{"gene":"TACC3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2000,"finding":"Maskin (TACC3 Xenopus ortholog) binds eIF4E and interacts with CPEB; this maskin-eIF4E interaction blocks eIF4G association with eIF4E, repressing translation of CPE-containing mRNAs such as cyclin B1 at the mitotic apparatus. CPEB also interacts with microtubules and is involved in localizing cyclin B1 mRNA to the mitotic apparatus.","method":"Co-immunoprecipitation, antibody injection assays, mRNA reporter injection, in situ localization in Xenopus embryos","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, antibody/mRNA injection functional assays, replicated across multiple experimental approaches in one study","pmids":["11081630"],"is_preprint":false},{"year":2002,"finding":"Maskin (TACC3 Xenopus ortholog) prevents oocyte maturation and translation of CPE-containing cyclin B1 mRNA by blocking eIF4G association with eIF4E. Dissociation of the maskin-eIF4E complex requires both cytoplasmic polyadenylation and poly(A)-binding protein (PABP), which binds eIF4G to displace maskin from eIF4E.","method":"Antibody injection, mRNA reporter injection, biochemical binding assays in Xenopus oocytes","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (antibody injection, mRNA reporter), mechanistic dissection of complex dissociation","pmids":["12110596"],"is_preprint":false},{"year":2005,"finding":"Aurora A (Eg2) phosphorylates maskin/TACC3 on a conserved serine residue; this phosphorylation regulates maskin localization to centrosomes and function in microtubule assembly during M-phase. Maskin interacts with XMAP215 and Aurora A kinase in vitro and in egg extracts.","method":"In vitro kinase assay, co-immunoprecipitation from egg extracts, depletion/reconstitution experiments in Xenopus egg extracts","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, reciprocal Co-IP, depletion/add-back reconstitution, replicated by multiple labs","pmids":["16172207"],"is_preprint":false},{"year":2005,"finding":"TACC3 (Xenopus) forms a one-to-one complex with XMAP215 and enhances XMAP215's microtubule-stabilizing activity in vitro. TACC3 increases the number of microtubules emanating from mitotic centrosomes, and its centrosomal targeting is regulated by Aurora A-dependent phosphorylation.","method":"Purified protein reconstitution, in vitro microtubule assay, Xenopus laevis egg extracts, Aurora A kinase assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, in vitro kinase assay, egg extract functional experiments; replicated across labs","pmids":["16172205"],"is_preprint":false},{"year":2005,"finding":"Maskin (TACC3) interacts with XMAP215 in Xenopus egg extracts; maskin depletion results in mislocalization of XMAP215 but not CPEB, demonstrating that maskin is required for XMAP215 centrosome/spindle localization. Maskin is required for two distinct steps of spindle assembly and microtubule aster formation.","method":"Immunodepletion, add-back reconstitution, in vitro spindle assembly assay in Xenopus egg extracts, co-immunoprecipitation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — immunodepletion with reconstitution, Co-IP, multiple orthogonal readouts, replicated across labs","pmids":["15788567"],"is_preprint":false},{"year":2005,"finding":"Aurora A phosphorylates maskin (TACC3) on a conserved serine (Ser626 in Xenopus) in vitro and in vivo; inhibition of this phosphorylation by microinjection of phospho-mimicking peptides causes premature synthesis of meiosis II proteins (cyclin B1, Cdc6) during meiosis I, indicating maskin phosphorylation by Aurora A controls sequential protein synthesis during oocyte maturation.","method":"Two-hybrid screen (interaction identification), in vitro kinase assay, co-immunoprecipitation from oocyte extracts, microinjection of synthetic peptides, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, co-IP, functional microinjection rescue/inhibition experiments","pmids":["15687499"],"is_preprint":false},{"year":2005,"finding":"Maskin (TACC3) undergoes multiple CDK1-dependent phosphorylation events (at T58, S152, S311, S343, S453, S638) during oocyte maturation; mutation of these sites to alanine prevents CDK1-induced dissociation of maskin from eIF4E. Separately, Maskin is phosphorylated on S626 by protein kinase A prior to maturation, which is required for its localization on the mitotic apparatus in somatic cells but does not affect translation during oocyte maturation.","method":"Mass spectrometry phosphosite mapping, site-directed mutagenesis, co-immunoprecipitation, in vitro kinase assay, localization studies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphosite mutagenesis combined with Co-IP and in vitro kinase assays, multiple orthogonal methods","pmids":["16107707"],"is_preprint":false},{"year":2006,"finding":"CDK1 phosphorylation promotes maskin (TACC3) dissociation from eIF4E, while the phosphatase calcineurin reverses this. This phosphorylation-dephosphorylation cycle oscillates with the cell cycle and controls maskin-eIF4E interaction and, consequently, cyclin B1 mRNA translation during early Xenopus cell cycles.","method":"In vitro kinase/phosphatase assays, co-immunoprecipitation, cell-free translation assays in Xenopus embryo extracts","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase/phosphatase assays, Co-IP, translational readout, mechanistically complete dissection","pmids":["17086181"],"is_preprint":false},{"year":2006,"finding":"NDEL1 is required for centrosome targeting of TACC3 through direct interaction with TACC3. Aurora A phosphorylates NDEL1 at Ser251, and expression of Aurora A phosphorylation-mimetic NDEL1 mutants rescues centrosomal maturation and separation defects caused by Aurora A depletion, including TACC3 recruitment.","method":"Co-immunoprecipitation, siRNA knockdown, phospho-mutant overexpression, immunofluorescence in mouse cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phospho-mutant rescue, single lab, mechanistic chain from Aurora A to NDEL1 to TACC3","pmids":["17060449"],"is_preprint":false},{"year":2007,"finding":"Human TACC3 Ser558 is phosphorylated by Aurora A kinase; this phosphorylation is essential for TACC3 localization to centrosomes and proximal mitotic spindles in human cells. Inhibition of Aurora A with MLN8054 causes dose-dependent mislocalization of TACC3 away from mitotic spindles.","method":"In vitro kinase assay, site-directed mutagenesis, immunofluorescence, Aurora A small-molecule inhibitor treatment, in vivo tumor xenograft pharmacodynamic studies","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay with mutagenesis, pharmacological inhibition, in vivo validation, multiple independent methods","pmids":["17545617"],"is_preprint":false},{"year":2004,"finding":"TACC3 interacts with FOG-1 (Friend of GATA-1) and controls FOG-1 nuclear localization. High levels of TACC3 inhibit FOG-1 function as a transcriptional cofactor of GATA-1. GATA-1 competes with TACC3 for interaction with FOG-1. Forced TACC3 overexpression delays terminal erythroid maturation.","method":"Co-immunoprecipitation, overexpression/knockdown in MEL and G1ER cells, nuclear/cytoplasmic fractionation, erythroid differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction, functional overexpression effects on differentiation, single lab","pmids":["15037632"],"is_preprint":false},{"year":2006,"finding":"TACC3 forms a complex in vivo with MBD2 and the histone acetyltransferase pCAF. The TACC3/pCAF-containing MBD2 complex and the HDAC2-containing MBD2 complex are mutually exclusive. HAT activity associates with MBD2 in vivo and increases when TACC3 is overexpressed. TACC3 can reactivate transcription from MBD2-repressed methylated promoters by favoring formation of an HAT-containing MBD2 complex.","method":"Co-immunoprecipitation, HAT enzymatic assay, reporter gene assay, overexpression","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro HAT activity assay, single lab with two orthogonal methods","pmids":["16410616"],"is_preprint":false},{"year":2008,"finding":"Maskin (TACC3) is required for microtubule anchoring at the centrosome but not for regulating microtubule dynamics per se (dynamics were unaffected by maskin depletion in time-lapse experiments). The conserved C-terminal TACC domain is necessary and sufficient for centrosome function; the N-terminus inhibits TACC domain function.","method":"Xenopus egg extract immunodepletion, in vitro aster assembly assay, time-lapse video microscopy, domain add-back reconstitution","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — depletion/reconstitution with domain mapping, live imaging, multiple orthogonal experiments in a single study","pmids":["18508920"],"is_preprint":false},{"year":2009,"finding":"Cdh1, an activator of APC/C, interacts with TACC3 and controls TACC3 protein stability during mitotic exit. Depletion of Cdh1 prolonged TACC3 protein levels; alteration of Cdh1 levels correlated with changes in ubiquitinated TACC3. Multiple domains of TACC3 are involved in Cdh1-regulated degradation.","method":"Yeast two-hybrid screen, co-immunoprecipitation (in vitro and in vivo), siRNA knockdown, ubiquitination assay, domain mapping","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, domain mapping, single lab","pmids":["19823035"],"is_preprint":false},{"year":2010,"finding":"Clathrin heavy chain (CHC) acts as an adaptor that binds Aurora A-phosphorylated TACC3 (pSer558) and recruits it to the mitotic spindle for microtubule stabilization. CHC binds phospho-S558 TACC3 via its linker domain and first CHC repeat. Depletion of CHC abolishes TACC3 spindle relocalization and causes loss of ch-TOG on spindles, disorganized spindles, and chromosome misalignment.","method":"Co-immunoprecipitation, siRNA knockdown, phospho-mutant analysis, immunofluorescence, domain mapping","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, phospho-mutant functional validation, domain mapping, RNAi phenotype; replicated by independent lab (Fu et al. 2010)","pmids":["20566684"],"is_preprint":false},{"year":2010,"finding":"Clathrin heavy chain (CHC) specifically binds phosphorylated TACC3 (at Ser620 and Ser626 in Xenopus; not Ser33) and recruits it to spindle poles. This CHC-phospho-TACC3 interaction is inhibited by importin β and reversed by RanGTP, linking spindle assembly to Ran gradient signaling.","method":"Co-immunoprecipitation, RNAi knockdown, phospho-mutant analysis, Ran/importin-β biochemical assays, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with phospho-mutant specificity, biochemical competition assay with Ran/importin-β, multiple orthogonal methods","pmids":["20923838"],"is_preprint":false},{"year":2010,"finding":"Integrin-linked kinase (ILK) is required for centrosome clustering in cancer cells with supernumerary centrosomes. ILK performs its centrosome clustering activity through TACC3 and ch-TOG. A specific TACC3 phosphorylation site is required for centrosome clustering, and ILK regulates this TACC3 phosphorylation in an Aurora-A-dependent manner.","method":"siRNA knockdown, ILK inhibitors, live-cell imaging, immunofluorescence, phospho-mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional epistasis (ILK→Aurora A→TACC3 phosphorylation→centrosome clustering), single lab, multiple cell lines","pmids":["20838383"],"is_preprint":false},{"year":2010,"finding":"TACC3 and TSC2 co-localize and co-purify with nuclear envelope components. TACC3 is necessary for proper localization of phospho-Ser939 TSC2 at spindle poles and cytokinetic bridges. TSC2 acts epistatically to TACC3 in regulating cell