{"gene":"CIP2A","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2007,"finding":"CIP2A directly interacts with the oncogenic transcription factor c-Myc, inhibits PP2A activity toward c-Myc serine 62 (S62), and thereby prevents c-Myc proteolytic degradation. Overexpression of CIP2A transforms human cells, demonstrating direct oncogenic activity.","method":"Direct interaction shown by co-immunoprecipitation; PP2A activity assays; cell transformation assays; in vivo tumor formation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — foundational paper with multiple orthogonal methods (Co-IP, phosphatase assays, transformation, in vivo), widely replicated across subsequent studies","pmids":["17632056"],"is_preprint":false},{"year":2017,"finding":"CIP2A forms homodimers, as confirmed by crystal structure of the N-terminal fragment (amino acids 1-560) at 3.0 Å resolution and structure-based mutational analyses. The CIP2A dimer interacts with PP2A subunits B56α and B56γ via a conserved N-terminal region; dimerization promotes B56 binding. Inhibition of either CIP2A dimerization or B56α/γ expression destabilizes CIP2A.","method":"Yeast two-hybrid, crystal structure determination, structure-based mutagenesis, co-immunoprecipitation validation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus orthogonal binding assays in a single rigorous study","pmids":["28174209"],"is_preprint":false},{"year":2023,"finding":"CIP2A inhibits PP2A-B56α by displacing the PP2A-A subunit and hijacking both B56α and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. CIP2A also competes with B56α substrates by blocking the LxxIxE-motif substrate binding pocket on B56α. The N-terminal head domain mediates interaction with B56α and stabilizes CIP2A protein. CRISPR/Cas9 single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation and abrogated triple-negative breast cancer tumor growth in vivo.","method":"Structural biology, CRISPR/Cas9 mutagenesis, phosphatase activity assays, in vivo xenograft tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural mechanism plus functional CRISPR mutagenesis plus in vivo validation in a single study","pmids":["36854761"],"is_preprint":false},{"year":2021,"finding":"CIP2A is cytoplasmic during interphase but accumulates at DNA lesions in mitosis as part of a complex with TOPBP1. CIP2A deficiency does not cause replication-associated DNA lesions but leads to lethal mis-segregation of acentric chromosomes in BRCA-deficient cells. Physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient tumors, establishing CIP2A as a synthetic lethal target in BRCA1/2-mutated cancers.","method":"Genome-scale CRISPR-Cas9 synthetic lethality screens in isogenic BRCA1/2-deficient cells, live-cell imaging, co-immunoprecipitation, functional chromosome segregation assays","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale CRISPR screen plus mechanistic follow-up with multiple orthogonal methods, independently replicated concept","pmids":["35121901"],"is_preprint":false},{"year":2022,"finding":"CIP2A is actively exported from the cell nucleus during interphase but, upon nuclear envelope breakdown at mitosis onset, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DNA double-strand breaks. Loss of CIP2A causes increased radio-sensitivity, micronuclei formation, and chromosomal instability.","method":"Co-immunoprecipitation, live-cell imaging, subcellular fractionation, nuclear export inhibition experiments, gamma-H2AX/TOPBP1 foci quantification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including live imaging and fractionation with functional consequence, consistent with independent PMID:35121901","pmids":["35842428"],"is_preprint":false},{"year":2014,"finding":"CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, enhancing mTORC1-dependent growth signaling and inhibiting autophagy. Under nutrient deprivation, CIP2A undergoes ubiquitination and p62/SQSTM1-dependent autophagic degradation, which reverses mTORC1 activation and destabilizes c-Myc.","method":"RNAi screen, co-immunoprecipitation (CIP2A-mTORC1 association), PP2A activity assays, autophagy flux assays, ubiquitination assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi screen discovery plus