{"gene":"TPR","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1997,"finding":"Tpr (p270) is a constitutive component of the intranuclear filaments attached to the nucleoplasmic annulus of the nuclear pore complex (NPC) in vertebrate cells, localized exclusively on the nucleoplasmic side, not the cytoplasmic surface.","method":"Immunoelectron microscopy with multiple antibodies against different Tpr epitopes in mammalian and amphibian cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunolocalization with multiple antibodies and multiple cell types, directly contradicting prior cytoplasmic localization claim; independently replicated in multiple organisms","pmids":["9024684"],"is_preprint":false},{"year":1994,"finding":"Tpr is a large (~265 kDa) coiled-coil protein and a component of the nuclear pore complex; its amino-terminal region is the portion incorporated into oncogenic kinase fusions (TPR-MET, TPR-TRK, TPR-RAF). Tpr is assembled into NPCs later than O-glycosylated nucleoporins during post-mitotic NPC reassembly.","method":"Monoclonal antibody immunofluorescence and immunogold EM; in vitro translation; peptide sequencing from rat liver NEs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM, immunofluorescence, biochemistry) in single study; foundational localization paper","pmids":["7798308"],"is_preprint":false},{"year":1998,"finding":"Tpr (via its N-terminal coiled-coil domain) associates with the nuclear basket of the NPC; its acidic C-terminal domain contains a nuclear localization signal and can mediate nuclear import. Ectopic expression of full-length Tpr or NPC-associated domains causes accumulation of poly(A)+ RNA in the nucleus, implicating Tpr in mRNA export.","method":"Mammalian cell transfection with full-length and deletion mutant constructs; fluorescence microscopy; poly(A)+ RNA in situ hybridization","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain dissection with transfection and fluorescence readout, single lab but multiple constructs tested","pmids":["9864356"],"is_preprint":false},{"year":1998,"finding":"Tpr forms stable subcomplexes with importin alpha and importin beta in Xenopus egg extracts (and in assembled nuclear pores), making it a major physiological binding site for importin beta. Unlike Nup153, Tpr binds importin beta/alpha heterodimers only when they are NOT carrying an NLS substrate, and the complex is disassembled by GMP-PNP.","method":"Immunoprecipitation from Xenopus egg extracts and isolated nuclei; solid-phase binding; immunofluorescence localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in physiological extract plus isolated nuclear pores, multiple orthogonal binding assays, clearly defined substrate specificity","pmids":["9531546"],"is_preprint":false},{"year":2002,"finding":"Tpr is concentrated within the nuclear basket of the NPC (not in long intranuclear filaments). Antibody-mediated depletion of Tpr from NPC (by injection into mitotic cells) did not affect nuclear import mediated by a basic NLS, but significantly retarded nuclear export mediated by a leucine-rich NES signal. Intra-nuclear injection of anti-Tpr antibodies in interphase cells similarly inhibited protein export but not import.","method":"Antibody microinjection into mitotic and interphase cells; GFP-Tpr live imaging; immunofluorescence; EM immunolocalization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional antibody perturbation with specific export vs. import readout, multiple experimental approaches, live imaging plus EM","pmids":["11839768"],"is_preprint":false},{"year":2001,"finding":"TPR directly binds Nup98 in vitro, and via Nup98 also associates with Nup96. TPR colocalizes with Nup98 in a characteristic intranuclear filamentous network extending from NPCs toward the nucleolus.","method":"In vitro translated protein binding assay; double immunofluorescence microscopy; overexpression of myc-tagged pyruvate kinase-6kDa fusion; double-immunoelectron microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus co-localization, single lab, two methods","pmids":["11248057"],"is_preprint":false},{"year":2002,"finding":"Tpr is required for normal intranuclear dynamics of RNA Pol II transcripts, including processing, intranuclear transport, and export of poly(A)+ RNA; depletion causes accumulation of poly(A)+ RNA in enlarged SC35-positive nuclear speckles, without affecting NLS-mediated import or NES-mediated export.","method":"Antibody microinjection into mammalian interphase cells; poly(A)+ RNA FISH; immunofluorescence","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional perturbation (antibody depletion) with specific RNA and protein transport readouts, single lab","pmids":["11952838"],"is_preprint":false},{"year":2008,"finding":"ERK2 directly phosphorylates Tpr and binds to a DEF (FXF) docking domain on Tpr. ERK2 phosphorylation and dimerization are both required for stable ERK2-Tpr binding, and phosphorylation of Tpr positively cooperates with the DEF domain to promote this binding (unlike most substrates). Ectopic expression or depletion of Tpr decreases movement of activated ERK2 from cytoplasm to nucleus, indicating Tpr functions as both substrate and scaffold for ERK2.","method":"In vitro kinase assays; mutagenesis of phosphorylation sites and DEF domain; co-immunoprecipitation; cell fractionation; ERK2 nuclear translocation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus in vivo binding and functional translocation assays, single lab but multiple orthogonal methods","pmids":["18794356"],"is_preprint":false},{"year":2008,"finding":"Tpr directly binds Mad1 and Mad2 at the NPC during interphase. Depletion of Tpr in HeLa cells disrupts NPC localization of Mad1 and Mad2 during interphase, decreases Mad1-bound Mad2 levels, and reduces Mad1 at kinetochores during prometaphase, resulting in failure to activate Mad2 and inhibit APC/Cdc20—implicating Tpr in spindle assembly checkpoint signaling.","method":"Mass spectrometry of affinity-purified Mad2-associated factors; direct binding assays; siRNA knockdown; immunofluorescence of kinetochore proteins","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS identification followed by direct binding confirmation, RNAi knockdown with specific checkpoint readout, multiple orthogonal methods","pmids":["18981471"],"is_preprint":false},{"year":2010,"finding":"Tpr associates with the molecular motors dynein and dynactin, and with spindle checkpoint proteins Mad1 and Mad2 during cell division. Tpr overexpression causes multinucleated cell formation; knockdown causes lagging chromosome phenotype and disrupts spindle checkpoint protein localization. Rescue and dominant-negative experiments confirm that Tpr orchestrates proper chromosome segregation through interaction with dynein light chain.","method":"Co-immunoprecipitation; RNAi knockdown; overexpression; rescue experiments; immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and RNAi with specific mitotic phenotype readout, single lab","pmids":["20133940"],"is_preprint":false},{"year":2011,"finding":"Tpr regulates export of mRNAs with retained introns that traffic through the Nxf1/Nxt1 pathway. Modest knockdown of Tpr by RNAi significantly increases export and translation of mRNA containing a CTE (Constitutive Transport Element), but has no effect on CRM1/Rev-RRE-dependent export or fully spliced mRNA export.","method":"RNAi knockdown; reporter constructs with CTE vs. RRE elements; cytoplasmic/nuclear RNA quantification","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific pathway dissection using distinct export pathway reporters, single lab","pmids":["21613532"],"is_preprint":false},{"year":2012,"finding":"Localization of Tpr to the NPC (dependent on Nup153) is necessary for its function in regulating unspliced RNA export. Tpr knockdown dramatically enhances export of CTE-containing unspliced RNA, an effect independent of Sam68 and Tap/Nxf1 but dependent on Nup153 co-action.","method":"siRNA knockdown; Gag/Pol-CTE reporter assay; rescue with siRNA-resistant Tpr; fractionation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with rescue experiment and pathway placement, single lab","pmids":["22253824"],"is_preprint":false},{"year":2013,"finding":"Tpr stabilizes Mad1 and Mad2 proteins (forms a Tpr/Mad1/Mad2 complex) during interphase and mitosis, and is required for normal SAC response by maintaining Mad1-cMad2 levels. Tpr is required for Mad2 (but not Mad1) kinetochore localization; SAC robustness depends on Mad2 levels at kinetochores. Mechanistically, Tpr may spatially regulate SAC proteostasis through SUMO-isopeptidases SENP1 and SENP2 at NPCs.","method":"Co-immunoprecipitation (Tpr with Mad1/Mad2); protein half-life measurements; siRNA depletion; GFP-Mad2 rescue; immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, half-life measurements, RNAi with rescue, multiple phenotypic readouts in single rigorous study","pmids":["24344181"],"is_preprint":false},{"year":2014,"finding":"Tpr