK1 association and AKT phosphorylation, placing AKTIP as a phospho-regulated scaffold in a TLK1→AKTIP→AKT axis.\",\n      \"evidence\": \"Phosphoproteomics, co-IP, TLK1 inhibitor and siRNA in prostate cancer cells\",\n      \"pmids\": [\"35366279\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional rescue with phospho-mimetic or phospho-dead AKTIP mutants not performed\",\n        \"Whether TLK1-AKTIP signaling operates in non-cancer contexts is untested\",\n        \"Direct binding interface between AKTIP and AKT/PDK1 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"AKTIP's role in cancer cell signaling was expanded by showing that its loss stabilizes ERα through a CAND1/cullin 2-dependent mechanism and activates JAK2-STAT3 as a compensatory survival pathway, conferring ERα-antagonist resistance in breast cancer.\",\n      \"evidence\": \"siRNA/shRNA, co-IP, proteasome inhibitor rescue, ERα reporter assay, patient-derived organoids, pharmacological JAK2/STAT3 inhibition\",\n      \"pmids\": [\"36516775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether AKTIP directly interacts with cullin 2 or CAND1 is not established\",\n        \"Mechanism by which AKTIP loss activates JAK2-STAT3 is indirect and not fully delineated\",\n        \"Generalizability beyond ERα-positive breast cancer unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The dependence of AKTIP localization on nuclear lamina integrity was refined by showing that progerin expression, but not EDMD2 lamin A mutations, mislocalizes AKTIP, indicating nuclear morphology rather than lamin expression level dictates AKTIP positioning.\",\n      \"evidence\": \"Super-resolution imaging and quantitative co-localization in HGPS, EDMD2, tumor, and progerin-transfected cells\",\n      \"pmids\": [\"36096808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of AKTIP mislocalization on telomere or ESCRT functions in laminopathy cells not tested\",\n        \"Whether AKTIP mislocalization in tumor cells contributes to genome instability is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model explaining how AKTIP's telomere replication, nuclear lamina, ESCRT I/abscission, and AKT signaling functions are coordinated across the cell cycle remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data for AKTIP in any of its functional complexes\",\n        \"How the UEV domain contributes to each distinct function is not dissected\",\n        \"Whether AKTIP's separate roles are independent or mechanistically linked is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"ESCRT I (midbody)\",\n      \"Shelterin-associated complex\"\n    ],\n    \"partners\": [\n      \"TRF1\",\n      \"TRF2\",\n      \"VPS28\",\n      \"LMNA\",\n      \"LMNB1\",\n      \"TSG101\",\n      \"PCNA\",\n      \"TLK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}