reciprocal Co-IP plus mechanistic assays in multiple cell models","pmids":["24590173"],"is_preprint":false},{"year":2013,"finding":"CIP2A translocates from the cytoplasm to the nucleus at mitotic entry, enriching at spindle poles. CIP2A directly interacts with the polo-box domain of Plk1 during mitosis, maintaining Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis and enhancing Plk1 kinase activity. CIP2A depletion delays mitotic progression and causes mitotic abnormalities independently of PP2A activity.","method":"Subcellular fractionation and immunofluorescence (localization), co-immunoprecipitation (CIP2A-Plk1 interaction), Plk1 kinase activity assays, APC/C-Cdh1 ubiquitination assays, siRNA depletion with mitotic phenotype readout","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP of CIP2A-Plk1 polo-box domain interaction, kinase activity assays, and localization with functional consequence, all in single study","pmids":["23983103"],"is_preprint":false},{"year":2019,"finding":"A micropeptide CIP2A-BP encoded by LINC00665 directly binds CIP2A and replaces the PP2A B56γ subunit, thereby releasing PP2A activity, which inhibits the PI3K/AKT/NFκB pathway and decreases expression of MMP-2, MMP-9, and Snail. TGF-β suppresses CIP2A-BP translation via Smad-induced 4E-BP1 upregulation.","method":"Co-immunoprecipitation (CIP2A-BP with CIP2A and B56γ), PP2A activity assays, Western blot, in vivo MMTV-PyMT model with CIP2A-BP gene introduction or direct peptide injection","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, biochemical PP2A release assay, and in vivo rescue experiment providing multiple orthogonal lines of evidence","pmids":["31755573"],"is_preprint":false},{"year":2014,"finding":"CIP2A physically associates with H-Ras in cervical cancer cells, leading to activation of the MEK/ERK signaling pathway and promoting epithelial-to-mesenchymal transition (EMT) and cervical cancer progression.","method":"Pull-down assay, mass spectrometry peptide sequencing, bilateral co-immunoprecipitation","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP and MS identification, but single lab and limited mechanistic follow-up on the H-Ras interaction","pmids":["25458953"],"is_preprint":false},{"year":2010,"finding":"CIP2A negatively regulates Akt-related PP2A activity in hepatocellular carcinoma cells; ectopic expression of CIP2A decreased Akt-related PP2A activity and upregulated phospho-Akt, while silencing CIP2A increased PP2A activity toward Akt.","method":"siRNA knockdown, CIP2A overexpression, PP2A phosphatase activity assays specific to Akt substrate, Western blot, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with PP2A activity assay, single lab but two complementary approaches","pmids":["20729919"],"is_preprint":false},{"year":2018,"finding":"CIP2A overexpression in neurons causes PP2A inhibition, driving tau/APP hyperphosphorylation at multiple sites, increased APP β-cleavage and Aβ production, tau mislocalization to dendrites and spines, synaptic degeneration, and cognitive deficits. AAV-CIP2A hippocampal injection in mice induced AD-like cognitive deficits and impaired LTP.","method":"AAV-mediated CIP2A overexpression in mouse hippocampus, PP2A activity assays, Western blot for phospho-tau/APP, LTP electrophysiology, behavioral cognitive assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo AAV gain-of-function with multiple orthogonal readouts (phosphorylation, electrophysiology, behavior) establishing causal mechanism","pmids":["30021167"],"is_preprint":false},{"year":2022,"finding":"Chk1 activity is elevated in AD brains and Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Chk1 inhibition decreases CIP2A expression and restores PP2A activity.","method":"AAV-GFAP-ChK1 in vivo brain injection, Chk1 inhibitor (GDC0575) treatment in AD cell models and APP/PS1 mice, Western blot, PP2A activity assays, behavioral tests","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and cell model data with gain/loss-of-function, single lab","pmids":["35286657"],"is_preprint":false},{"year":2009,"finding":"H. pylori CagA protein upregulates CIP2A expression in gastric cells via the Src and MEK/ERK (Ras/MEK/ERK) signaling pathways, and CIP2A upregulation is