is phosphorylated at S2059 by CDK1 during mitosis, causing distinct chromatin localization in telophase. Phosphorylation at S2094 by protein kinase A is hyperphosphorylated during mitosis. Abrogation of S2059 phosphorylation abolishes Tpr-Mad1 interaction and disrupts Mad1/Mad2 localization, causing cell cycle defects.","method":"Mass spectrometry identification of phosphosites; in vitro kinase assays with CDK1 and PKA; phospho-mutant analysis; Co-IP; immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assays identifying writers plus mutagenesis with functional consequence on Mad1 interaction and cell cycle, single lab with multiple orthogonal methods","pmids":["24938596"],"is_preprint":false},{"year":2018,"finding":"Depletion of Tpr (but not Nup153) dramatically increases the total NPC number in various cell types. This negative regulation operates through a phosphorylation cascade: ERK (MAPK) phosphorylates Nup153 (using Tpr as a scaffold), which is critical for early stages of NPC biogenesis.","method":"Auxin-inducible degron (AID) depletion; NPC counting; kinase inhibitor experiments; phosphorylation assays; Co-IP","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — acute AID depletion system, mechanistic kinase cascade identified with multiple readouts, specific to Tpr vs. Nup153","pmids":["30228202"],"is_preprint":false},{"year":2020,"finding":"Acute TPR depletion causes rapid transcriptomic changes closely related to those from loss of NXF1 or GANP (TREX-2 subunit), distinct from NUP153 or NUP50 depletion. TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) with NPCs, indicating TPR is an integral component of the TREX-2 mRNA export pathway.","method":"Auxin-induced degron (AID) system for acute depletion; RNA-seq; NPC association assays for TREX-2 subunits","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — AID system for acute depletion, transcriptomics plus biochemical NPC-association assay, pathway placed by comparison to NXF1/GANP depletion","pmids":["32917881"],"is_preprint":false},{"year":2020,"finding":"TPR is required for efficient nuclear export of mRNAs and lncRNAs from short, intron-poor genes. In TPR-depleted cells, mRNAs from short transcripts accumulate in nuclear speckles while remaining bound to Nxf1, suggesting TPR acts downstream of Nxf1 recruitment to allow mRNAs to leave nuclear speckles and dock with the nuclear pore.","method":"Nuclear/cytoplasmic RNA-seq in TPR-depleted cells; reporter constructs; co-localization with nuclear speckle markers; Nxf1 association assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-wide analysis with reporter validation and specific pathway placement, single lab","pmids":["33091126"],"is_preprint":false},{"year":2021,"finding":"Tpr depletion generates transcription-dependent replication stress, DNA-RNA hybrids, DNA breaks, and genomic instability. Tpr interacts with RNA-processing proteins MATR3 and SUGP2, and with GANP (TREX-2 component). Tpr-deficient cells show slow and asymmetric replication forks, linking TPR to a network connecting replication forks with transcription, splicing, and mRNA export.","method":"DNA fiber assays; electron microscopy of replication intermediates; proteomic interaction screen; siRNA depletion of interactors; immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (replication assays, EM, proteomics, functional validation of interactors) in single rigorous study","pmids":["34168151"],"is_preprint":false},{"year":2009,"finding":"Recombinant Tpr binds strongly and specifically to importin alpha, importin beta, and a CRM1-containing trimeric export complex via distinct binding sites. Nuclear import of Tpr is dependent on cytosolic factors and energy, efficiently mediated by the importin alpha/beta import pathway. Tpr preferentially binds CRM1 in an export complex, consistent with a role in protein export.","method":"Solid-phase binding assays with recombinant proteins; in vitro nuclear import assays; competition binding experiments","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution of binding and import with recombinant proteins, multiple karyopherin binding sites mapped, single lab","pmids":["19835572"],"is_preprint":false},{"year":2012,"finding":"Tpr depletion impairs NES-dependent nuclear export of proteins and causes partial co-depletion of Nup153. Tpr depletion also affects levels and function of SUMO-protease SENP2, disrupting SUMOylation regulation at the nuclear pore. Tpr depletion triggers G0/G1 arrest and a p53-dependent senescent-like phenotype.","method":"RNAi (siRNA) knockdown; NES-export assay; SUMO conjugation analysis; cell cycle analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with specific export and SUMOylation readouts, p53 dependency established, single lab","pmids":["21811608"],"is_preprint":false},{"year":2015,"finding":"Tpr interacts with Aurora A kinase via its central domain but not with Aurora B. Tpr depletion reduces Aurora A expression levels, centrosomal localization, and phosphorylation. Tpr also sequesters excess Aurora A at centrosomes to safeguard spindle bipolarity. Aurora A inhibitor Alisertib disrupts centrosomal localization of Tpr and induces mitotic catastrophe.","method":"Co-immunoprecipitation; siRNA knockdown; overexpression; immunofluorescence; domain mapping","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, RNAi phenotype, and chemical inhibitor cross-validation; single lab","pmids":["25789545"],"is_preprint":false},{"year":2019,"finding":"TPR associates with lamin B1 (but not lamin A/C). TPR depletion affects lamin B1 organization within the nuclear lamina (detected by STED microscopy) and alters NPC distribution within the nuclear envelope; this effect is reversed by simultaneous lamin A/C knockdown or lamin B1 overexpression.","method":"Co-immunoprecipitation; STED microscopy; siRNA knockdown; double knockdown epistasis","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with super-resolution functional imaging and genetic epistasis, single lab","pmids":["30762072"],"is_preprint":false},{"year":1992,"finding":"The human tpr gene encodes a large protein (2094 amino acids, designated tpr-L) with extensive coiled-coil regions and a highly acidic C-terminal domain. The amino-terminal sequences are those that appear in oncogenic kinase fusions.","method":"cDNA cloning and sequencing; structural prediction; tissue expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — molecular cloning with structural analysis, foundational protein characterization paper; replicated by subsequent studies","pmids":["1437155"],"is_preprint":false},{"year":1998,"finding":"Distinct molecular segments of Tpr confer different topogenetic properties: a short region in the C-terminal domain is essential and sufficient for nuclear import; the N-terminal coiled-coil domain, when imported into the nucleus, mediates association with the NPC via segments containing heptad repeat clusters.","method":"Transfection of deletion mutants and chimeric Tpr-pyruvate kinase constructs in mammalian cells; immunofluorescence localization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — systematic domain dissection with multiple constructs, single lab","pmids":["9828100"],"is_preprint":false},{"year":1988,"finding":"The TPR-MET oncogene encodes p65tpr-met, a constitutively active protein-tyrosine kinase that is autophosphorylated in vitro on tyrosine residues. In vivo, p65tpr-met is phosphorylated on both serine and tyrosine residues.","method":"Immunocomplex kinase assay; in vitro autophosphorylation; in vivo 32P labeling; cell-surface iodination","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay with multiple phosphorylation site analyses; foundational biochemical characterization replicated across labs","pmids":["3277171"],"is_preprint":false},{"year":1995,"finding":"A single tyrosine residue (Tyr489) in the C-terminus of Tpr-Met is essential for efficient cell transformation. Tyr489 is required for association with Grb2, phosphatidylinositol 3-kinase, phospholipase Cγ, and SHPTP2/Syp. Transformation of fibroblasts depends on downstream pathways of Shc and Grb2, while PI3K, PLCγ, and SHPTP2 pathways alone are insufficient.","method":"Site-directed mutagenesis (Tyr→Phe); transformation assays in Fr3T3 fibroblasts; co-immunoprecipitation of signaling proteins","journal":"Oncogene / The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis with transformation and biochemical binding readouts, independently confirmed across two publications","pmids":["7838524","8662733"],"is_preprint":false},{"year":1999,"finding":"Loss of the juxtamembrane domain of Met is essential for Tpr-Met oncogenic transformation. Tpr-juxtaMet (containing juxtamembrane domain aa 962-1009) strongly inhibits transformation, proliferation, anchorage-independent growth, motility, and invasion without altering kinase activity. The juxtamembrane domain impairs association