division. Loss of TACC3 or TSC2 causes nuclear envelope morphological alterations, abscission defects, and increased binucleated cells.","method":"Co-immunoprecipitation/interactome mapping, subcellular fractionation, immunofluorescence, siRNA knockdown, epistasis analysis, electron microscopy","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interactome, localization, epistasis by double knockdown; single lab, multiple methods","pmids":["20237422"],"is_preprint":false},{"year":2011,"finding":"TACC3, ch-TOG, and clathrin form a trimeric complex at kinetochore fibers (K-fibers). The complex is anchored to the spindle by TACC3 and ch-TOG. Clathrin depletion and TACC3 depletion both cause selective loss of short inter-microtubule bridges in K-fibers and general MT loss. Immunogold labeling confirmed clathrin is present at inter-MT bridges in K-fibers.","method":"Co-immunoprecipitation, siRNA knockdown, electron microscopy ultrastructural analysis, immunogold labeling","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ultrastructural EM with immunogold, Co-IP, RNAi depletion; multiple orthogonal high-resolution methods","pmids":["21297582"],"is_preprint":false},{"year":2012,"finding":"DOCK7 interacts with TACC3 and antagonizes TACC3's microtubule growth-promoting function at centrosomes. DOCK7 silencing impedes neuronal differentiation and maintains cells as cycling progenitors; DOCK7 overexpression promotes differentiation. DOCK7 controls interkinetic nuclear migration of radial glial progenitors by opposing TACC3 centrosomal activity.","method":"Co-immunoprecipitation, in utero electroporation (gain/loss of function), immunofluorescence, live imaging in developing mouse cortex","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo epistasis by co-expression/knockdown, single lab","pmids":["22842144"],"is_preprint":false},{"year":2013,"finding":"Within the TACC3-ch-TOG-clathrin complex, TACC3 and clathrin are interdependent for spindle recruitment—each requires the other to be present to bind the spindle. The N-terminal domain of clathrin and the TACC domain of TACC3 together form a microtubule-interaction surface, coordinated by TACC3-clathrin binding mediated through a dileucine motif and Aurora A-phosphorylated Ser558 on TACC3 binding to the 'ankle' of clathrin. A stutter in the TACC3 coiled-coil interacts with a novel sixth TOG domain of ch-TOG required for ch-TOG microtubule localization.","method":"Domain mapping, co-immunoprecipitation, microtubule cosedimentation assay, NMR structural characterization, mutagenesis, cell-based localization assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — NMR, mutagenesis, Co-IP, microtubule binding assay, multiple orthogonal methods in one study","pmids":["23918938"],"is_preprint":false},{"year":2013,"finding":"The TACC domain of TACC3 contains two functionally distinct subdomains: CC1 (aa 414–530) mediates interaction with chTOG, while CC2 (aa 530–630) performs an intradomain interaction with the central repeat region of TACC3 that masks the TACC domain before effector binding. Aurora A kinase does not regulate TACC3-chTOG complex formation per se, but functions as a recruitment factor for the complex to centrosomes/proximal spindles.","method":"Purified recombinant protein biochemistry, gel filtration, analytical ultracentrifugation, in vitro binding assays, domain deletion/truncation mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro with purified proteins, multiple biophysical methods, domain mutagenesis; single lab","pmids":["24273164"],"is_preprint":false},{"year":2013,"finding":"TACC3 is essential for kinetochore capture during spindle assembly. TACC3-associated acentrosomal microtubule asters form near kinetochores and bind kinetochores as an initial capture step; sorting of these asters with centrosomal microtubules then leads to capture by centrosomal microtubules from both poles.","method":"siRNA knockdown, live-cell imaging, nocodazole washout experiments, immunofluorescence in HeLa cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with live imaging and multiple readouts, single lab","pmids":["24003142"],"is_preprint":false},{"year":2013,"finding":"Aurora A kinase activity is required for localization of the TACC3/ch-TOG/clathrin complex to K-fibers. Inhibition of Aurora A with MLN8237 results in loss of clathrin and TACC3 from spindles, destabilization of K-fibers, and loss of inter-MT bridges, phenocopying TACC3 or clathrin depletion.","method":"Aurora A small-molecule inhibition (MLN8237), immunofluorescence, electron microscopy of K-fibers","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological inhibition with EM and IF readouts, single lab, mechanistically confirmatory","pmids":["21966557"],"is_preprint":false},{"year":2013,"finding":"Aurora A kinase activity is required for central spindle assembly during anaphase; TACC3 is identified as an Aurora A substrate essential for this process. Inhibiting Aurora A after bipolar spindle formation specifically disrupts central spindle (anaphase) assembly.","method":"Aurora A inhibitor treatment in anaphase cells, siRNA knockdown, immunofluorescence in Xenopus and human cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological and genetic inhibition, single lab, temporal control of inhibition","pmids":["23887685"],"is_preprint":false},{"year":2013,"finding":"Rapid removal of the TACC3-ch-TOG-clathrin complex from K-fibers at metaphase (using knocksideways) reduces kinetochore fiber tension and prevents spindle checkpoint satisfaction without causing significant loss of K-fiber microtubules, distinguishing a maintenance role in tension generation from a structural role in MT number.","method":"Knocksideways (rapid inducible protein relocalization), FRET-based tension measurements, immunofluorescence, live imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — acute inducible removal with defined temporal control, kinetochore tension measurement, multiple readouts; single lab with rigorous approach","pmids":["23532825"],"is_preprint":false},{"year":2014,"finding":"TACC3 promotes microtubule nucleation at centrosomes and facilitates γ-tubulin ring complex (γ-TuRC) assembly. TACC3 mediates interactions with both γ-TuRC and γ-TuSC proteins. TACC3 depletion reduces γ-TuRC levels and increases γ-TuSC levels, indicating TACC3 is required for γ-TuRC assembly from γ-TuSC components. The TACC domain of TACC3 has intrinsic microtubule nucleating activity.","method":"siRNA knockdown, co-immunoprecipitation, microtubule sedimentation assay, immunofluorescence, recombinant TACC domain microtubule nucleation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro nucleation assay with recombinant protein, Co-IP, sedimentation, loss-of-function; multiple orthogonal methods single lab","pmids":["25246530"],"is_preprint":false},{"year":2014,"finding":"TACC3 functions as a microtubule plus end-tracking protein (+TIP) in multiple embryonic cell types via its conserved C-terminal TACC domain. TACC3 localizes distal to EB1 and directly overlaps with XMAP215 at plus ends. TACC3 promotes axon outgrowth by increasing microtubule plus end velocities. TACC3 also regulates XMAP215 stability and localizes XMAP215 to microtubule plus ends.","method":"Live fluorescence imaging with tagged +TIPs, morpholino knockdown/overexpression in Xenopus, domain truncation analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with multiple +TIP markers, loss/gain of function, domain analysis; single lab","pmids":["25187649"],"is_preprint":false},{"year":2014,"finding":"APC/C(CDH1) ubiquitin ligase mediates SNIPER(TACC3)-induced polyubiquitylation and proteasomal degradation of TACC3. This provides a mechanism for cell-cycle-regulated TACC3 turnover via ubiquitin-proteasome pathway.","method":"Mechanistic analysis with small molecule SNIPER(TACC3), ubiquitination assay, proteasome inhibitor rescue, CDH1-knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination assay, genetic knockdown of E3 ligase activator, chemical biology approach; single lab","pmids":["25375378"],"is_preprint":false},{"year":2015,"finding":"TACC3 contains a hydrophobic motif centered on F525 that docks to a previously uncharacterized pocket on Aurora A, potently activating Aurora A. Cells carrying homozygous F525A mutation show perturbed TACC3 localization, reduced Ser558 phosphorylation, weakened clathrin interaction, and markedly shorter mitosis due to rapid spindle assembly, without chromosome missegregation. By contrast, S558A mutation causes aneuploidy without major change in mitotic duration.","method":"Endogenous TACC3 knock-in mutagenesis (F525A, S558A), biochemical Aurora A activation assay, co-immunoprecipitation, immunofluorescence, time-lapse imaging","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — endogenous knock-in mutagenesis, in vitro Aurora A activation assay, Co-IP, live imaging; multiple orthogonal methods, single lab but rigorous","pmids":["26134678"],"is_preprint":false},{"year":2015,"finding":"TACC3-ch-TOG can track microtubule plus ends independently of clathrin and Aurora A-dependent Ser558 phosphorylation or EB1/EB3. This Aurora A/clathrin-independent pool is defined by the direct TACC3-ch-TOG interaction and is distinct from the TACC3-ch-TOG-clathrin spindle pool.","method":"Live fluorescence imaging, co-immunoprecipitation, siRNA knockdown, domain mapping","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging of endogenous-tagged proteins, Co-IP, domain analysis; single lab","pmids":["25596274"],"is_preprint":false},{"year":2018,"finding":"Aurora A recruits TACC3 to the mitotic spindle through a phospho-dependent three-motif mechanism: (1) a hydrophobic docking motif binds a novel pocket on Aurora A; (2) phosphorylation of Ser558 induces a conformational switch from disordered to helical in a second motif; (3) the resulting helix extends into a third motif recognized by the ankle helical-repeat region of clathrin heavy chain. Abrogation of the docking motif causes a delay in late mitosis.","method":"Crystal structure, NMR, mutagenesis, cell-based localization assays, mitotic timing assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + NMR + mutagenesis + functional cell biology; multiple orthogonal methods in one rigorous study","pmids":["29510984"],"is_preprint":false},{"year":2019,"finding":"Aurora A-specific phosphorylation of TACC3 at Ser558 regulates astral microtubule formation by stabilizing γ-TuRC assembly at spindle poles. S558A mutation causes loss of astral MTs and disrupts γ-TuRC protein localization at poles; S558D (phospho-mimetic) retains astral MTs and γ-TuRC proteins. Ser558-phosphorylated TACC3 physically interacts with γ-TuRC proteins, and S558A impairs this interaction.","method":"Phospho-mutant overexpression (S558A, S558D), co-immunoprecipitation with γ-TuRC proteins, immunofluorescence, time-lapse imaging","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-mutant analysis, Co-IP, live imaging; single lab, multiple methods","pmids":["31823729"],"is_preprint":false},{"year":2010,"finding":"Tacc3 binds to the intracellular domain of all Notch receptor family members via CDC10/Ankyrin repeats, co-localizes with Notch3 ICD in mammary tissue, and acts as a negative regulator of Notch signaling. Knockdown of Tacc3 upregulates the Notch target gene Hey2. Notch4/Int3 ICD-Tacc3 interaction inhibits transcription from a Hes1-Luciferase reporter, reversed by increasing Rbpj.","method":"Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, dual-label immunofluorescence, siRNA knockdown, reporter gene assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of endogenous proteins, reporter assay, knockdown phenotype; single lab","pmids":["20804727"],"is_preprint":false},{"year":2017,"finding":"In FGFR3-TACC3 (FT3) fusion-positive bladder cancer cells, the FT3 fusion protein is not localized to the mitotic spindle; instead, via its TACC domain, FT3 sequesters endogenous TACC3 away from the spindle, reducing spindle TACC3 levels. This depletion causes mitotic defects (chromosome segregation errors). Knockdown of the fusion gene or overexpression of TACC3 partially rescues these defects. FGFR3 kinase inhibition does not rescue spindle TACC3 levels, confirming the mechanism is TACC3-dominant rather than FGFR3 signaling-dependent.","method":"Immunofluorescence, siRNA knockdown of fusion gene, TACC3 overexpression rescue, FGFR3 inhibitor treatment, chromosome segregation assay in bladder cancer cell lines","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological epistasis experiments, single lab, several orthogonal approaches","pmids":["28855393"],"is_preprint":false},{"year":2021,"finding":"TACC3 and clathrin are core members of the mitotic spindle complex; chTOG and GTSE1 are ancillary—chTOG binds TACC3 and GTSE1 binds clathrin, but chTOG and GTSE1 do not interact with each other. PIK3C2A, previously proposed to stabilize the complex, is not a member. This was established using induced relocalization of endogenous CRISPR-tagged complex members.","method":"CRISPR/Cas9 knock-in tagging, induced relocalization (knocksideways) of endogenous proteins, co-relocalization assay, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous protein tagging by CRISPR, systematic induced relocalization to map all interactions, rigorous negative controls for PIK3C2A","pmids":["33380489"],"is_preprint":false},{"year":2018,"finding":"The oncogenic activity of FGFR3-TACC3 requires entrance to the secretory pathway or plasma membrane localization; nuclear-targeted or signal-sequence-deleted FGFR3-TACC3 lacks oncogenic activity. FGFR3-TACC3 transformation is not affected by its interactions with Aurora-A, clathrin, or ch-TOG. FGFR3 kinase activity (K508R abrogates) is essential for transformation; the TACC3 domain drives nuclear localization of the fusion.","method":"Subcellular localization targeting constructs (NLS, myristylation signal, signal sequence deletion), focus formation assay, IL-3 independent proliferation, Western blot signaling analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple localization-altering constructs with functional readouts, kinase-dead mutagenesis; single lab","pmids":["30344944"],"is_preprint":false},{"year":2016,"finding":"The coiled-coil TACC3 domain in FGFR3-TACC3 leads to constitutive phosphorylation of key activating FGFR3 tyrosine residues (shown by TiO2-LC-MS/MS phosphoproteomics). FGFR3-TACC3 causes increased FGFR3 activation, altered phosphorylation, MAPK pathway activation, nuclear localization, and cellular transformation. The TACC3 domain alone drives nuclear localization; FGFR3 kinase activity is required for transformation (K508R mutation abrogates it). Phosphorylated tyrosines in the TACC3-derived portion are not critical for activity.","method":"TiO2-LC-MS/MS phosphopeptide enrichment, kinase-dead mutagenesis, focus formation assay, Western blot, nuclear localization assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry phosphoproteomics, kinase-dead mutagenesis, functional transformation assay; single lab","pmids":["26869289"],"is_preprint":false},{"year":2018,"finding":"The FGFR3-TACC3 fusion activates oxidative phosphorylation and mitochondrial biogenesis via phosphorylation of PIN4 as an intermediate signaling step. The F3-T3-PIN4 axis triggers peroxisome biogenesis and new protein synthesis; this anabolic response converges on PGC1α through intracellular ROS production, enabling mitochondrial respiration and tumor growth.","method":"Transcriptional subgroup analysis, phosphoproteomics, metabolic flux assays, organelle biogenesis assays, ROS measurement, in vivo tumor growth assays","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics identifying PIN4, multiple functional metabolic assays; single lab, complex mechanistic chain","pmids":["29323298"],"is_preprint":false},{"year":2022,"finding":"The FGFR3-TACC3 fusion protein is a client of HSP90, forming a ternary complex with CDC37. Deprivation of HSP90 or CDC37 disrupts this ternary complex, destabilizes glycosylated FGFR3-TACC3, and suppresses its oncogenic activity. HSP90 inhibitors sensitize FGFR3-TACC3-positive glioma cells to temozolomide.","method":"Co-immunoprecipitation of HSP90/CDC37/F3T3, HSP90 inhibitor treatment, CDC37 knockdown, cell viability assays, glycosylation analysis","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of ternary complex, genetic and pharmacological perturbation, single lab","pmids":["35151844"],"is_preprint":false},{"year":2020,"finding":"TACC3 promotes prostate cancer cell proliferation and restrains primary cilium formation. TACC3 interacts with filamin A; elevated TACC3 disrupts the filamin A-meckelin interaction, thereby restraining primary cilium formation.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, in vitro and in vivo proliferation assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifying filamin A interaction, functional knockdown phenotypes, single lab","pmids":["32156598"],"is_preprint":false},{"year":2021,"finding":"The 5' UTR of Tacc3 mRNA contains upstream open reading frames (uORFs) that direct P-eIF2α-dependent translation, enabling preferential Tacc3 protein synthesis under conditions of elevated eIF2α phosphorylation. TACC3-deficient satellite cells exhibit defects in expansion, self-renewal, and skeletal muscle regeneration.","method":"Transcriptomics, quantitative proteomics, 5' UTR reporter assays, sal003 pharmacological treatment, TACC3 conditional knockout in satellite cells","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — uORF reporter assay, proteomics, conditional KO phenotype; single lab, multiple methods","pmids":["33318147"],"is_preprint":false},{"year":2023,"finding":"TACC3 forms distinct functional interactomes in mitosis and interphase in cancer cells with centrosome amplification. In mitosis, TACC3 interacts with KIFC1 (a kinesin) to cluster extra centrosomes; disrupting this interaction causes multipolar spindle formation and mitotic cell death. In interphase, TACC3 interacts with the NuRD complex (HDAC2 and MBD2) in the nucleus to suppress expression of tumor suppressors (p21, p16, APAF1), driving G1/S progression. FOXM1 drives upregulation of TACC3 and KIFC1 in response to p53 loss/centrosome amplification.","method":"Co-immunoprecipitation, proximity ligation assay, siRNA/CRISPR knockdown, ChIP, qRT-PCR, immunofluorescence, organoid and PDX tumor models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IP interactions, chromatin-IP, distinct mitotic/interphase phenotypes, organoid and in vivo PDX validation; multiple orthogonal methods single lab","pmids":["36864125"],"is_preprint":false},{"year":2018,"finding":"TACC3 inhibition in T-DM1-resistant HER2+ breast cancer cells restores spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD). TACC3 overexpression in resistant cells abolishes SAC activation and ICD markers. In vivo, TACC3 inhibition elicited ICD and enhanced T-DM1 antitumor activity by inducing dendritic cell maturation and increasing intratumoral cytotoxic T cells.","method":"TACC3 siRNA/inhibitor, flow cytometry (calreticulin, ATP, HMGB1 release), vaccination assay, in vivo tumor models with immune profiling","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological inhibition, multiple ICD markers, in vivo immune functional assays; single lab","pmids":["38319231"],"is_preprint":false},{"year":2018,"finding":"HURP directly interacts with TACC3 (mapped to HURP residues 1–625) in vivo and in vitro. HURP is required for TACC3 function during kinetochore microtubule assembly at the chromosome region in prometaphase; HURP modulates stable lateral kinetochore attachment and chromosome congression through TACC3.","method":"Co-immunoprecipitation, bimolecular fluorescence complementation, siRNA knockdown, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, BiFC, RNAi functional analysis; single lab","pmids":["30054275"],"is_preprint":false}],"current_model":"TACC3 is a centrosomal/spindle-associated protein that is phosphorylated by Aurora A kinase at Ser558 (human), which induces a conformational switch enabling TACC3 to bind clathrin heavy chain; together with ch-TOG, the resulting TACC3–ch-TOG–clathrin trimeric complex crosslinks adjacent microtubules in kinetochore fibers to maintain spindle stability and kinetochore tension, while a separate Aurora A/clathrin-independent TACC3–ch-TOG pool tracks microtubule plus ends to promote polymerization; TACC3 also stabilizes γ-TuRC assembly at centrosomes to regulate astral microtubule nucleation, interacts with multiple nuclear partners (FOG-1, MBD2/pCAF, NuRD complex, Notch ICDs) to control transcription and hematopoietic/erythroid differentiation, and its protein levels are regulated by APC/C(CDH1)-mediated ubiquitin-proteasome degradation during mitotic exit."},"narrative":{"mechanistic_narrative":"TACC3 is a centrosome- and spindle-associated coiled-coil protein that organizes mitotic microtubule architecture downstream of Aurora A kinase, and additionally moonlights as a nuclear transcriptional regulator and translational repressor [PMID:16172205, PMID:17545617, PMID:36864125]. Its central activity in mitosis is governed by Aurora A: TACC3 docks onto a pocket on Aurora A via a hydrophobic motif centered on F525, potently activating the kinase, which in turn phosphorylates human TACC3 at Ser558 [PMID:26134678, PMID:29510984]. This phosphorylation drives a disordered-to-helical conformational switch that creates a binding surface for the ankle region of clathrin heavy chain, recruiting TACC3 to the mitotic spindle [PMID:29510984, PMID:20566684]. There, TACC3, ch-TOG, and clathrin assemble into a complex that crosslinks microtubules within kinetochore fibers via inter-microtubule bridges, maintaining K-fiber tension and enabling spindle checkpoint satisfaction [PMID:21297582, PMID:23532825, PMID:33380489]. The TACC domain of TACC3 binds ch-TOG and possesses intrinsic microtubule-nucleating activity, and TACC3 facilitates γ-TuRC assembly at spindle poles to control astral microtubule nucleation in a Ser558-phosphorylation-dependent manner [PMID:24273164, PMID:25246530, PMID:31823729]. A distinct Aurora A/clathrin-independent TACC3–ch-TOG pool tracks microtubule plus ends together with XMAP215 to promote microtubule polymerization and axon outgrowth [PMID:25187649, PMID:25596274]. Originally characterized as the Xenopus protein Maskin, TACC3 represses translation of CPE-containing mRNAs such as cyclin B1 by binding eIF4E and blocking eIF4G, an interaction released by CDK1 phosphorylation during the cell cycle [PMID:11081630, PMID:12110596, PMID:17086181]. In the nucleus, TACC3 partners with FOG-1, an MBD2/pCAF acetyltransferase complex, the NuRD complex, and Notch intracellular domains to regulate transcription and differentiation [PMID:15037632, PMID:16410616, PMID:20804727, PMID:36864125]. TACC3 protein levels are controlled by APC/C(CDH1)-mediated ubiquitin-proteasome degradation during mitotic exit [PMID:19823035, PMID:25375378]. In cancer, the recurrent FGFR3-TACC3 fusion drives transformation through FGFR3 kinase activity and a TACC3-dominant sequestration of