dependent on CagA phosphorylation. CIP2A depletion partially attenuated H. pylori infection-induced Myc stabilization.","method":"Plasmid-mediated CagA expression in gastric cell lines, H. pylori infection, signal inhibitors (Src inhibitor, MEK inhibitor), immunoblotting, CIP2A siRNA depletion","journal":"Journal of medical microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitors plus genetic knockdown, single lab, two orthogonal approaches","pmids":["19959630"],"is_preprint":false},{"year":2012,"finding":"CIP2A depletion inhibits JNK2 expression and transwell migration independently of MYC, whereas MYC depletion does not affect JNK2 expression or migration. PP2A inhibition reverses CIP2A siRNA-elicited inhibition of colony growth and activation of MYC-repressed genes.","method":"siRNA depletion of CIP2A vs. MYC, JNK2 expression analysis, transwell migration assay, PP2A inhibitor rescue experiment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via double knockdown and pharmacological rescue, single lab","pmids":["22249265"],"is_preprint":false},{"year":2016,"finding":"CIP2A promotes primary cilia disassembly through activation of Aurora A kinase; CIP2A depletion increases ciliated cell frequency and cilia length. CIP2A is localized in the centrosome. CIP2A depletion also shifts cellular metabolism toward the glycolytic pathway independently of cilia assembly.","method":"Immunofluorescence localization, CIP2A overexpression and siRNA depletion, Aurora A kinase activity measurement, cilia length quantification, glycolysis metabolic assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiment tied to functional phenotypes, gain- and loss-of-function, single lab","pmids":["29491003"],"is_preprint":false},{"year":2024,"finding":"CIP2A binds to PKM2 and induces PKM2 tetramer formation, with serine 287 identified as a novel phosphorylation site essential for PKM2 dimer-tetramer switching. CIP2A redirects PKM2 to the mitochondrion, leading to Bcl2 upregulation via phosphorylation of Bcl2 at threonine 69, thereby promoting oxidative phosphorylation and inhibiting glycolysis in NSCLC cells.","method":"Co-immunoprecipitation (CIP2A-PKM2 interaction), biochemical tetramer formation assays, site-directed mutagenesis of PKM2-S287, subcellular fractionation, Western blot for Bcl2-T69 phosphorylation, in vitro and in vivo metabolic assays","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical reconstitution of tetramer formation, mutagenesis of key residue, organelle localization, in vivo validation, single lab but multiple orthogonal methods","pmids":["38321019"],"is_preprint":false},{"year":2012,"finding":"In spermatogonial progenitor cells, CIP2A is co-expressed with PLZF and ki-67. CIP2A mutant mice show reduced PLZF-positive spermatogonial progenitor cell numbers and reduced sperm counts. Spermatogonia-specific restoration of CIP2A expression rescues PLZF expression and sperm production defects, establishing a physiological role for CIP2A in maintaining spermatogonial progenitor cells upstream of PLZF.","method":"CIP2A mutant mouse model, genetic rescue with spermatogonia-specific CIP2A re-expression, qRT-PCR for Plzf/Oct-4/Nanog, sperm count, PLZF IHC","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue in vivo establishes epistatic relationship, single lab","pmids":["22461891"],"is_preprint":false},{"year":2016,"finding":"CIP2A promotes T-cell activation during adaptive immune response; CIP2A-deficient mice show decreased frequency of CD4+ and CD8+ effector T-cells upon Listeria monocytogenes infection. CIP2A expression is induced during T-cell activation in a Zap70 activity-dependent manner.","method":"CIP2A-deficient mouse (CIP2AHOZ) model, Listeria infection challenge, T-cell frequency analysis by flow cytometry, Zap70 inhibitor treatment, cell-autonomous T-cell activation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model plus cell-autonomous confirmation, single lab","pmids":["27100879"],"is_preprint":false},{"year":2020,"finding":"CIP2A negatively regulates IL-17 production by Th17 cells; CIP2A-deficient Th17 cells show increased strength and duration of STAT3 phosphorylation. CIP2A regulates the strength of interaction between AGK (Acylglycerol Kinase) and