of Tpr-Met with cytoplasmic signal transducers and downstream signaling.","method":"Chimeric protein construction; cell transformation assays; in vitro kinase assay; co-immunoprecipitation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain insertion mutagenesis with multiple functional readouts and biochemical signaling analysis, single lab","pmids":["10435641"],"is_preprint":false},{"year":2007,"finding":"Tpr-Met oncogenic activation is dependent on cytoplasmic localization and exclusion from the endocytic/lysosomal degradation pathway. Plasma membrane targeting of Tpr-Met allows Cbl-dependent ubiquitination and degradation, reducing transforming activity. Cytoplasmic Tpr-Met lacks the Cbl-binding site and escapes downregulation; ubiquitination of cytosolic Tpr-Met alone does not alter its transforming activity.","method":"Membrane-targeting constructs; Cbl co-expression; ubiquitination assays; transformation assays; protein stability measurements","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic domain and localization mutants with transformation and degradation readouts, single lab","pmids":["17533376"],"is_preprint":false},{"year":2012,"finding":"Tpr depletion caused reduction in nuclear pore number and reduction in inner nuclear filaments (by electron microscopy). Tpr depletion increased p53 nuclear accumulation and facilitated autophagy. Tpr controls HSP70 and HSF1 mRNA export, and p53 trafficking via CRM1/exportin.","method":"siRNA knockdown; electron microscopy; immunofluorescence; mRNA export assays; Western blotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with EM structural readout and specific mRNA/protein trafficking phenotypes, single lab","pmids":["23170199"],"is_preprint":false},{"year":1996,"finding":"Tpr is a phosphoprotein of the nuclear pore complex; immunoprecipitation from 32P-labeled cells confirms in vivo phosphorylation. The protein has multiple leucine zipper motifs and numerous predicted phosphorylation sites.","method":"Immunoprecipitation from 32P-orthophosphate-labeled cells; monoclonal antibody characterization; cDNA library screening; immunofluorescence","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 32P labeling and immunoprecipitation demonstrating in vivo phosphorylation, single lab","pmids":["8726355"],"is_preprint":false}],"current_model":"TPR (translocated promoter region) is a large coiled-coil nucleoporin (~267 kDa) that constitutively localizes to the nuclear basket of the nuclear pore complex (NPC) via its N-terminal coiled-coil domain, where it functions as a scaffold for: (1) mRNA export through the TREX-2/NXF1 pathway, especially for short and intron-poor transcripts; (2) spindle assembly checkpoint (SAC) signaling by stabilizing Mad1/Mad2 proteins and facilitating their NPC and kinetochore localization; (3) ERK2/MAPK signal transduction as both a substrate and scaffold that influences ERK2 nuclear translocation; (4) NPC number homeostasis by scaffolding ERK-dependent phosphorylation of Nup153; (5) interaction with lamin B1 to organize the nuclear lamina; and (6) regulation of unspliced mRNA retention. The N-terminal region of TPR also participates in oncogenic fusions (TPR-MET, TPR-TRK, TPR-RAF) where it provides a dimerization/coiled-coil domain that drives constitutive kinase activation."},"narrative":{"mechanistic_narrative":"TPR is a large coiled-coil nucleoporin that constitutes the intranuclear filaments anchored to the nucleoplasmic face of the nuclear pore complex (NPC), where it serves as a multifunctional scaffold of the nuclear basket [PMID:9024684, PMID:7798308]. It is recruited to the NPC through N-terminal heptad-repeat coiled-coil segments while its acidic C-terminal domain carries the nuclear localization signal that directs its own importin alpha/beta-mediated import [PMID:9864356, PMID:9828100, PMID:19835572]. Anchored at the basket, TPR organizes nucleocytoplasmic transport: it is required for nuclear export of leucine-rich NES-bearing proteins [PMID:11839768] and operates as an integral component of the TREX-2/NXF1 mRNA export pathway, where its loss disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) with NPCs and traps short, intron-poor transcripts in nuclear speckles downstream of NXF1 recruitment [PMID:32917881, PMID:33091126]; TPR conversely restrains export of intron-retaining transcripts trafficking through the NXF1/NXT1 pathway, an activity dependent on Nup153-mediated NPC docking [PMID:21613532, PMID:22253824]. TPR also governs mitotic fidelity through the spindle assembly checkpoint: it directly binds and stabilizes Mad1 and Mad2, maintaining their NPC and kinetochore localization and the Mad1-cMad2 pool needed for robust APC/Cdc20 inhibition [PMID:18981471, PMID:24344181], a function gated by CDK1 phosphorylation of Ser2059 that is required for the TPR–Mad1 interaction [PMID:24938596]. Beyond transport and checkpoint roles, TPR acts as both substrate and scaffold for ERK2, binding it through a DEF docking motif and promoting ERK2 nuclear translocation [PMID:18794356], and scaffolds an ERK-dependent phosphorylation of Nup153 that negatively regulates NPC biogenesis [PMID:30228202]. TPR additionally associates with lamin B1 to organize the nuclear lamina and NPC distribution [PMID:30762072] and protects genome stability by preventing transcription-associated replication stress and DNA-RNA hybrid accumulation [PMID:34168151]. The N-terminal coiled-coil region of TPR is recurrently captured in oncogenic kinase fusions including TPR-MET, providing a dimerization domain that yields a constitutively active, autophosphorylating tyrosine kinase that signals through Grb2/Shc to transform cells [PMID:7798308, PMID:3277171, PMID:7838524, PMID:8662733].","teleology":[{"year":1992,"claim":"Establishing the primary structure of TPR was the prerequisite for understanding both its scaffolding and its oncogenic-fusion roles.","evidence":"cDNA cloning and sequencing of the human gene with structural prediction","pmids":["1437155"],"confidence":"Medium","gaps":["Sequence alone did not assign molecular function","Did not localize the protein"]},{"year":1988,"claim":"Characterizing the TPR-MET fusion product answered how a TPR rearrangement causes transformation, showing TPR contributes a constitutively activating module to a tyrosine kinase.","evidence":"Immunocomplex kinase assays and in vivo phosphorylation analysis of p65tpr-met","pmids":["3277171"],"confidence":"High","gaps":["Did not identify which downstream effectors are required","Did not address normal TPR function"]},{"year":1995,"claim":"Mapping the signaling requirements of TPR-MET defined which effector couplings drive transformation.","evidence":"Site-directed Tyr489 mutagenesis with fibroblast transformation and Co-IP of signaling proteins","pmids":["7838524","8662733"],"confidence":"High","gaps":["Tested in fibroblast models only","Did not address subcellular localization requirements"]},{"year":1997,"claim":"Resolving TPR's localization to the nucleoplasmic side of the NPC established it as a nuclear basket component rather than a cytoplasmic filament protein, redirecting functional hypotheses.","evidence":"Reciprocal immunoelectron microscopy with multiple epitope antibodies across vertebrate species","pmids":["9024684","7798308"],"confidence":"High","gaps":["Did not define transport function","Mechanism of basket assembly not addressed"]},{"year":1998,"claim":"Domain dissection separated TPR's NPC-anchoring and self-import determinants and provided the first functional link to mRNA export.","evidence":"Deletion/chimeric constructs with poly(A)+ RNA FISH and importin Co-IP in mammalian cells and Xenopus extracts","pmids":["9864356","9531546","9828100"],"confidence":"Medium","gaps":["Overexpression readout may not reflect endogenous mechanism","Export pathway specificity not resolved"]},{"year":2002,"claim":"Functional perturbation distinguished TPR's role in protein/RNA export from import, refining its transport function.","evidence":"Antibody microinjection in mitotic and interphase cells with NES-export versus NLS-import readouts and poly(A)+ FISH","pmids":["11839768","11952838"],"confidence":"High","gaps":["Did not identify the molecular export machinery TPR engages","Speckle-accumulation mechanism unresolved"]},{"year":2008,"claim":"Discovery of direct Mad1/Mad2 binding and ERK2 scaffolding assigned TPR mitotic-checkpoint and MAPK-signaling functions beyond transport.","evidence":"Affinity-purification MS, direct binding assays, siRNA with checkpoint readouts, and in vitro ERK2 kinase/translocation assays","pmids":["18981471","18794356"],"confidence":"High","gaps":["How TPR coordinates checkpoint and export functions unclear","Structural basis of Mad1 binding not defined"]},{"year":2013,"claim":"Demonstrating that TPR stabilizes Mad1/Mad2 proteostasis clarified the mechanism by which it sustains SAC robustness.","evidence":"Co-IP, protein half-life