endogenous spindle TACC3, and TACC3 supports proliferation in centrosome-amplified tumors via KIFC1-dependent centrosome clustering and NuRD-mediated tumor-suppressor silencing [PMID:28855393, PMID:30344944, PMID:36864125].","teleology":[{"year":2000,"claim":"Established that the TACC3 ortholog Maskin couples mRNA translational control to the mitotic apparatus by repressing cyclin B1 translation, revealing a non-microtubule function.","evidence":"Co-IP, antibody/mRNA injection and in situ localization in Xenopus embryos","pmids":["11081630"],"confidence":"High","gaps":["Whether mammalian TACC3 retains this eIF4E-binding translational role was not addressed","Link between translational repression and spindle function unresolved"]},{"year":2002,"claim":"Defined how the Maskin-eIF4E repressive complex is dissolved, showing PABP binding to eIF4G displaces Maskin upon cytoplasmic polyadenylation.","evidence":"Antibody/mRNA injection and biochemical binding assays in Xenopus oocytes","pmids":["12110596"],"confidence":"High","gaps":["Cell-cycle timing of dissociation not yet integrated with kinase signaling"]},{"year":2005,"claim":"Identified Aurora A as the kinase phosphorylating TACC3/Maskin on a conserved serine and demonstrated this controls centrosomal targeting and XMAP215-dependent microtubule assembly, linking TACC3 to spindle organization.","evidence":"In vitro kinase assays, reciprocal Co-IP, immunodepletion/add-back and purified-protein reconstitution in Xenopus egg extracts","pmids":["16172207","16172205","15788567","15687499"],"confidence":"High","gaps":["Exact human phosphosite not yet mapped","How phosphorylation alters protein structure unknown"]},{"year":2006,"claim":"Resolved how CDK1 phosphorylation cycling, opposed by calcineurin/PKA, oscillates TACC3-eIF4E binding with the cell cycle, separating translational from localization functions.","evidence":"Phosphosite mapping by MS, site-directed mutagenesis, in vitro kinase/phosphatase and cell-free translation assays in Xenopus","pmids":["16107707","17086181"],"confidence":"High","gaps":["Conservation of CDK1-regulated eIF4E control in mammalian cells not established"]},{"year":2006,"claim":"Showed NDEL1 mediates Aurora A-dependent centrosome targeting of TACC3, placing TACC3 recruitment downstream of an Aurora A-NDEL1 axis.","evidence":"Co-IP, siRNA knockdown and phospho-mutant rescue in mouse cells","pmids":["17060449"],"confidence":"Medium","gaps":["Single lab","Direct vs indirect NDEL1-TACC3 contact not structurally defined"]},{"year":2007,"claim":"Mapped the human Aurora A phosphosite to Ser558 and established it as essential for TACC3 spindle/centrosome localization in human cells, providing a pharmacologically tractable handle.","evidence":"In vitro kinase assay, mutagenesis, Aurora A inhibitor (MLN8054) and xenograft pharmacodynamics","pmids":["17545617"],"confidence":"High","gaps":["Downstream effector of pSer558 not yet identified"]},{"year":2010,"claim":"Identified clathrin heavy chain as the phospho-Ser558 reader that recruits TACC3 (with ch-TOG) to the spindle, and showed this is gated by the Ran/importin-β gradient.","evidence":"Co-IP, phospho-mutant analysis, domain mapping and Ran/importin-β competition assays","pmids":["20566684","20923838"],"confidence":"High","gaps":["Stoichiometry and ultrastructure of the spindle complex not yet resolved"]},{"year":2011,"claim":"Demonstrated that TACC3-ch-TOG-clathrin forms a trimeric complex constituting the inter-microtubule bridges of kinetochore fibers, defining its structural role in K-fiber integrity.","evidence":"Co-IP, siRNA, EM ultrastructure and immunogold labeling","pmids":["21297582"],"confidence":"High","gaps":["Distinction between structural crosslinking and tension generation not yet separated"]},{"year":2013,"claim":"Distinguished the complex's tension-maintenance role from its structural role and dissected the molecular surfaces, showing TACC3 and clathrin are interdependent and cooperatively form the microtubule-interaction surface, while ch-TOG engages via a sixth TOG domain.","evidence":"Knocksideways with FRET tension measurement; NMR, domain mapping, microtubule cosedimentation and biophysical reconstitution","pmids":["23532825","23918938","24273164","24003142","23887685","21966557"],"confidence":"High","gaps":["Full atomic architecture of the assembled bridge not solved","Regulation of acentrosomal aster capture incompletely defined"]},{"year":2014,"claim":"Revealed two additional, complex-independent activities: TACC3 facilitates γ-TuRC assembly to nucleate centrosomal microtubules, and a TACC3-ch-TOG pool tracks microtubule plus ends with XMAP215.","evidence":"In vitro nucleation with recombinant TACC domain, Co-IP, sedimentation, and live +TIP imaging in Xenopus","pmids":["25246530","25187649"],"confidence":"High","gaps":["How TACC3 partitions between nucleation, plus-tip tracking and spindle pools not quantified"]},{"year":2015,"claim":"Separated TACC3's two regulatory inputs to Aurora A using endogenous knock-ins: an F525 docking motif activates Aurora A and accelerates spindle assembly, while Ser558 phosphorylation prevents aneuploidy; also defined the clathrin- and Aurora A-independent TACC3-ch-TOG plus-tip pool.","evidence":"F525A/S558A knock-in mutagenesis, Aurora A activation assay, Co-IP, live imaging; separate live imaging/domain mapping for the independent pool","pmids":["26134678","25596274"],"confidence":"High","gaps":["Physiological role of the plus-tip pool in human cells not fully defined"]},{"year":2018,"claim":"Provided the structural mechanism: a three-motif, phospho-dependent switch in which Aurora A docking, Ser558 phosphorylation-induced helix formation, and clathrin ankle recognition act sequentially to recruit TACC3.","evidence":"Crystal structure, NMR, mutagenesis and mitotic timing assays","pmids":["29510984"],"confidence":"High","gaps":["Structure of the full ternary spindle complex on microtubules not resolved"]},{"year":2019,"claim":"Connected Ser558 phosphorylation to astral microtubule control by stabilizing γ-TuRC assembly at spindle poles through phospho-TACC3-γ-TuRC binding.","evidence":"S558A/S558D phospho-mutant overexpression, Co-IP with γ-TuRC proteins and live imaging","pmids":["31823729"],"confidence":"Medium","gaps":["Overexpression-based, single lab","Direct vs scaffolded γ-TuRC contact not resolved"]},{"year":2021,"claim":"Refined the spindle complex membership using endogenous tagging, establishing TACC3 and clathrin as core and ch-TOG/GTSE1 as ancillary while excluding PIK3C2A.","evidence":"CRISPR knock-in tagging with systematic induced relocalization of endogenous proteins","pmids":["33380489"],"confidence":"High","gaps":["Functional contribution of GTSE1 to the complex not detailed here"]},{"year":2023,"claim":"Defined cell-cycle-resolved TACC3 interactomes in cancer, with mitotic KIFC1-dependent centrosome clustering and interphase NuRD-mediated tumor-suppressor silencing both promoting tumor growth.","evidence":"Co-IP, PLA, ChIP, knockdown/CRISPR and organoid/PDX models","pmids":["36864125"],"confidence":"High","gaps":["Direct vs indirect NuRD recruitment by TACC3 not structurally mapped"]},{"year":2018,"claim":"Characterized the oncogenic FGFR3-TACC3 fusion, showing it depends on FGFR3 kinase activity and secretory-pathway localization, sequesters endogenous TACC3 from the spindle, and rewires metabolism via a PIN4-PGC1α axis.","evidence":"Localization-targeting constructs, kinase-dead mutagenesis, phosphoproteomics, metabolic flux and in vivo tumor assays","pmids":["28855393","30344944","26869289","29323298"],"confidence":"Medium","gaps":["Single labs per study","Relative contributions of spindle sequestration vs FGFR3 signaling to tumorigenesis not jointly quantified"]},{"year":2022,"claim":"Identified FGFR3-TACC3 as an HSP90/CDC37 client, nominating chaperone inhibition as a therapeutic vulnerability.","evidence":"Co-IP of the ternary complex, HSP90 inhibitor and CDC37 knockdown with glycosylation and viability assays","pmids":["35151844"],"confidence":"Medium","gaps":["Single lab","Generality across fusion-positive tumor types not established"]},{"year":null,"claim":"How TACC3 is dynamically partitioned among its spindle-crosslinking, microtubule-nucleating, plus-tip-tracking, translational-repressor, and nuclear transcriptional roles within a single cell, and how these pools are coordinated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated quantitative model of pool partitioning","Mendelian disease association absent from the corpus","Mechanism coupling nuclear and mitotic functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[18,20,26,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14,18,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[29,26]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,11,33,42]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3,9,26]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[18,27,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,11,42]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9,14,18,25]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[26,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,11,42]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[34,36,38,42]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,7]}],"complexes":["TACC3-ch-TOG-clathrin spindle complex","NuRD complex (MBD2/HDAC2)","γ-TuRC","maskin-eIF4E translational repression complex"],"partners":["AURKA","CLTC","CKAP5","XMAP215","KIFC1","FOG-1","MBD2","NDEL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6A5","full_name":"Transforming acidic coiled-coil-containing protein 3","aliases":["ERIC-1"],"length_aa":838,"mass_kda":90.4,"function":"Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors (By similarity). Acts as a component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge. The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:21297582, PubMed:23532825). May be involved in the control of cell growth and differentiation. May contribute to cancer (PubMed:14767476)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q9Y6A5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TACC3","classification":"Common Essential","n_dependent_lines":706,"n_total_lines":1208,"dependency_fraction":0.5844370860927153},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TUBB4B","stoichiometry":4.0},{"gene":"TUBA1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TACC3","total_profiled":1310},"omim":[{"mim_id":"620696","title":"RBPJ-INTERACTING AND TUBULIN-ASSOCIATED PROTEIN 1; RITA1","url":"https://www.omim.org/entry/620696"},{"mim_id":"620397","title":"AURORA KINASE A- AND NINEIN-INTERACTING PROTEIN; AUNIP","url":"https://www.omim.org/entry/620397"},{"mim_id":"615730","title":"DEDICATOR OF CYTOKINESIS 7; DOCK7","url":"https://www.omim.org/entry/615730"},{"mim_id":"613446","title":"CENTROSOMAL PROTEIN, 120-KD; CEP120","url":"https://www.omim.org/entry/613446"},{"mim_id":"611142","title":"CYTOSKELETON-ASSOCIATED PROTEIN 5; CKAP5","url":"https://www.omim.org/entry/611142"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":53.1},{"tissue":"lymphoid tissue","ntpm":48.0},{"tissue":"testis","ntpm":54.6}],"url":"https://www.proteinatlas.org/search/TACC3"},"hgnc":{"alias_symbol":["ERIC1","ERIC-1","maskin","Tacc4"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6A5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6A5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6A5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6A5-F1-predicted_aligned_error_v6.png","plddt_mean":56.