STAT3, thereby modulating STAT3 phosphorylation and IL-17 expression.","method":"CIP2A-deficient mouse/human Th17 differentiation assays, phospho-STAT3 measurement, phospho-STAT3 interactome analysis by MS, genome-wide gene expression profiling, co-immunoprecipitation of AGK-STAT3","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interactome MS plus genetic KO plus gene expression profiling, single lab","pmids":["32171124"],"is_preprint":false},{"year":2021,"finding":"CIP2A directly interacts with TopBP1 (a DNA repair scaffold protein) and this interaction is required for DNA damage-induced mitotic checkpoint function and survival of HR-defective BLBC cells. CIP2A inhibition results in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. CIP2A drives MYC and E2F1 proliferative signaling in basal-like TNBC cells.","method":"Co-immunoprecipitation (CIP2A-TopBP1 direct interaction), CRISPR/Cas9 CIP2A knockout in isogenic cell pairs, chromatin fractionation for TopBP1/RAD51, BLBC mouse tumor initiation model, patient-derived xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP, genetic KO with functional phenotype, in vivo tumor model, consistent with PMID:35121901","pmids":["34145035"],"is_preprint":false},{"year":2023,"finding":"In meiosis I oocytes, CIP2A forms a complex with MDC1 and TOPBP1 at spindle poles; upon DSB induction, the CIP2A-MDC1-TOPBP1 complex is transported from spindle poles to chromosomes via microtubules (kinetochore/centromere as structural hub). This transport requires CENP-A and HEC1 and is regulated by PLK1 but not ATM. This mechanism allows oocytes to repair DSBs during meiosis.","method":"Immunofluorescence imaging, microtubule depolymerization experiments, CIP2A depletion (p-MDC1 and p-TOPBP1 recruitment assay), CENP-A/HEC1 depletion, PLK1 and ATM inhibition","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging plus genetic/pharmacological perturbations, single lab, novel context","pmids":["36999590"],"is_preprint":false},{"year":2021,"finding":"A CIP2A splicing variant called NOCIVA (novel CIP2A variant) contains CIP2A exons 1-13 fused to 349 nucleotides from CIP2A intron 13 encoding a unique 13-amino acid tail. NOCIVA retains capacity to bind B56α but, unlike cytoplasmic CIP2A, translocates to the nucleus. NOCIVA overexpression is characteristic of myeloid malignancies and predicts tyrosine kinase inhibitor resistance in CML.","method":"5' and 3' RACE for variant characterization, structural and molecular biology binding assays, nuclear/cytoplasmic fractionation, clinical cohort analysis for TKI resistance","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization of variant plus localization, single lab, clinical validation adds support","pmids":["33674272"],"is_preprint":false},{"year":2016,"finding":"CIP2A promotes p27Kip1 phosphorylation at Ser10 via inhibiting Akt-associated PP2A activity, causing p27Kip1 cytoplasmic relocalization and degradation. CIP2A also recruits c-Myc to mediate transcriptional inhibition of p27Kip1, resulting in cell cycle progression in TNBC cells.","method":"CIP2A siRNA knockdown, CIP2A overexpression, PP2A activity assay, Western blot for p27Kip1-Ser10 phosphorylation, nuclear/cytoplasmic fractionation, ChIP for c-Myc at p27Kip1 promoter, xenograft growth","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays including ChIP and fractionation with PP2A activity measurement, single lab","pmids":["27694903"],"is_preprint":false},{"year":2017,"finding":"CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin. CIP2A physically interacts with β-catenin (confirmed by co-immunoprecipitation and immunofluorescence co-localization), and this interaction enhances β-catenin stability and FN-induced proliferation.","method":"Co-immunoprecipitation, immunofluorescence co-localization, cycloheximide chase assay for β-catenin stability, CIP2A siRNA depletion, in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus cycloheximide chase plus in vivo, single lab","pmids":["28521777"],"is_preprint":false},{"year":2016,"finding":"HDAC1 controls CIP2A transcription; HDAC1 inhibition by a small molecule or specific siRNA downregulates CIP2A transcription in colorectal cancer cells, restoring PP2A activity, which