measurements, siRNA with GFP-Mad2 rescue and kinetochore imaging","pmids":["24344181","20133940"],"confidence":"High","gaps":["Role of SENP1/SENP2 in this proteostasis only correlative","Dynein-dependent contribution from Medium-confidence study"]},{"year":2014,"claim":"Identifying CDK1 phosphorylation of Ser2059 provided a cell-cycle switch controlling the TPR-Mad1 interaction.","evidence":"MS phosphosite mapping, in vitro CDK1/PKA kinase assays, phospho-mutant Co-IP and imaging","pmids":["24938596","8726355"],"confidence":"High","gaps":["Functional role of PKA S2094 site unresolved","Phosphatase counteracting these sites not identified"]},{"year":2018,"claim":"Acute degron depletion revealed TPR as a negative regulator of NPC number acting through ERK-mediated Nup153 phosphorylation.","evidence":"Auxin-inducible degron depletion, NPC counting, kinase inhibition and phospho/Co-IP assays","pmids":["30228202"],"confidence":"High","gaps":["How ERK is recruited to the basket scaffold not fully defined","Connection to TPR's transport roles unclear"]},{"year":2020,"claim":"Acute depletion plus transcriptomics placed TPR as an integral TREX-2/NXF1 export factor required for short, intron-poor transcripts to exit nuclear speckles.","evidence":"AID depletion, nuclear/cytoplasmic RNA-seq, TREX-2 NPC-association assays and speckle co-localization","pmids":["32917881","33091126"],"confidence":"High","gaps":["Molecular step linking speckle release to pore docking unresolved","How transcript length is sensed unknown"]},{"year":2021,"claim":"Linking TPR loss to replication stress and DNA-RNA hybrids connected its export/processing scaffolding to genome stability.","evidence":"DNA fiber assays, EM of replication intermediates, proteomic interaction screen (MATR3, SUGP2, GANP) and functional validation","pmids":["34168151"],"confidence":"High","gaps":["Causal chain from export defect to fork stress not fully dissected","Direct versus indirect interactions with MATR3/SUGP2 unclear"]},{"year":null,"claim":"How TPR's multiple functions — TREX-2 export, SAC proteostasis, ERK scaffolding, NPC homeostasis, and lamina organization — are partitioned or coordinated on a single basket scaffold remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the assembled basket scaffold with bound partners","Mechanism integrating transport and checkpoint roles unknown","Relationship between full-length TPR functions and the N-terminal oncogenic fusions not bridged mechanistically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,12,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,22]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[12,20]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,23]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15,16,10,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,18,28]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[24,25,26]}],"complexes":["nuclear pore complex (nuclear basket)","TREX-2","TPR/Mad1/Mad2 complex"],"partners":["MAD1","MAD2","NUP98","NUP153","MAPK1","LMNB1","GANP","AURKA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P12270","full_name":"Nucleoprotein TPR","aliases":["Megator","NPC-associated intranuclear protein","Translocated promoter region protein"],"length_aa":2363,"mass_kda":267.3,"function":"Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with NUP153, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Negatively regulates both the association of CTE-containing mRNA with large polyribosomes and translation initiation. Does not play any role in Rev response element (RRE)-mediated export of unspliced mRNAs. Implicated in nuclear export of mRNAs transcribed from heat shock gene promoters; associates both with chromatin in the HSP70 promoter and with mRNAs transcribed from this promoter under stress-induced conditions. Modulates the nucleocytoplasmic transport of activated MAPK1/ERK2 and huntingtin/HTT and may serve as a docking site for the XPO1/CRM1-mediated nuclear export complex. According to some authors, plays a limited role in the regulation of nuclear protein export (PubMed:11952838, PubMed:22253824). Also plays a role as a structural and functional element of the perinuclear chromatin distribution; involved in the formation and/or maintenance of NPC-associated perinuclear heterochromatin exclusion zones (HEZs). Finally, acts as a spatial regulator of the spindle-assembly checkpoint (SAC) response ensuring a timely and effective recruitment of spindle checkpoint proteins like MAD1L1 and MAD2L1 to unattached kinetochore during the metaphase-anaphase transition before chromosome congression. Its N-terminus is involved in activation of oncogenic kinases","subcellular_location":"Nucleus; Nucleus membrane; Nucleus envelope; Nucleus, nuclear pore complex; Cytoplasm; Cytoplasm, cytoskeleton, spindle; Chromosome, centromere, kinetochore; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/P12270/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TPR","classification":"Common 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ZFC3H1","url":"https://www.omim.org/entry/620956"},{"mim_id":"620875","title":"FIC DOMAIN-CONTAINING PROTEIN ADENYLYLTRANSFERASE; FICD","url":"https://www.omim.org/entry/620875"},{"mim_id":"620742","title":"INTRAFLAGELLAR TRANSPORT 70B; IFT70B","url":"https://www.omim.org/entry/620742"},{"mim_id":"620741","title":"INTRAFLAGELLAR TRANSPORT 70A; IFT70A","url":"https://www.omim.org/entry/620741"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TPR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P12270","domains":[{"cath_id":"-","chopping":"845-906","consensus_level":"medium","plddt":76.4682,"start":845,"end":906},{"cath_id":"1.20.5","chopping":"1367-1450","consensus_level":"medium","plddt":74.6669,"start":1367,"end":1450}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12270","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12270-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12270-F1-predicted_aligned_error_v6.png","plddt_mean":60.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TPR","jax_strain_url":"https://www.jax.org/strain/search?query=TPR"},"sequence":{"accession":"P12270","fasta_url":"https://rest.uniprot.org/uniprotkb/P12270.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12270/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12270"}},"corpus_meta":[{"pmid":"14659697","id":"PMC_14659697","title":"TPR 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23898829","citation_count":34,"is_preprint":false},{"pmid":"23727266","id":"PMC_23727266","title":"Chaperone-interacting TPR proteins in Caenorhabditis elegans.","date":"2013","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23727266","citation_count":33,"is_preprint":false},{"pmid":"8406803","id":"PMC_8406803","title":"Characterization of the tpr gene product and isolation of a specific protease-deficient mutant of Porphyromonas gingivalis W83.","date":"1993","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8406803","citation_count":33,"is_preprint":false},{"pmid":"9828100","id":"PMC_9828100","title":"Molecular segments of protein Tpr that confer nuclear targeting and association with the nuclear pore complex.","date":"1998","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/9828100","citation_count":33,"is_preprint":false},{"pmid":"15047801","id":"PMC_15047801","title":"RoXaN, a novel cellular protein containing TPR, LD, and zinc finger motifs, forms a ternary complex with eukaryotic initiation factor 4G and rotavirus NSP3.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15047801","citation_count":33,"is_preprint":false},{"pmid":"15223324","id":"PMC_15223324","title":"The crystal structure of Helicobacter cysteine-rich protein C at 2.0 A resolution: similar peptide-binding sites in TPR and SEL1-like repeat proteins.","date":"2004","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15223324","citation_count":32,"is_preprint":false},{"pmid":"21811608","id":"PMC_21811608","title":"Silencing nuclear pore protein Tpr elicits a senescent-like phenotype in cancer cells.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21811608","citation_count":31,"is_preprint":false},{"pmid":"26037924","id":"PMC_26037924","title":"The Non-canonical Tetratricopeptide Repeat (TPR) Domain of Fluorescent (FLU) Mediates Complex Formation with Glutamyl-tRNA Reductase.