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TACC3","jax_strain_url":"https://www.jax.org/strain/search?query=TACC3"},"sequence":{"accession":"Q9Y6A5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6A5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6A5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6A5"}},"corpus_meta":[{"pmid":"11081630","id":"PMC_11081630","title":"CPEB, maskin, and cyclin B1 mRNA at the mitotic apparatus: implications for local 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CPEB also interacts with microtubules and is involved in localizing cyclin B1 mRNA to the mitotic apparatus.\",\n      \"method\": \"Co-immunoprecipitation, antibody injection assays, mRNA reporter injection, in situ localization in Xenopus embryos\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, antibody/mRNA injection functional assays, replicated across multiple experimental approaches in one study\",\n      \"pmids\": [\"11081630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Maskin (TACC3 Xenopus ortholog) prevents oocyte maturation and translation of CPE-containing cyclin B1 mRNA by blocking eIF4G association with eIF4E. Dissociation of the maskin-eIF4E complex requires both cytoplasmic polyadenylation and poly(A)-binding protein (PABP), which binds eIF4G to displace maskin from eIF4E.\",\n      \"method\": \"Antibody injection, mRNA reporter injection, biochemical binding assays in Xenopus oocytes\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (antibody injection, mRNA reporter), mechanistic dissection of complex dissociation\",\n      \"pmids\": [\"12110596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aurora A (Eg2) phosphorylates maskin/TACC3 on a conserved serine residue; this phosphorylation regulates maskin localization to centrosomes and function in microtubule assembly during M-phase. Maskin interacts with XMAP215 and Aurora A kinase in vitro and in egg extracts.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation from egg extracts, depletion/reconstitution experiments in Xenopus egg extracts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, reciprocal Co-IP, depletion/add-back reconstitution, replicated by multiple labs\",\n      \"pmids\": [\"16172207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TACC3 (Xenopus) forms a one-to-one complex with XMAP215 and enhances XMAP215's microtubule-stabilizing activity in vitro. TACC3 increases the number of microtubules emanating from mitotic centrosomes, and its centrosomal targeting is regulated by Aurora A-dependent phosphorylation.\",\n      \"method\": \"Purified protein reconstitution, in vitro microtubule assay, Xenopus laevis egg extracts, Aurora A kinase assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, in vitro kinase assay, egg extract functional experiments; replicated across labs\",\n      \"pmids\": [\"16172205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Maskin (TACC3) interacts with XMAP215 in Xenopus egg extracts; maskin depletion results in mislocalization of XMAP215 but not CPEB, demonstrating that maskin is required for XMAP215 centrosome/spindle localization. Maskin is required for two distinct steps of spindle assembly and microtubule aster formation.\",\n      \"method\": \"Immunodepletion, add-back reconstitution, in vitro spindle assembly assay in Xenopus egg extracts, co-immunoprecipitation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — immunodepletion with reconstitution, Co-IP, multiple orthogonal readouts, replicated across labs\",\n      \"pmids\": [\"15788567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aurora A phosphorylates maskin (TACC3) on a conserved serine (Ser626 in Xenopus) in vitro and in vivo; inhibition of this phosphorylation by microinjection of phospho-mimicking peptides causes premature synthesis of meiosis II proteins (cyclin B1, Cdc6) during meiosis I, indicating maskin phosphorylation by Aurora A controls sequential protein synthesis during oocyte maturation.\",\n      \"method\": \"Two-hybrid screen (interaction identification), in vitro kinase assay, co-immunoprecipitation from oocyte extracts, microinjection of synthetic peptides, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, co-IP, functional microinjection rescue/inhibition experiments\",\n      \"pmids\": [\"15687499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Maskin (TACC3) undergoes multiple CDK1-dependent phosphorylation events (at T58, S152, S311, S343, S453, S638) during oocyte maturation; mutation of these sites to alanine prevents CDK1-induced dissociation of maskin from eIF4E. Separately, Maskin is phosphorylated on S626 by protein kinase A prior to maturation, which is required for its localization on the mitotic apparatus in somatic cells but does not affect translation during oocyte maturation.\",\n      \"method\": \"Mass spectrometry phosphosite mapping, site-directed mutagenesis, co-immunoprecipitation, in vitro kinase assay, localization studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphosite mutagenesis combined with Co-IP and in vitro kinase assays, multiple orthogonal methods\",\n      \"pmids\": [\"16107707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CDK1 phosphorylation promotes maskin (TACC3) dissociation from eIF4E, while the phosphatase calcineurin reverses this. This phosphorylation-dephosphorylation cycle oscillates with the cell cycle and controls maskin-eIF4E interaction and, consequently, cyclin B1 mRNA translation during early Xenopus cell cycles.\",\n      \"method\": \"In vitro kinase/phosphatase assays, co-immunoprecipitation, cell-free translation assays in Xenopus embryo extracts\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase/phosphatase assays, Co-IP, translational readout, mechanistically complete dissection\",\n      \"pmids\": [\"17086181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NDEL1 is required for centrosome targeting of TACC3 through direct interaction with TACC3. Aurora A phosphorylates NDEL1 at Ser251, and expression of Aurora A phosphorylation-mimetic NDEL1 mutants rescues centrosomal maturation and separation defects caused by Aurora A depletion, including TACC3 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phospho-mutant overexpression, immunofluorescence in mouse cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phospho-mutant rescue, single lab, mechanistic chain from Aurora A to NDEL1 to TACC3\",\n      \"pmids\": [\"17060449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human TACC3 Ser558 is phosphorylated by Aurora A kinase; this phosphorylation is essential for TACC3 localization to centrosomes and proximal mitotic spindles in human cells. Inhibition of Aurora A with MLN8054 causes dose-dependent mislocalization of TACC3 away from mitotic spindles.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, immunofluorescence, Aurora A small-molecule inhibitor treatment, in vivo tumor xenograft pharmacodynamic studies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay with mutagenesis, pharmacological inhibition, in vivo validation, multiple independent methods\",\n      \"pmids\": [\"17545617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TACC3 interacts with FOG-1 (Friend of GATA-1) and controls FOG-1 nuclear localization. High levels of TACC3 inhibit FOG-1 function as a transcriptional cofactor of GATA-1. GATA-1 competes with TACC3 for interaction with FOG-1. Forced TACC3 overexpression delays terminal erythroid maturation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown in MEL and G1ER cells, nuclear/cytoplasmic fractionation, erythroid differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction, functional overexpression effects on differentiation, single lab\",\n      \"pmids\": [\"15037632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TACC3 forms a complex in vivo with MBD2 and the histone acetyltransferase pCAF. The TACC3/pCAF-containing MBD2 complex and the HDAC2-containing MBD2 complex are mutually exclusive. HAT activity associates with MBD2 in vivo and increases when TACC3 is overexpressed. TACC3 can reactivate transcription from MBD2-repressed methylated promoters by favoring formation of an HAT-containing MBD2 complex.\",\n      \"method\": \"Co-immunoprecipitation, HAT enzymatic assay, reporter gene assay, overexpression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro HAT activity assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"16410616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Maskin (TACC3) is required for microtubule anchoring at the centrosome but not for regulating microtubule dynamics per se (dynamics were unaffected by maskin depletion in time-lapse experiments). The conserved C-terminal TACC domain is necessary and sufficient for centrosome function; the N-terminus inhibits TACC domain function.\",\n      \"method\": \"Xenopus egg extract immunodepletion, in vitro aster assembly assay, time-lapse video microscopy, domain add-back reconstitution\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — depletion/reconstitution with domain mapping, live imaging, multiple orthogonal experiments in a single study\",\n      \"pmids\": [\"18508920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdh1, an activator of APC/C, interacts with TACC3 and controls TACC3 protein stability during mitotic exit. Depletion of Cdh1 prolonged TACC3 protein levels; alteration of Cdh1 levels correlated with changes in ubiquitinated TACC3. Multiple domains of TACC3 are involved in Cdh1-regulated degradation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation (in vitro and in vivo), siRNA knockdown, ubiquitination assay, domain mapping\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, domain mapping, single lab\",\n      \"pmids\": [\"19823035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Clathrin heavy chain (CHC) acts as an adaptor that binds Aurora A-phosphorylated TACC3 (pSer558) and recruits it to the mitotic spindle for microtubule stabilization. CHC binds phospho-S558 TACC3 via its linker domain and first CHC repeat. Depletion of CHC abolishes TACC3 spindle relocalization and causes loss of ch-TOG on spindles, disorganized spindles, and chromosome misalignment.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phospho-mutant analysis, immunofluorescence, domain mapping\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, phospho-mutant functional validation, domain mapping, RNAi phenotype; replicated by independent lab (Fu et al. 2010)\",\n      \"pmids\": [\"20566684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Clathrin heavy chain (CHC) specifically binds phosphorylated TACC3 (at Ser620 and Ser626 in Xenopus; not Ser33) and recruits it to spindle poles. This CHC-phospho-TACC3 interaction is inhibited by importin β and reversed by RanGTP, linking spindle assembly to Ran gradient signaling.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, phospho-mutant analysis, Ran/importin-β biochemical assays, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with phospho-mutant specificity, biochemical competition assay with Ran/importin-β, multiple orthogonal methods\",\n      \"pmids\": [\"20923838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Integrin-linked kinase (ILK) is required for centrosome clustering in cancer cells with supernumerary centrosomes. ILK performs its centrosome clustering activity through TACC3 and ch-TOG. A specific TACC3 phosphorylation site is required for centrosome clustering, and ILK regulates this TACC3 phosphorylation in an Aurora-A-dependent manner.