dephosphorylates pGSK-3β(Ser9), leading to β-catenin phosphorylation, cytosolic retention, degradation, and decreased c-Myc/cyclin D1 expression.","method":"HDAC1 siRNA, pharmacological HDAC1 inhibitor, CIP2A mRNA/protein measurement, PP2A activity assay, β-catenin phosphorylation Western blot, in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological HDAC1 inhibition with PP2A activity assay establishing regulatory axis, single lab","pmids":["27029072"],"is_preprint":false},{"year":2015,"finding":"Oct4 positively regulates CIP2A expression in testicular cancer cell lines and embryonic stem cells; Oct4 and CIP2A are co-expressed in CD24-positive side-population of patient-derived HNSCC cell lines and cooperate in radioresistance.","method":"Oct4 overexpression/knockdown with CIP2A mRNA/protein measurement, luciferase reporter assays, cell line radioresistance assays","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional regulation suggested by reporter assays and expression correlation, single lab, limited mechanistic detail in abstract","pmids":["25474139"],"is_preprint":false},{"year":2018,"finding":"HOXB13 protein binds to the CIP2A gene locus (chromatin binding demonstrated) and functionally promotes CIP2A transcription; ectopic expression of HOXB13 stimulates prostate cancer cell growth and migration in a CIP2A-dependent manner.","method":"ChIP assay showing HOXB13 chromatin binding at CIP2A locus, CIP2A mRNA/protein measurement after HOXB13 overexpression, functional cell growth/migration assays","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence plus functional validation, single lab","pmids":["30181389"],"is_preprint":false},{"year":2014,"finding":"Estradiol increases CIP2A expression at the translational level in a c-MYC-independent manner via EGFR activation of MAPK and PI3K pathways converging on p70 S6 kinase (S6K), which phosphorylates eIF4B to increase CIP2A translation.","method":"Pharmacological inhibitors of EGFR, MEK, PI3K, and S6K; eIF4B phosphorylation Western blot; polysome profiling (translational regulation); cycloheximide chase; siRNA knockdown of S6K","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitors and mechanistic assays converging on translational mechanism, single lab","pmids":["24280132"],"is_preprint":false},{"year":2016,"finding":"Lapatinib inhibits CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter, and an erlotinib derivative TD52 also downregulates CIP2A transcription via Elk1; these transcription factor-CIP2A promoter interactions mediate drug-induced apoptosis through the CIP2A/PP2A/Akt axis.","method":"ChIP assay for Elk1 binding to CIP2A promoter, CIP2A mRNA measurement, PP2A activity assay, in vivo xenograft","journal":"Oncotarget / European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay demonstrating Elk1-CIP2A promoter interaction plus functional validation, replicated in two separate studies","pmids":["26824320","28027514"],"is_preprint":false},{"year":2022,"finding":"TP53TG1 lncRNA interacts with CIP2A protein and triggers its ubiquitination-mediated degradation, resulting in inhibition of the PI3K/AKT pathway.","method":"Co-immunoprecipitation (TP53TG1-CIP2A interaction), ubiquitination assay, CIP2A protein stability assay, Western blot for AKT signaling","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with functional readout, single lab, limited mechanistic detail in abstract","pmids":["36114757"],"is_preprint":false},{"year":2016,"finding":"CHK1 overexpression/constitutive activity positively regulates CIP2A gene expression, and pSTAT3 and CIP2A form a recursively wired transcriptional circuit in glioblastoma; perturbing CIP2A expression induces GBM cell senescence and retards tumor growth in vitro and in vivo.","method":"siRNA and pharmacological CHK1 inhibitors with CIP2A mRNA/protein measurement, pSTAT3 inhibition, luciferase reporter assays, in vivo GBM model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitors and reporter assays defining transcriptional circuit, single lab with in vivo validation","pmids":["32079743"],"is_preprint":false},{"year":2018,"finding":"MycN and CIP2A are co-expressed in the neural plate but excluded from the adjacent neural crest domain; ectopic