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26037924","citation_count":31,"is_preprint":false},{"pmid":"19835572","id":"PMC_19835572","title":"Karyopherin binding interactions and nuclear import mechanism of nuclear pore complex protein Tpr.","date":"2009","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19835572","citation_count":30,"is_preprint":false},{"pmid":"15719029","id":"PMC_15719029","title":"RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis.","date":"2005","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/15719029","citation_count":30,"is_preprint":false},{"pmid":"14729056","id":"PMC_14729056","title":"The human small glutamine-rich TPR-containing protein is required for progress through cell division.","date":"2004","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/14729056","citation_count":30,"is_preprint":false},{"pmid":"11523050","id":"PMC_11523050","title":"Absence of tpr-met and expression of c-met in human gastric mucosa and carcinoma.","date":"2001","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11523050","citation_count":29,"is_preprint":false},{"pmid":"24563354","id":"PMC_24563354","title":"Roles of the nucleoporin Tpr in cancer and aging.","date":"2014","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/24563354","citation_count":28,"is_preprint":false},{"pmid":"24938596","id":"PMC_24938596","title":"Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic function.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24938596","citation_count":28,"is_preprint":false},{"pmid":"17877371","id":"PMC_17877371","title":"TPR-Mediated self-association of plant SGT1.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17877371","citation_count":27,"is_preprint":false},{"pmid":"25789545","id":"PMC_25789545","title":"Therapeutic potential of mitotic interaction between the nucleoporin Tpr and aurora kinase A.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25789545","citation_count":27,"is_preprint":false},{"pmid":"18320024","id":"PMC_18320024","title":"The human TPR protein TTC4 is a putative Hsp90 co-chaperone which interacts with CDC6 and shows alterations in transformed cells.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18320024","citation_count":27,"is_preprint":false},{"pmid":"17878237","id":"PMC_17878237","title":"Structurally related TPR subunits contribute differently to the function of the anaphase-promoting complex in Drosophila melanogaster.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17878237","citation_count":27,"is_preprint":false},{"pmid":"31023093","id":"PMC_31023093","title":"TPR-containing proteins control protein organization and homeostasis for the endoplasmic reticulum.","date":"2019","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31023093","citation_count":26,"is_preprint":false},{"pmid":"32071397","id":"PMC_32071397","title":"Cancer-derived UTX TPR mutations G137V and D336G impair interaction with MLL3/4 complexes and affect UTX subcellular localization.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32071397","citation_count":26,"is_preprint":false},{"pmid":"12027452","id":"PMC_12027452","title":"Structures and dynamics of Drosophila Tpr inconsistent with a static, filamentous structure.","date":"2002","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12027452","citation_count":26,"is_preprint":false},{"pmid":"34725712","id":"PMC_34725712","title":"Truncation of the TPR domain of OGT alters substrate and glycosite selection.","date":"2021","source":"Analytical and bioanalytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34725712","citation_count":25,"is_preprint":false},{"pmid":"30762072","id":"PMC_30762072","title":"Nuclear pore protein TPR associates with lamin B1 and affects nuclear lamina organization and nuclear pore distribution.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/30762072","citation_count":25,"is_preprint":false},{"pmid":"22346747","id":"PMC_22346747","title":"The TPR domain in the host Cyp40-like cyclophilin binds to the viral replication protein and inhibits the assembly of the tombusviral replicase.","date":"2012","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/22346747","citation_count":25,"is_preprint":false},{"pmid":"8726355","id":"PMC_8726355","title":"Product of the oncogene-activating gene Tpr is a phosphorylated protein of the nuclear pore complex.","date":"1996","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8726355","citation_count":24,"is_preprint":false},{"pmid":"15546961","id":"PMC_15546961","title":"Novel interaction partners of the TPR/MET tyrosine kinase.","date":"2004","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/15546961","citation_count":24,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46030,"output_tokens":7354,"usd":0.1242,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16716,"output_tokens":4124,"usd":0.09334,"stage2_stop_reason":"end_turn"},"total_usd":0.21754,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Tpr (p270) is a constitutive component of the intranuclear filaments attached to the nucleoplasmic annulus of the nuclear pore complex (NPC) in vertebrate cells, localized exclusively on the nucleoplasmic side, not the cytoplasmic surface.\",\n      \"method\": \"Immunoelectron microscopy with multiple antibodies against different Tpr epitopes in mammalian and amphibian cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunolocalization with multiple antibodies and multiple cell types, directly contradicting prior cytoplasmic localization claim; independently replicated in multiple organisms\",\n      \"pmids\": [\"9024684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Tpr is a large (~265 kDa) coiled-coil protein and a component of the nuclear pore complex; its amino-terminal region is the portion incorporated into oncogenic kinase fusions (TPR-MET, TPR-TRK, TPR-RAF). Tpr is assembled into NPCs later than O-glycosylated nucleoporins during post-mitotic NPC reassembly.\",\n      \"method\": \"Monoclonal antibody immunofluorescence and immunogold EM; in vitro translation; peptide sequencing from rat liver NEs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM, immunofluorescence, biochemistry) in single study; foundational localization paper\",\n      \"pmids\": [\"7798308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tpr (via its N-terminal coiled-coil domain) associates with the nuclear basket of the NPC; its acidic C-terminal domain contains a nuclear localization signal and can mediate nuclear import. Ectopic expression of full-length Tpr or NPC-associated domains causes accumulation of poly(A)+ RNA in the nucleus, implicating Tpr in mRNA export.\",\n      \"method\": \"Mammalian cell transfection with full-length and deletion mutant constructs; fluorescence microscopy; poly(A)+ RNA in situ hybridization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain dissection with transfection and fluorescence readout, single lab but multiple constructs tested\",\n      \"pmids\": [\"9864356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tpr forms stable subcomplexes with importin alpha and importin beta in Xenopus egg extracts (and in assembled nuclear pores), making it a major physiological binding site for importin beta. Unlike Nup153, Tpr binds importin beta/alpha heterodimers only when they are NOT carrying an NLS substrate, and the complex is disassembled by GMP-PNP.\",\n      \"method\": \"Immunoprecipitation from Xenopus egg extracts and isolated nuclei; solid-phase binding; immunofluorescence localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in physiological extract plus isolated nuclear pores, multiple orthogonal binding assays, clearly defined substrate specificity\",\n      \"pmids\": [\"9531546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tpr is concentrated within the nuclear basket of the NPC (not in long intranuclear filaments). Antibody-mediated depletion of Tpr from NPC (by injection into mitotic cells) did not affect nuclear import mediated by a basic NLS, but significantly retarded nuclear export mediated by a leucine-rich NES signal. Intra-nuclear injection of anti-Tpr antibodies in interphase cells similarly inhibited protein export but not import.\",\n      \"method\": \"Antibody microinjection into mitotic and interphase cells; GFP-Tpr live imaging; immunofluorescence; EM immunolocalization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional antibody perturbation with specific export vs. import readout, multiple experimental approaches, live imaging plus EM\",\n      \"pmids\": [\"11839768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TPR directly binds Nup98 in vitro, and via Nup98 also associates with Nup96. TPR colocalizes with Nup98 in a characteristic intranuclear filamentous network extending from NPCs toward the nucleolus.\",\n      \"method\": \"In vitro translated protein binding assay; double immunofluorescence microscopy; overexpression of myc-tagged pyruvate kinase-6kDa fusion; double-immunoelectron microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus co-localization, single lab, two methods\",\n      \"pmids\": [\"11248057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tpr is required for normal intranuclear dynamics of RNA Pol II transcripts, including processing, intranuclear transport, and export of poly(A)+ RNA; depletion causes accumulation of poly(A)+ RNA in enlarged SC35-positive nuclear speckles, without affecting NLS-mediated import or NES-mediated export.