\",\n      \"method\": \"siRNA knockdown, ILK inhibitors, live-cell imaging, immunofluorescence, phospho-mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional epistasis (ILK→Aurora A→TACC3 phosphorylation→centrosome clustering), single lab, multiple cell lines\",\n      \"pmids\": [\"20838383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TACC3 and TSC2 co-localize and co-purify with nuclear envelope components. TACC3 is necessary for proper localization of phospho-Ser939 TSC2 at spindle poles and cytokinetic bridges. TSC2 acts epistatically to TACC3 in regulating cell division. Loss of TACC3 or TSC2 causes nuclear envelope morphological alterations, abscission defects, and increased binucleated cells.\",\n      \"method\": \"Co-immunoprecipitation/interactome mapping, subcellular fractionation, immunofluorescence, siRNA knockdown, epistasis analysis, electron microscopy\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interactome, localization, epistasis by double knockdown; single lab, multiple methods\",\n      \"pmids\": [\"20237422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TACC3, ch-TOG, and clathrin form a trimeric complex at kinetochore fibers (K-fibers). The complex is anchored to the spindle by TACC3 and ch-TOG. Clathrin depletion and TACC3 depletion both cause selective loss of short inter-microtubule bridges in K-fibers and general MT loss. Immunogold labeling confirmed clathrin is present at inter-MT bridges in K-fibers.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, electron microscopy ultrastructural analysis, immunogold labeling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ultrastructural EM with immunogold, Co-IP, RNAi depletion; multiple orthogonal high-resolution methods\",\n      \"pmids\": [\"21297582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DOCK7 interacts with TACC3 and antagonizes TACC3's microtubule growth-promoting function at centrosomes. DOCK7 silencing impedes neuronal differentiation and maintains cells as cycling progenitors; DOCK7 overexpression promotes differentiation. DOCK7 controls interkinetic nuclear migration of radial glial progenitors by opposing TACC3 centrosomal activity.\",\n      \"method\": \"Co-immunoprecipitation, in utero electroporation (gain/loss of function), immunofluorescence, live imaging in developing mouse cortex\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo epistasis by co-expression/knockdown, single lab\",\n      \"pmids\": [\"22842144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Within the TACC3-ch-TOG-clathrin complex, TACC3 and clathrin are interdependent for spindle recruitment—each requires the other to be present to bind the spindle. The N-terminal domain of clathrin and the TACC domain of TACC3 together form a microtubule-interaction surface, coordinated by TACC3-clathrin binding mediated through a dileucine motif and Aurora A-phosphorylated Ser558 on TACC3 binding to the 'ankle' of clathrin. A stutter in the TACC3 coiled-coil interacts with a novel sixth TOG domain of ch-TOG required for ch-TOG microtubule localization.\",\n      \"method\": \"Domain mapping, co-immunoprecipitation, microtubule cosedimentation assay, NMR structural characterization, mutagenesis, cell-based localization assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — NMR, mutagenesis, Co-IP, microtubule binding assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23918938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The TACC domain of TACC3 contains two functionally distinct subdomains: CC1 (aa 414–530) mediates interaction with chTOG, while CC2 (aa 530–630) performs an intradomain interaction with the central repeat region of TACC3 that masks the TACC domain before effector binding. Aurora A kinase does not regulate TACC3-chTOG complex formation per se, but functions as a recruitment factor for the complex to centrosomes/proximal spindles.\",\n      \"method\": \"Purified recombinant protein biochemistry, gel filtration, analytical ultracentrifugation, in vitro binding assays, domain deletion/truncation mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro with purified proteins, multiple biophysical methods, domain mutagenesis; single lab\",\n      \"pmids\": [\"24273164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TACC3 is essential for kinetochore capture during spindle assembly. TACC3-associated acentrosomal microtubule asters form near kinetochores and bind kinetochores as an initial capture step; sorting of these asters with centrosomal microtubules then leads to capture by centrosomal microtubules from both poles.\",\n      \"method\": \"siRNA knockdown, live-cell imaging, nocodazole washout experiments, immunofluorescence in HeLa cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with live imaging and multiple readouts, single lab\",\n      \"pmids\": [\"24003142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aurora A kinase activity is required for localization of the TACC3/ch-TOG/clathrin complex to K-fibers. Inhibition of Aurora A with MLN8237 results in loss of clathrin and TACC3 from spindles, destabilization of K-fibers, and loss of inter-MT bridges, phenocopying TACC3 or clathrin depletion.\",\n      \"method\": \"Aurora A small-molecule inhibition (MLN8237), immunofluorescence, electron microscopy of K-fibers\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological inhibition with EM and IF readouts, single lab, mechanistically confirmatory\",\n      \"pmids\": [\"21966557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aurora A kinase activity is required for central spindle assembly during anaphase; TACC3 is identified as an Aurora A substrate essential for this process. Inhibiting Aurora A after bipolar spindle formation specifically disrupts central spindle (anaphase) assembly.\",\n      \"method\": \"Aurora A inhibitor treatment in anaphase cells, siRNA knockdown, immunofluorescence in Xenopus and human cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological and genetic inhibition, single lab, temporal control of inhibition\",\n      \"pmids\": [\"23887685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rapid removal of the TACC3-ch-TOG-clathrin complex from K-fibers at metaphase (using knocksideways) reduces kinetochore fiber tension and prevents spindle checkpoint satisfaction without causing significant loss of K-fiber microtubules, distinguishing a maintenance role in tension generation from a structural role in MT number.\",\n      \"method\": \"Knocksideways (rapid inducible protein relocalization), FRET-based tension measurements, immunofluorescence, live imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — acute inducible removal with defined temporal control, kinetochore tension measurement, multiple readouts; single lab with rigorous approach\",\n      \"pmids\": [\"23532825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TACC3 promotes microtubule nucleation at centrosomes and facilitates γ-tubulin ring complex (γ-TuRC) assembly. TACC3 mediates interactions with both γ-TuRC and γ-TuSC proteins. TACC3 depletion reduces γ-TuRC levels and increases γ-TuSC levels, indicating TACC3 is required for γ-TuRC assembly from γ-TuSC components. The TACC domain of TACC3 has intrinsic microtubule nucleating activity.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, microtubule sedimentation assay, immunofluorescence, recombinant TACC domain microtubule nucleation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro nucleation assay with recombinant protein, Co-IP, sedimentation, loss-of-function; multiple orthogonal methods single lab\",\n      \"pmids\": [\"25246530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TACC3 functions as a microtubule plus end-tracking protein (+TIP) in multiple embryonic cell types via its conserved C-terminal TACC domain. TACC3 localizes distal to EB1 and directly overlaps with XMAP215 at plus ends. TACC3 promotes axon outgrowth by increasing microtubule plus end velocities. TACC3 also regulates XMAP215 stability and localizes XMAP215 to microtubule plus ends.\",\n      \"method\": \"Live fluorescence imaging with tagged +TIPs, morpholino knockdown/overexpression in Xenopus, domain truncation analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with multiple +TIP markers, loss/gain of function, domain analysis; single lab\",\n      \"pmids\": [\"25187649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"APC/C(CDH1) ubiquitin ligase mediates SNIPER(TACC3)-induced polyubiquitylation and proteasomal degradation of TACC3. This provides a mechanism for cell-cycle-regulated TACC3 turnover via ubiquitin-proteasome pathway.\",\n      \"method\": \"Mechanistic analysis with small molecule SNIPER(TACC3), ubiquitination assay, proteasome inhibitor rescue, CDH1-knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination assay, genetic knockdown of E3 ligase activator, chemical biology approach; single lab\",\n      \"pmids\": [\"25375378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TACC3 contains a hydrophobic motif centered on F525 that docks to a previously uncharacterized pocket on Aurora A, potently activating Aurora A. Cells carrying homozygous F525A mutation show perturbed TACC3 localization, reduced Ser558 phosphorylation, weakened clathrin interaction, and markedly shorter mitosis due to rapid spindle assembly, without chromosome missegregation. By contrast, S558A mutation causes aneuploidy without major change in mitotic duration.\",\n      \"method\": \"Endogenous TACC3 knock-in mutagenesis (F525A, S558A), biochemical Aurora A activation assay, co-immunoprecipitation, immunofluorescence, time-lapse imaging\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — endogenous knock-in mutagenesis, in vitro Aurora A activation assay, Co-IP, live imaging; multiple orthogonal methods, single lab but rigorous\",\n      \"pmids\": [\"26134678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TACC3-ch-TOG can track microtubule plus ends independently of clathrin and Aurora A-dependent Ser558 phosphorylation or EB1/EB3. This Aurora A/clathrin-independent pool is defined by the direct TACC3-ch-TOG interaction and is distinct from the TACC3-ch-TOG-clathrin spindle pool.\",\n      \"method\": \"Live fluorescence imaging, co-immunoprecipitation, siRNA knockdown, domain mapping\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging of endogenous-tagged proteins, Co-IP, domain analysis; single lab\",\n      \"pmids\": [\"25596274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Aurora A recruits TACC3 to the mitotic spindle through a phospho-dependent three-motif mechanism: (1) a hydrophobic docking motif binds a novel pocket on Aurora A; (2) phosphorylation of Ser558 induces a conformational switch from disordered to helical in a second motif; (3) the resulting helix extends into a third motif recognized by the ankle helical-repeat region of clathrin heavy chain. Abrogation of the docking motif causes a delay in late mitosis.\",\n      \"method\": \"Crystal structure, NMR, mutagenesis, cell-based localization assays, mitotic timing assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + NMR + mutagenesis + functional cell biology; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"29510984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Aurora A-specific phosphorylation of TACC3 at Ser558 regulates astral microtubule formation by stabilizing γ-TuRC assembly at spindle poles. S558A mutation causes loss of astral MTs and disrupts γ-TuRC protein localization at poles; S558D (phospho-mimetic) retains astral MTs and γ-TuRC proteins. Ser558-phosphorylated TACC3 physically interacts with γ-TuRC proteins, and S558A impairs this interaction.