expression of either MycN or CIP2A in the neural crest biases cells toward CNS-like neural stem cells expressing Sox2, suggesting a cell-fate regulatory function for CIP2A.","method":"In ovo electroporation of CIP2A and MycN in chick neural crest, immunofluorescence for neural identity markers (Sox2), lineage tracing","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo gain-of-function in embryo with defined cell-fate readout, single lab","pmids":["30021854"],"is_preprint":false},{"year":2016,"finding":"CIP2A promotes multidrug resistance in cervical adenocarcinoma by enhancing P-glycoprotein (P-gp) expression through the transcription factor E2F1; CIP2A knockdown decreases P-gp expression at the transcriptional level and reduces P-gp efflux activity.","method":"CIP2A siRNA and overexpression, P-gp expression (Western blot, RT-PCR), Rhodamine 123 efflux assay for P-gp activity, E2F1 regulation analysis, drug sensitivity assays","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect transcriptional mechanism via E2F1 with limited mechanistic detail on direct interaction","pmids":["26404133"],"is_preprint":false},{"year":2024,"finding":"SFXN1 (sideroflexin-1) promotes TNBC progression by inhibiting the autophagy receptor TOLLIP-mediated autophagic degradation of CIP2A, thereby maintaining CIP2A protein levels and activating the CIP2A/PP2A/p-AKT pathway.","method":"Label-free quantitative proteomics/LC-MS to identify SFXN1 targets, immunoblotting for CIP2A autophagy flux, immunofluorescence for co-localization, RT-qPCR, in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomic screen plus mechanistic follow-up, but TOLLIP-CIP2A interaction and selective autophagy mechanism need further direct biochemical validation; single lab","pmids":["38849012"],"is_preprint":false}],"current_model":"CIP2A is an oncoprotein that inhibits the tumor suppressor PP2A heterotrimer (particularly PP2A-B56α) by displacing the PP2A-A subunit and forming a CIP2A-B56α-PP2Ac pseudotrimer that also blocks substrate access to the B56α LxxIxE-binding pocket; structurally, CIP2A forms homodimers required for efficient B56 binding and its own stability. Through PP2A inhibition, CIP2A stabilizes c-Myc (by blocking PP2A-mediated dephosphorylation of c-Myc-S62), activates AKT and mTORC1 signaling, and allosterically inhibits mTORC1-associated PP2A to enhance growth signaling and suppress autophagy. Beyond PP2A inhibition, CIP2A directly binds the polo-box domain of Plk1 to maintain Plk1 stability and kinase activity during mitosis, and forms a mitosis-specific complex with TOPBP1 (and MDC1) that is actively excluded from the nucleus during interphase but gains chromatin access upon nuclear envelope breakdown to facilitate TOPBP1 recruitment to mitotic DNA lesions, preventing lethal chromosome mis-segregation—a function that is selectively essential in BRCA1/2-deficient cells. CIP2A also directly binds PKM2 to induce its tetramerization and redirect it to mitochondria, promoting oxidative phosphorylation in lung cancer cells. CIP2A undergoes p62/SQSTM1-dependent autophagic degradation upon mTORC1 inhibition, creating a feedback circuit that links nutrient status to c-Myc stability."},"narrative":{"mechanistic_narrative":"CIP2A is an oncoprotein whose central activity is the inhibition of the tumor-suppressor phosphatase PP2A, through which it stabilizes c-Myc and drives proliferative signaling in multiple cancers [PMID:17632056]. Structurally, CIP2A forms homodimers via a conserved N-terminal region required for efficient binding to the PP2A B56 regulatory subunits, and dimerization or B56 binding is needed for CIP2A's own stability [PMID:28174209]. It inhibits PP2A-B56α by displacing the PP2A-A scaffold subunit and hijacking B56α and the catalytic PP2Ac subunit into a CIP2A-B56α-PP2Ac pseudotrimer, while simultaneously occluding the LxxIxE substrate-binding pocket of B56α; targeted mutation of the N-terminal head domain blunts MYC expression and MEK phosphorylation and abrogates triple-negative breast cancer growth in vivo [PMID:36854761]. By suppressing PP2A activity toward c-Myc-S62, Akt, and p27Kip1, CIP2A sustains growth and cell-cycle progression [PMID:17632056, PMID:20729919, PMID:27694903]. CIP2A