\",\n      \"method\": \"Antibody microinjection into mammalian interphase cells; poly(A)+ RNA FISH; immunofluorescence\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional perturbation (antibody depletion) with specific RNA and protein transport readouts, single lab\",\n      \"pmids\": [\"11952838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERK2 directly phosphorylates Tpr and binds to a DEF (FXF) docking domain on Tpr. ERK2 phosphorylation and dimerization are both required for stable ERK2-Tpr binding, and phosphorylation of Tpr positively cooperates with the DEF domain to promote this binding (unlike most substrates). Ectopic expression or depletion of Tpr decreases movement of activated ERK2 from cytoplasm to nucleus, indicating Tpr functions as both substrate and scaffold for ERK2.\",\n      \"method\": \"In vitro kinase assays; mutagenesis of phosphorylation sites and DEF domain; co-immunoprecipitation; cell fractionation; ERK2 nuclear translocation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus in vivo binding and functional translocation assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18794356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tpr directly binds Mad1 and Mad2 at the NPC during interphase. Depletion of Tpr in HeLa cells disrupts NPC localization of Mad1 and Mad2 during interphase, decreases Mad1-bound Mad2 levels, and reduces Mad1 at kinetochores during prometaphase, resulting in failure to activate Mad2 and inhibit APC/Cdc20—implicating Tpr in spindle assembly checkpoint signaling.\",\n      \"method\": \"Mass spectrometry of affinity-purified Mad2-associated factors; direct binding assays; siRNA knockdown; immunofluorescence of kinetochore proteins\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS identification followed by direct binding confirmation, RNAi knockdown with specific checkpoint readout, multiple orthogonal methods\",\n      \"pmids\": [\"18981471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tpr associates with the molecular motors dynein and dynactin, and with spindle checkpoint proteins Mad1 and Mad2 during cell division. Tpr overexpression causes multinucleated cell formation; knockdown causes lagging chromosome phenotype and disrupts spindle checkpoint protein localization. Rescue and dominant-negative experiments confirm that Tpr orchestrates proper chromosome segregation through interaction with dynein light chain.\",\n      \"method\": \"Co-immunoprecipitation; RNAi knockdown; overexpression; rescue experiments; immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and RNAi with specific mitotic phenotype readout, single lab\",\n      \"pmids\": [\"20133940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tpr regulates export of mRNAs with retained introns that traffic through the Nxf1/Nxt1 pathway. Modest knockdown of Tpr by RNAi significantly increases export and translation of mRNA containing a CTE (Constitutive Transport Element), but has no effect on CRM1/Rev-RRE-dependent export or fully spliced mRNA export.\",\n      \"method\": \"RNAi knockdown; reporter constructs with CTE vs. RRE elements; cytoplasmic/nuclear RNA quantification\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific pathway dissection using distinct export pathway reporters, single lab\",\n      \"pmids\": [\"21613532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Localization of Tpr to the NPC (dependent on Nup153) is necessary for its function in regulating unspliced RNA export. Tpr knockdown dramatically enhances export of CTE-containing unspliced RNA, an effect independent of Sam68 and Tap/Nxf1 but dependent on Nup153 co-action.\",\n      \"method\": \"siRNA knockdown; Gag/Pol-CTE reporter assay; rescue with siRNA-resistant Tpr; fractionation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with rescue experiment and pathway placement, single lab\",\n      \"pmids\": [\"22253824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tpr stabilizes Mad1 and Mad2 proteins (forms a Tpr/Mad1/Mad2 complex) during interphase and mitosis, and is required for normal SAC response by maintaining Mad1-cMad2 levels. Tpr is required for Mad2 (but not Mad1) kinetochore localization; SAC robustness depends on Mad2 levels at kinetochores. Mechanistically, Tpr may spatially regulate SAC proteostasis through SUMO-isopeptidases SENP1 and SENP2 at NPCs.\",\n      \"method\": \"Co-immunoprecipitation (Tpr with Mad1/Mad2); protein half-life measurements; siRNA depletion; GFP-Mad2 rescue; immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, half-life measurements, RNAi with rescue, multiple phenotypic readouts in single rigorous study\",\n      \"pmids\": [\"24344181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tpr is phosphorylated at S2059 by CDK1 during mitosis, causing distinct chromatin localization in telophase. Phosphorylation at S2094 by protein kinase A is hyperphosphorylated during mitosis. Abrogation of S2059 phosphorylation abolishes Tpr-Mad1 interaction and disrupts Mad1/Mad2 localization, causing cell cycle defects.\",\n      \"method\": \"Mass spectrometry identification of phosphosites; in vitro kinase assays with CDK1 and PKA; phospho-mutant analysis; Co-IP; immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assays identifying writers plus mutagenesis with functional consequence on Mad1 interaction and cell cycle, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24938596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Depletion of Tpr (but not Nup153) dramatically increases the total NPC number in various cell types. This negative regulation operates through a phosphorylation cascade: ERK (MAPK) phosphorylates Nup153 (using Tpr as a scaffold), which is critical for early stages of NPC biogenesis.\",\n      \"method\": \"Auxin-inducible degron (AID) depletion; NPC counting; kinase inhibitor experiments; phosphorylation assays; Co-IP\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — acute AID depletion system, mechanistic kinase cascade identified with multiple readouts, specific to Tpr vs. Nup153\",\n      \"pmids\": [\"30228202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Acute TPR depletion causes rapid transcriptomic changes closely related to those from loss of NXF1 or GANP (TREX-2 subunit), distinct from NUP153 or NUP50 depletion. TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) with NPCs, indicating TPR is an integral component of the TREX-2 mRNA export pathway.\",\n      \"method\": \"Auxin-induced degron (AID) system for acute depletion; RNA-seq; NPC association assays for TREX-2 subunits\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AID system for acute depletion, transcriptomics plus biochemical NPC-association assay, pathway placed by comparison to NXF1/GANP depletion\",\n      \"pmids\": [\"32917881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TPR is required for efficient nuclear export of mRNAs and lncRNAs from short, intron-poor genes. In TPR-depleted cells, mRNAs from short transcripts accumulate in nuclear speckles while remaining bound to Nxf1, suggesting TPR acts downstream of Nxf1 recruitment to allow mRNAs to leave nuclear speckles and dock with the nuclear pore.\",\n      \"method\": \"Nuclear/cytoplasmic RNA-seq in TPR-depleted cells; reporter constructs; co-localization with nuclear speckle markers; Nxf1 association assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-wide analysis with reporter validation and specific pathway placement, single lab\",\n      \"pmids\": [\"33091126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tpr depletion generates transcription-dependent replication stress, DNA-RNA hybrids, DNA breaks, and genomic instability. Tpr interacts with RNA-processing proteins MATR3 and SUGP2, and with GANP (TREX-2 component). Tpr-deficient cells show slow and asymmetric replication forks, linking TPR to a network connecting replication forks with transcription, splicing, and mRNA export.\",\n      \"method\": \"DNA fiber assays; electron microscopy of replication intermediates; proteomic interaction screen; siRNA depletion of interactors; immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (replication assays, EM, proteomics, functional validation of interactors) in single rigorous study\",\n      \"pmids\": [\"34168151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant Tpr binds strongly and specifically to importin alpha, importin beta, and a CRM1-containing trimeric export complex via distinct binding sites. Nuclear import of Tpr is dependent on cytosolic factors and energy, efficiently mediated by the importin alpha/beta import pathway. Tpr preferentially binds CRM1 in an export complex, consistent with a role in protein export.