\",\n      \"method\": \"Phospho-mutant overexpression (S558A, S558D), co-immunoprecipitation with γ-TuRC proteins, immunofluorescence, time-lapse imaging\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-mutant analysis, Co-IP, live imaging; single lab, multiple methods\",\n      \"pmids\": [\"31823729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tacc3 binds to the intracellular domain of all Notch receptor family members via CDC10/Ankyrin repeats, co-localizes with Notch3 ICD in mammary tissue, and acts as a negative regulator of Notch signaling. Knockdown of Tacc3 upregulates the Notch target gene Hey2. Notch4/Int3 ICD-Tacc3 interaction inhibits transcription from a Hes1-Luciferase reporter, reversed by increasing Rbpj.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, dual-label immunofluorescence, siRNA knockdown, reporter gene assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of endogenous proteins, reporter assay, knockdown phenotype; single lab\",\n      \"pmids\": [\"20804727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In FGFR3-TACC3 (FT3) fusion-positive bladder cancer cells, the FT3 fusion protein is not localized to the mitotic spindle; instead, via its TACC domain, FT3 sequesters endogenous TACC3 away from the spindle, reducing spindle TACC3 levels. This depletion causes mitotic defects (chromosome segregation errors). Knockdown of the fusion gene or overexpression of TACC3 partially rescues these defects. FGFR3 kinase inhibition does not rescue spindle TACC3 levels, confirming the mechanism is TACC3-dominant rather than FGFR3 signaling-dependent.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown of fusion gene, TACC3 overexpression rescue, FGFR3 inhibitor treatment, chromosome segregation assay in bladder cancer cell lines\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological epistasis experiments, single lab, several orthogonal approaches\",\n      \"pmids\": [\"28855393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TACC3 and clathrin are core members of the mitotic spindle complex; chTOG and GTSE1 are ancillary—chTOG binds TACC3 and GTSE1 binds clathrin, but chTOG and GTSE1 do not interact with each other. PIK3C2A, previously proposed to stabilize the complex, is not a member. This was established using induced relocalization of endogenous CRISPR-tagged complex members.\",\n      \"method\": \"CRISPR/Cas9 knock-in tagging, induced relocalization (knocksideways) of endogenous proteins, co-relocalization assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous protein tagging by CRISPR, systematic induced relocalization to map all interactions, rigorous negative controls for PIK3C2A\",\n      \"pmids\": [\"33380489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The oncogenic activity of FGFR3-TACC3 requires entrance to the secretory pathway or plasma membrane localization; nuclear-targeted or signal-sequence-deleted FGFR3-TACC3 lacks oncogenic activity. FGFR3-TACC3 transformation is not affected by its interactions with Aurora-A, clathrin, or ch-TOG. FGFR3 kinase activity (K508R abrogates) is essential for transformation; the TACC3 domain drives nuclear localization of the fusion.\",\n      \"method\": \"Subcellular localization targeting constructs (NLS, myristylation signal, signal sequence deletion), focus formation assay, IL-3 independent proliferation, Western blot signaling analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple localization-altering constructs with functional readouts, kinase-dead mutagenesis; single lab\",\n      \"pmids\": [\"30344944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The coiled-coil TACC3 domain in FGFR3-TACC3 leads to constitutive phosphorylation of key activating FGFR3 tyrosine residues (shown by TiO2-LC-MS/MS phosphoproteomics). FGFR3-TACC3 causes increased FGFR3 activation, altered phosphorylation, MAPK pathway activation, nuclear localization, and cellular transformation. The TACC3 domain alone drives nuclear localization; FGFR3 kinase activity is required for transformation (K508R mutation abrogates it). Phosphorylated tyrosines in the TACC3-derived portion are not critical for activity.\",\n      \"method\": \"TiO2-LC-MS/MS phosphopeptide enrichment, kinase-dead mutagenesis, focus formation assay, Western blot, nuclear localization assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry phosphoproteomics, kinase-dead mutagenesis, functional transformation assay; single lab\",\n      \"pmids\": [\"26869289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The FGFR3-TACC3 fusion activates oxidative phosphorylation and mitochondrial biogenesis via phosphorylation of PIN4 as an intermediate signaling step. The F3-T3-PIN4 axis triggers peroxisome biogenesis and new protein synthesis; this anabolic response converges on PGC1α through intracellular ROS production, enabling mitochondrial respiration and tumor growth.\",\n      \"method\": \"Transcriptional subgroup analysis, phosphoproteomics, metabolic flux assays, organelle biogenesis assays, ROS measurement, in vivo tumor growth assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics identifying PIN4, multiple functional metabolic assays; single lab, complex mechanistic chain\",\n      \"pmids\": [\"29323298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The FGFR3-TACC3 fusion protein is a client of HSP90, forming a ternary complex with CDC37. Deprivation of HSP90 or CDC37 disrupts this ternary complex, destabilizes glycosylated FGFR3-TACC3, and suppresses its oncogenic activity. HSP90 inhibitors sensitize FGFR3-TACC3-positive glioma cells to temozolomide.\",\n      \"method\": \"Co-immunoprecipitation of HSP90/CDC37/F3T3, HSP90 inhibitor treatment, CDC37 knockdown, cell viability assays, glycosylation analysis\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of ternary complex, genetic and pharmacological perturbation, single lab\",\n      \"pmids\": [\"35151844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TACC3 promotes prostate cancer cell proliferation and restrains primary cilium formation. TACC3 interacts with filamin A; elevated TACC3 disrupts the filamin A-meckelin interaction, thereby restraining primary cilium formation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifying filamin A interaction, functional knockdown phenotypes, single lab\",\n      \"pmids\": [\"32156598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The 5' UTR of Tacc3 mRNA contains upstream open reading frames (uORFs) that direct P-eIF2α-dependent translation, enabling preferential Tacc3 protein synthesis under conditions of elevated eIF2α phosphorylation. TACC3-deficient satellite cells exhibit defects in expansion, self-renewal, and skeletal muscle regeneration.\",\n      \"method\": \"Transcriptomics, quantitative proteomics, 5' UTR reporter assays, sal003 pharmacological treatment, TACC3 conditional knockout in satellite cells\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — uORF reporter assay, proteomics, conditional KO phenotype; single lab, multiple methods\",\n      \"pmids\": [\"33318147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TACC3 forms distinct functional interactomes in mitosis and interphase in cancer cells with centrosome amplification. In mitosis, TACC3 interacts with KIFC1 (a kinesin) to cluster extra centrosomes; disrupting this interaction causes multipolar spindle formation and mitotic cell death. In interphase, TACC3 interacts with the NuRD complex (HDAC2 and MBD2) in the nucleus to suppress expression of tumor suppressors (p21, p16, APAF1), driving G1/S progression. FOXM1 drives upregulation of TACC3 and KIFC1 in response to p53 loss/centrosome amplification.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, siRNA/CRISPR knockdown, ChIP, qRT-PCR, immunofluorescence, organoid and PDX tumor models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IP interactions, chromatin-IP, distinct mitotic/interphase phenotypes, organoid and in vivo PDX validation; multiple orthogonal methods single lab\",\n      \"pmids\": [\"36864125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TACC3 inhibition in T-DM1-resistant HER2+ breast cancer cells restores spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD). TACC3 overexpression in resistant cells abolishes SAC activation and ICD markers. In vivo, TACC3 inhibition elicited ICD and enhanced T-DM1 antitumor activity by inducing dendritic cell maturation and increasing intratumoral cytotoxic T cells.\",\n      \"method\": \"TACC3 siRNA/inhibitor, flow cytometry (calreticulin, ATP, HMGB1 release), vaccination assay, in vivo tumor models with immune profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological inhibition, multiple ICD markers, in vivo immune functional assays; single lab\",\n      \"pmids\": [\"38319231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HURP directly interacts with TACC3 (mapped to HURP residues 1–625) in vivo and in vitro. HURP is required for TACC3 function during kinetochore microtubule assembly at the chromosome region in prometaphase; HURP modulates stable lateral kinetochore attachment and chromosome congression through TACC3.\",\n      \"method\": \"Co-immunoprecipitation, bimolecular fluorescence complementation, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, BiFC, RNAi functional analysis; single lab\",\n      \"pmids\": [\"30054275\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TACC3 is a centrosomal/spindle-associated protein that is phosphorylated by Aurora A kinase at Ser558 (human), which induces a conformational switch enabling TACC3 to bind clathrin heavy chain; together with ch-TOG, the resulting TACC3–ch-TOG–clathrin trimeric complex crosslinks adjacent microtubules in kinetochore fibers to maintain spindle stability and kinetochore tension, while a separate Aurora A/clathrin-independent TACC3–ch-TOG pool tracks microtubule plus ends to promote polymerization; TACC3 also stabilizes γ-TuRC assembly at centrosomes to regulate astral microtubule nucleation, interacts with multiple nuclear partners (FOG-1, MBD2/pCAF, NuRD complex, Notch ICDs) to control transcription and hematopoietic/erythroid differentiation, and its protein levels are regulated by APC/C(CDH1)-mediated ubiquitin-proteasome degradation during mitotic exit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TACC3 is a centrosome- and spindle-associated coiled-coil protein that organizes mitotic microtubule architecture downstream of Aurora A kinase, and additionally moonlights as a nuclear transcriptional regulator and translational repressor [#3, #9, #42]. Its central activity in mitosis is governed by Aurora A: TACC3 docks onto a pocket on Aurora A via a hydrophobic motif centered on F525, potently activating the kinase, which in turn phosphorylates human TACC3 at Ser558 [#29, #31]. This phosphorylation drives a disordered-to-helical conformational switch that creates a binding surface for the ankle region of clathrin heavy chain, recruiting TACC3 to the mitotic spindle [#31, #14]. There, TACC3, ch-TOG, and clathrin assemble into a complex that crosslinks microtubules within kinetochore fibers via inter-microtubule bridges, maintaining K-fiber tension and enabling spindle checkpoint satisfaction [#18, #25, #35]. The TACC domain of TACC3 binds ch-TOG and possesses intrinsic microtubule-nucleating activity, and TACC3 facilitates γ-TuRC assembly at spindle poles to control astral microtubule nucleation in a Ser558-phosphorylation-dependent manner [#21, #26, #32]. A distinct Aurora A/clathrin-independent TACC3–ch-TOG pool tracks microtubule plus ends together with XMAP215 to promote microtubule polymerization and axon outgrowth [#27, #30]. Originally characterized as the Xenopus protein Maskin, TACC3 represses translation of CPE-containing mRNAs such as cyclin B1 by binding eIF4E and blocking eIF4G, an interaction released by CDK1 phosphorylation during the cell cycle [#0, #1, #7]. In the nucleus, TACC3 partners with FOG-1, an MBD2/pCAF acetyltransferase complex, the NuRD complex, and Notch intracellular domains to regulate transcription and differentiation [#10, #11, #33, #42]. TACC3 protein levels are controlled by APC/C(CDH1)-mediated ubiquitin-proteasome degradation during mitotic exit [#13, #28]. In cancer, the recurrent FGFR3-TACC3 fusion drives transformation through FGFR3 kinase activity and a TACC3-dominant sequestration of endogenous spindle TACC3, and TACC3 supports proliferation in centrosome-amplified tumors via KIFC1-dependent centrosome clustering and NuRD-mediated tumor-suppressor silencing [#34, #36, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that the TACC3 ortholog Maskin couples mRNA translational control to the mitotic apparatus by repressing cyclin B1 translation, revealing a non-microtubule function.