\",\n      \"method\": \"Solid-phase binding assays with recombinant proteins; in vitro nuclear import assays; competition binding experiments\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution of binding and import with recombinant proteins, multiple karyopherin binding sites mapped, single lab\",\n      \"pmids\": [\"19835572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tpr depletion impairs NES-dependent nuclear export of proteins and causes partial co-depletion of Nup153. Tpr depletion also affects levels and function of SUMO-protease SENP2, disrupting SUMOylation regulation at the nuclear pore. Tpr depletion triggers G0/G1 arrest and a p53-dependent senescent-like phenotype.\",\n      \"method\": \"RNAi (siRNA) knockdown; NES-export assay; SUMO conjugation analysis; cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with specific export and SUMOylation readouts, p53 dependency established, single lab\",\n      \"pmids\": [\"21811608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tpr interacts with Aurora A kinase via its central domain but not with Aurora B. Tpr depletion reduces Aurora A expression levels, centrosomal localization, and phosphorylation. Tpr also sequesters excess Aurora A at centrosomes to safeguard spindle bipolarity. Aurora A inhibitor Alisertib disrupts centrosomal localization of Tpr and induces mitotic catastrophe.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; overexpression; immunofluorescence; domain mapping\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, RNAi phenotype, and chemical inhibitor cross-validation; single lab\",\n      \"pmids\": [\"25789545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TPR associates with lamin B1 (but not lamin A/C). TPR depletion affects lamin B1 organization within the nuclear lamina (detected by STED microscopy) and alters NPC distribution within the nuclear envelope; this effect is reversed by simultaneous lamin A/C knockdown or lamin B1 overexpression.\",\n      \"method\": \"Co-immunoprecipitation; STED microscopy; siRNA knockdown; double knockdown epistasis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with super-resolution functional imaging and genetic epistasis, single lab\",\n      \"pmids\": [\"30762072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human tpr gene encodes a large protein (2094 amino acids, designated tpr-L) with extensive coiled-coil regions and a highly acidic C-terminal domain. The amino-terminal sequences are those that appear in oncogenic kinase fusions.\",\n      \"method\": \"cDNA cloning and sequencing; structural prediction; tissue expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — molecular cloning with structural analysis, foundational protein characterization paper; replicated by subsequent studies\",\n      \"pmids\": [\"1437155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Distinct molecular segments of Tpr confer different topogenetic properties: a short region in the C-terminal domain is essential and sufficient for nuclear import; the N-terminal coiled-coil domain, when imported into the nucleus, mediates association with the NPC via segments containing heptad repeat clusters.\",\n      \"method\": \"Transfection of deletion mutants and chimeric Tpr-pyruvate kinase constructs in mammalian cells; immunofluorescence localization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — systematic domain dissection with multiple constructs, single lab\",\n      \"pmids\": [\"9828100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The TPR-MET oncogene encodes p65tpr-met, a constitutively active protein-tyrosine kinase that is autophosphorylated in vitro on tyrosine residues. In vivo, p65tpr-met is phosphorylated on both serine and tyrosine residues.\",\n      \"method\": \"Immunocomplex kinase assay; in vitro autophosphorylation; in vivo 32P labeling; cell-surface iodination\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay with multiple phosphorylation site analyses; foundational biochemical characterization replicated across labs\",\n      \"pmids\": [\"3277171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A single tyrosine residue (Tyr489) in the C-terminus of Tpr-Met is essential for efficient cell transformation. Tyr489 is required for association with Grb2, phosphatidylinositol 3-kinase, phospholipase Cγ, and SHPTP2/Syp. Transformation of fibroblasts depends on downstream pathways of Shc and Grb2, while PI3K, PLCγ, and SHPTP2 pathways alone are insufficient.\",\n      \"method\": \"Site-directed mutagenesis (Tyr→Phe); transformation assays in Fr3T3 fibroblasts; co-immunoprecipitation of signaling proteins\",\n      \"journal\": \"Oncogene / The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis with transformation and biochemical binding readouts, independently confirmed across two publications\",\n      \"pmids\": [\"7838524\", \"8662733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Loss of the juxtamembrane domain of Met is essential for Tpr-Met oncogenic transformation. Tpr-juxtaMet (containing juxtamembrane domain aa 962-1009) strongly inhibits transformation, proliferation, anchorage-independent growth, motility, and invasion without altering kinase activity. The juxtamembrane domain impairs association of Tpr-Met with cytoplasmic signal transducers and downstream signaling.\",\n      \"method\": \"Chimeric protein construction; cell transformation assays; in vitro kinase assay; co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain insertion mutagenesis with multiple functional readouts and biochemical signaling analysis, single lab\",\n      \"pmids\": [\"10435641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Tpr-Met oncogenic activation is dependent on cytoplasmic localization and exclusion from the endocytic/lysosomal degradation pathway. Plasma membrane targeting of Tpr-Met allows Cbl-dependent ubiquitination and degradation, reducing transforming activity. Cytoplasmic Tpr-Met lacks the Cbl-binding site and escapes downregulation; ubiquitination of cytosolic Tpr-Met alone does not alter its transforming activity.\",\n      \"method\": \"Membrane-targeting constructs; Cbl co-expression; ubiquitination assays; transformation assays; protein stability measurements\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic domain and localization mutants with transformation and degradation readouts, single lab\",\n      \"pmids\": [\"17533376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tpr depletion caused reduction in nuclear pore number and reduction in inner nuclear filaments (by electron microscopy). Tpr depletion increased p53 nuclear accumulation and facilitated autophagy. Tpr controls HSP70 and HSF1 mRNA export, and p53 trafficking via CRM1/exportin.\",\n      \"method\": \"siRNA knockdown; electron microscopy; immunofluorescence; mRNA export assays; Western blotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with EM structural readout and specific mRNA/protein trafficking phenotypes, single lab\",\n      \"pmids\": [\"23170199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Tpr is a phosphoprotein of the nuclear pore complex; immunoprecipitation from 32P-labeled cells confirms in vivo phosphorylation. The protein has multiple leucine zipper motifs and numerous predicted phosphorylation sites.\",\n      \"method\": \"Immunoprecipitation from 32P-orthophosphate-labeled cells; monoclonal antibody characterization; cDNA library screening; immunofluorescence\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 32P labeling and immunoprecipitation demonstrating in vivo phosphorylation, single lab\",\n      \"pmids\": [\"8726355\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TPR (translocated promoter region) is a large coiled-coil nucleoporin (~267 kDa) that constitutively localizes to the nuclear basket of the nuclear pore complex (NPC) via its N-terminal coiled-coil domain, where it functions as a scaffold for: (1) mRNA export through the TREX-2/NXF1 pathway, especially for short and intron-poor transcripts; (2) spindle assembly checkpoint (SAC) signaling by stabilizing Mad1/Mad2 proteins and facilitating their NPC and kinetochore localization; (3) ERK2/MAPK signal transduction as both a substrate and scaffold that influences ERK2 nuclear translocation; (4) NPC number homeostasis by scaffolding ERK-dependent phosphorylation of Nup153; (5) interaction with lamin B1 to organize the nuclear lamina; and (6) regulation of unspliced mRNA retention. The N-terminal region of TPR also participates in oncogenic fusions (TPR-MET, TPR-TRK, TPR-RAF) where it provides a dimerization/coiled-coil domain that drives constitutive kinase activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TPR is a large coiled-coil nucleoporin that constitutes the intranuclear filaments anchored to the nucleoplasmic face of the nuclear pore complex (NPC), where it serves as a multifunctional scaffold of the nuclear basket [#0, #1]. It is recruited to the NPC through N-terminal heptad-repeat coiled-coil segments while its acidic C-terminal domain carries the nuclear localization signal that directs its own importin alpha/beta-mediated import [#2, #23, #18]. Anchored at the