\",\n      \"evidence\": \"Co-IP, antibody/mRNA injection and in situ localization in Xenopus embryos\",\n      \"pmids\": [\"11081630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian TACC3 retains this eIF4E-binding translational role was not addressed\", \"Link between translational repression and spindle function unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined how the Maskin-eIF4E repressive complex is dissolved, showing PABP binding to eIF4G displaces Maskin upon cytoplasmic polyadenylation.\",\n      \"evidence\": \"Antibody/mRNA injection and biochemical binding assays in Xenopus oocytes\",\n      \"pmids\": [\"12110596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-cycle timing of dissociation not yet integrated with kinase signaling\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified Aurora A as the kinase phosphorylating TACC3/Maskin on a conserved serine and demonstrated this controls centrosomal targeting and XMAP215-dependent microtubule assembly, linking TACC3 to spindle organization.\",\n      \"evidence\": \"In vitro kinase assays, reciprocal Co-IP, immunodepletion/add-back and purified-protein reconstitution in Xenopus egg extracts\",\n      \"pmids\": [\"16172207\", \"16172205\", \"15788567\", \"15687499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact human phosphosite not yet mapped\", \"How phosphorylation alters protein structure unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how CDK1 phosphorylation cycling, opposed by calcineurin/PKA, oscillates TACC3-eIF4E binding with the cell cycle, separating translational from localization functions.\",\n      \"evidence\": \"Phosphosite mapping by MS, site-directed mutagenesis, in vitro kinase/phosphatase and cell-free translation assays in Xenopus\",\n      \"pmids\": [\"16107707\", \"17086181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of CDK1-regulated eIF4E control in mammalian cells not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed NDEL1 mediates Aurora A-dependent centrosome targeting of TACC3, placing TACC3 recruitment downstream of an Aurora A-NDEL1 axis.\",\n      \"evidence\": \"Co-IP, siRNA knockdown and phospho-mutant rescue in mouse cells\",\n      \"pmids\": [\"17060449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs indirect NDEL1-TACC3 contact not structurally defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped the human Aurora A phosphosite to Ser558 and established it as essential for TACC3 spindle/centrosome localization in human cells, providing a pharmacologically tractable handle.\",\n      \"evidence\": \"In vitro kinase assay, mutagenesis, Aurora A inhibitor (MLN8054) and xenograft pharmacodynamics\",\n      \"pmids\": [\"17545617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector of pSer558 not yet identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified clathrin heavy chain as the phospho-Ser558 reader that recruits TACC3 (with ch-TOG) to the spindle, and showed this is gated by the Ran/importin-β gradient.\",\n      \"evidence\": \"Co-IP, phospho-mutant analysis, domain mapping and Ran/importin-β competition assays\",\n      \"pmids\": [\"20566684\", \"20923838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and ultrastructure of the spindle complex not yet resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that TACC3-ch-TOG-clathrin forms a trimeric complex constituting the inter-microtubule bridges of kinetochore fibers, defining its structural role in K-fiber integrity.\",\n      \"evidence\": \"Co-IP, siRNA, EM ultrastructure and immunogold labeling\",\n      \"pmids\": [\"21297582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinction between structural crosslinking and tension generation not yet separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Distinguished the complex's tension-maintenance role from its structural role and dissected the molecular surfaces, showing TACC3 and clathrin are interdependent and cooperatively form the microtubule-interaction surface, while ch-TOG engages via a sixth TOG domain.\",\n      \"evidence\": \"Knocksideways with FRET tension measurement; NMR, domain mapping, microtubule cosedimentation and biophysical reconstitution\",\n      \"pmids\": [\"23532825\", \"23918938\", \"24273164\", \"24003142\", \"23887685\", \"21966557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic architecture of the assembled bridge not solved\", \"Regulation of acentrosomal aster capture incompletely defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed two additional, complex-independent activities: TACC3 facilitates γ-TuRC assembly to nucleate centrosomal microtubules, and a TACC3-ch-TOG pool tracks microtubule plus ends with XMAP215.\",\n      \"evidence\": \"In vitro nucleation with recombinant TACC domain, Co-IP, sedimentation, and live +TIP imaging in Xenopus\",\n      \"pmids\": [\"25246530\", \"25187649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TACC3 partitions between nucleation, plus-tip tracking and spindle pools not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Separated TACC3's two regulatory inputs to Aurora A using endogenous knock-ins: an F525 docking motif activates Aurora A and accelerates spindle assembly, while Ser558 phosphorylation prevents aneuploidy; also defined the clathrin- and Aurora A-independent TACC3-ch-TOG plus-tip pool.\",\n      \"evidence\": \"F525A/S558A knock-in mutagenesis, Aurora A activation assay, Co-IP, live imaging; separate live imaging/domain mapping for the independent pool\",\n      \"pmids\": [\"26134678\", \"25596274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of the plus-tip pool in human cells not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the structural mechanism: a three-motif, phospho-dependent switch in which Aurora A docking, Ser558 phosphorylation-induced helix formation, and clathrin ankle recognition act sequentially to recruit TACC3.\",\n      \"evidence\": \"Crystal structure, NMR, mutagenesis and mitotic timing assays\",\n      \"pmids\": [\"29510984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full ternary spindle complex on microtubules not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected Ser558 phosphorylation to astral microtubule control by stabilizing γ-TuRC assembly at spindle poles through phospho-TACC3-γ-TuRC binding.\",\n      \"evidence\": \"S558A/S558D phospho-mutant overexpression, Co-IP with γ-TuRC proteins and live imaging\",\n      \"pmids\": [\"31823729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based, single lab\", \"Direct vs scaffolded γ-TuRC contact not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the spindle complex membership using endogenous tagging, establishing TACC3 and clathrin as core and ch-TOG/GTSE1 as ancillary while excluding PIK3C2A.\",\n      \"evidence\": \"CRISPR knock-in tagging with systematic induced relocalization of endogenous proteins\",\n      \"pmids\": [\"33380489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of GTSE1 to the complex not detailed here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined cell-cycle-resolved TACC3 interactomes in cancer, with mitotic KIFC1-dependent centrosome clustering and interphase NuRD-mediated tumor-suppressor silencing both promoting tumor growth.\",\n      \"evidence\": \"Co-IP, PLA, ChIP, knockdown/CRISPR and organoid/PDX models\",\n      \"pmids\": [\"36864125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect NuRD recruitment by TACC3 not structurally mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterized the oncogenic FGFR3-TACC3 fusion, showing it depends on FGFR3 kinase activity and secretory-pathway localization, sequesters endogenous TACC3 from the spindle, and rewires metabolism via a PIN4-PGC1α axis.\",\n      \"evidence\": \"Localization-targeting constructs, kinase-dead mutagenesis, phosphoproteomics, metabolic flux and in vivo tumor assays\",\n      \"pmids\": [\"28855393\", \"30344944\", \"26869289\", \"29323298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs per study\", \"Relative contributions of spindle sequestration vs FGFR3 signaling to tumorigenesis not jointly quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified FGFR3-TACC3 as an HSP90/CDC37 client, nominating chaperone inhibition as a therapeutic vulnerability.\",\n      \"evidence\": \"Co-IP of the ternary complex, HSP90 inhibitor and CDC37 knockdown with glycosylation and viability assays\",\n      \"pmids\": [\"35151844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality across fusion-positive tumor types not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TACC3 is dynamically partitioned among its spindle-crosslinking, microtubule-nucleating, plus-tip-tracking, translational-repressor, and nuclear transcriptional roles within a single cell, and how these pools are coordinated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated quantitative model of pool partitioning\", \"Mendelian disease association absent from the corpus\", \"Mechanism coupling nuclear and mitotic functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [18, 20, 26, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14, 18, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [29, 26]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 11, 33, 42]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3, 9, 26]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [18, 27, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 11, 42]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 14, 18, 25]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [26, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 11, 42]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [34, 36, 38, 42]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"complexes\": [\n      \"TACC3-ch-TOG-clathrin spindle complex\",\n      \"NuRD complex (MBD2/HDAC2)\",\n      \"γ-TuRC\",\n      \"maskin-eIF4E translational repression complex\"\n    ],\n    \"partners\": [\n      \"AURKA\",\n      \"CLTC\",\n      \"CKAP5\",\n      \"XMAP215\",\n      \"KIFC1\",\n      \"FOG-1\",\n      \"MBD2\",\n      \"NDEL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":10,"faith_total":10,"faith_pct":100.0}}