basket, TPR organizes nucleocytoplasmic transport: it is required for nuclear export of leucine-rich NES-bearing proteins [#4] and operates as an integral component of the TREX-2/NXF1 mRNA export pathway, where its loss disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) with NPCs and traps short, intron-poor transcripts in nuclear speckles downstream of NXF1 recruitment [#15, #16]; TPR conversely restrains export of intron-retaining transcripts trafficking through the NXF1/NXT1 pathway, an activity dependent on Nup153-mediated NPC docking [#10, #11]. TPR also governs mitotic fidelity through the spindle assembly checkpoint: it directly binds and stabilizes Mad1 and Mad2, maintaining their NPC and kinetochore localization and the Mad1-cMad2 pool needed for robust APC/Cdc20 inhibition [#8, #12], a function gated by CDK1 phosphorylation of Ser2059 that is required for the TPR–Mad1 interaction [#13]. Beyond transport and checkpoint roles, TPR acts as both substrate and scaffold for ERK2, binding it through a DEF docking motif and promoting ERK2 nuclear translocation [#7], and scaffolds an ERK-dependent phosphorylation of Nup153 that negatively regulates NPC biogenesis [#14]. TPR additionally associates with lamin B1 to organize the nuclear lamina and NPC distribution [#21] and protects genome stability by preventing transcription-associated replication stress and DNA-RNA hybrid accumulation [#17]. The N-terminal coiled-coil region of TPR is recurrently captured in oncogenic kinase fusions including TPR-MET, providing a dimerization domain that yields a constitutively active, autophosphorylating tyrosine kinase that signals through Grb2/Shc to transform cells [#1, #24, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the primary structure of TPR was the prerequisite for understanding both its scaffolding and its oncogenic-fusion roles.\",\n      \"evidence\": \"cDNA cloning and sequencing of the human gene with structural prediction\",\n      \"pmids\": [\"1437155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence alone did not assign molecular function\", \"Did not localize the protein\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Characterizing the TPR-MET fusion product answered how a TPR rearrangement causes transformation, showing TPR contributes a constitutively activating module to a tyrosine kinase.\",\n      \"evidence\": \"Immunocomplex kinase assays and in vivo phosphorylation analysis of p65tpr-met\",\n      \"pmids\": [\"3277171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify which downstream effectors are required\", \"Did not address normal TPR function\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping the signaling requirements of TPR-MET defined which effector couplings drive transformation.\",\n      \"evidence\": \"Site-directed Tyr489 mutagenesis with fibroblast transformation and Co-IP of signaling proteins\",\n      \"pmids\": [\"7838524\", \"8662733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested in fibroblast models only\", \"Did not address subcellular localization requirements\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolving TPR's localization to the nucleoplasmic side of the NPC established it as a nuclear basket component rather than a cytoplasmic filament protein, redirecting functional hypotheses.\",\n      \"evidence\": \"Reciprocal immunoelectron microscopy with multiple epitope antibodies across vertebrate species\",\n      \"pmids\": [\"9024684\", \"7798308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define transport function\", \"Mechanism of basket assembly not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Domain dissection separated TPR's NPC-anchoring and self-import determinants and provided the first functional link to mRNA export.\",\n      \"evidence\": \"Deletion/chimeric constructs with poly(A)+ RNA FISH and importin Co-IP in mammalian cells and Xenopus extracts\",\n      \"pmids\": [\"9864356\", \"9531546\", \"9828100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression readout may not reflect endogenous mechanism\", \"Export pathway specificity not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Functional perturbation distinguished TPR's role in protein/RNA export from import, refining its transport function.\",\n      \"evidence\": \"Antibody microinjection in mitotic and interphase cells with NES-export versus NLS-import readouts and poly(A)+ FISH\",\n      \"pmids\": [\"11839768\", \"11952838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular export machinery TPR engages\", \"Speckle-accumulation mechanism unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of direct Mad1/Mad2 binding and ERK2 scaffolding assigned TPR mitotic-checkpoint and MAPK-signaling functions beyond transport.\",\n      \"evidence\": \"Affinity-purification MS, direct binding assays, siRNA with checkpoint readouts, and in vitro ERK2 kinase/translocation assays\",\n      \"pmids\": [\"18981471\", \"18794356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TPR coordinates checkpoint and export functions unclear\", \"Structural basis of Mad1 binding not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that TPR stabilizes Mad1/Mad2 proteostasis clarified the mechanism by which it sustains SAC robustness.\",\n      \"evidence\": \"Co-IP, protein half-life measurements, siRNA with GFP-Mad2 rescue and kinetochore imaging\",\n      \"pmids\": [\"24344181\", \"20133940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of SENP1/SENP2 in this proteostasis only correlative\", \"Dynein-dependent contribution from Medium-confidence study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying CDK1 phosphorylation of Ser2059 provided a cell-cycle switch controlling the TPR-Mad1 interaction.\",\n      \"evidence\": \"MS phosphosite mapping, in vitro CDK1/PKA kinase assays, phospho-mutant Co-IP and imaging\",\n      \"pmids\": [\"24938596\", \"8726355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of PKA S2094 site unresolved\", \"Phosphatase counteracting these sites not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Acute degron depletion revealed TPR as a negative regulator of NPC number acting through ERK-mediated Nup153 phosphorylation.\",\n      \"evidence\": \"Auxin-inducible degron depletion, NPC counting, kinase inhibition and phospho/Co-IP assays\",\n      \"pmids\": [\"30228202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ERK is recruited to the basket scaffold not fully defined\", \"Connection to TPR's transport roles unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Acute depletion plus transcriptomics placed TPR as an integral TREX-2/NXF1 export factor required for short, intron-poor transcripts to exit nuclear speckles.\",\n      \"evidence\": \"AID depletion, nuclear/cytoplasmic RNA-seq, TREX-2 NPC-association assays and speckle co-localization\",\n      \"pmids\": [\"32917881\", \"33091126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular step linking speckle release to pore docking unresolved\", \"How transcript length is sensed unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking TPR loss to replication stress and DNA-RNA hybrids connected its export/processing scaffolding to genome stability.\",\n      \"evidence\": \"DNA fiber assays, EM of replication intermediates, proteomic interaction screen (MATR3, SUGP2, GANP) and functional validation\",\n      \"pmids\": [\"34168151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from export defect to fork stress not fully dissected\", \"Direct versus indirect interactions with MATR3/SUGP2 unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TPR's multiple functions — TREX-2 export, SAC proteostasis, ERK scaffolding, NPC homeostasis, and lamina organization — are partitioned or coordinated on a single basket scaffold remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the assembled basket scaffold with bound partners\", \"Mechanism integrating transport and checkpoint roles unknown\", \"Relationship between full-length TPR functions and the N-terminal oncogenic fusions not bridged mechanistically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 12, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 22]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [12, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005643\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 23]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15, 16, 10, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 18, 28]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [24, 25, 26]}\n    ],\n    \"complexes\": [\n      \"nuclear pore complex (nuclear basket)\",\n      \"TREX-2\",\n      \"TPR/Mad1/Mad2 complex\"\n    ],\n    \"partners\": [\n      \"MAD1\",\n      \"MAD2\",\n      \"NUP98\",\n      \"NUP153\",\n      \"MAPK1\",\n      \"LMNB1\",\n      \"GANP\",\n      \"AURKA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}