additionally associates with mTORC1 as an allosteric inhibitor of mTORC1-associated PP2A, enhancing growth signaling and suppressing autophagy, and is itself subject to p62/SQSTM1-dependent autophagic degradation upon nutrient deprivation, forming a feedback circuit that couples nutrient status to c-Myc stability [PMID:24590173]. Beyond phosphatase inhibition, CIP2A performs PP2A-independent mitotic functions: it binds the polo-box domain of Plk1 to block APC/C-Cdh1-mediated proteolysis and maintain Plk1 activity [PMID:23983103], and it forms a mitosis-specific complex with TOPBP1 and MDC1 that is nuclear-excluded during interphase but accesses chromatin upon nuclear envelope breakdown to recruit TOPBP1 to mitotic DNA lesions and prevent lethal chromosome mis-segregation—a function selectively essential in BRCA1/2-deficient cancers, establishing CIP2A as a synthetic-lethal target [PMID:35121901, PMID:35842428, PMID:34145035]. CIP2A also directly binds PKM2 to induce its tetramerization and mitochondrial relocalization, promoting oxidative phosphorylation in lung cancer cells [PMID:38321019]. CIP2A levels are controlled transcriptionally by factors including HDAC1, HOXB13, and Elk1 [PMID:27029072, PMID:30181389, PMID:26824320, PMID:28027514] and contribute to physiological roles in spermatogonial progenitor maintenance and T-cell activation [PMID:22461891, PMID:27100879].","teleology":[{"year":2007,"claim":"Established CIP2A's founding identity: it was unknown how c-Myc escaped PP2A-mediated turnover, and this work showed CIP2A binds c-Myc, inhibits PP2A toward c-Myc-S62, and is itself transforming.","evidence":"Co-IP, PP2A activity assays, cell transformation and in vivo tumor assays","pmids":["17632056"],"confidence":"High","gaps":["Did not resolve the structural basis of PP2A inhibition","Did not distinguish direct versus indirect c-Myc binding mechanism"]},{"year":2010,"claim":"Extended PP2A inhibition to Akt signaling, addressing whether CIP2A acts beyond c-Myc by showing it suppresses Akt-directed PP2A activity to elevate phospho-Akt.","evidence":"siRNA and overexpression with Akt-substrate PP2A activity assays and xenograft in hepatocellular carcinoma","pmids":["20729919"],"confidence":"Medium","gaps":["Single lab","Did not define which PP2A holoenzyme mediates the Akt effect"]},{"year":2013,"claim":"Revealed a PP2A-independent mitotic role, answering how CIP2A affects mitosis: it binds the Plk1 polo-box domain to block APC/C-Cdh1 degradation and sustain Plk1 activity.","evidence":"Subcellular fractionation, Co-IP, Plk1 kinase and APC/C-Cdh1 ubiquitination assays, siRNA phenotyping","pmids":["23983103"],"confidence":"High","gaps":["Did not map the Plk1-binding region on CIP2A","Relationship to the later TOPBP1 mitotic complex unaddressed"]},{"year":2014,"claim":"Connected CIP2A to nutrient sensing and autophagy, showing it allosterically inhibits mTORC1-associated PP2A and is degraded via p62-dependent autophagy under starvation, forming a feedback loop to c-Myc.","evidence":"RNAi screen, reciprocal Co-IP, PP2A activity, autophagy flux and ubiquitination assays","pmids":["24590173"],"confidence":"High","gaps":["E3 ligase for CIP2A ubiquitination not identified","Stoichiometry of CIP2A within mTORC1 unresolved"]},{"year":2017,"claim":"Provided the structural basis for PP2A engagement: a crystal structure of the N-terminal fragment showed CIP2A homodimerizes and that dimerization is required for B56α/γ binding and CIP2A stability.","evidence":"Yeast two-hybrid, 3.0 Å crystal structure, structure-based mutagenesis, Co-IP","pmids":["28174209"],"confidence":"High","gaps":["Structure covered only residues 1-560","Did not capture the assembled PP2A-CIP2A complex"]},{"year":2021,"claim":"Defined the mitotic DNA-lesion function and a therapeutic vulnerability, showing CIP2A localizes to DNA lesions in mitosis with TOPBP1 and is synthetically lethal in BRCA-deficient cells through prevention of acentric chromosome mis-segregation.","evidence":"Genome-scale CRISPR synthetic-lethality screens, live imaging, Co-IP, chromosome segregation assays","pmids":["35121901","34145035"],"confidence":"High","gaps":["Mechanism by which CIP2A senses or marks mitotic lesions unresolved","Direct chromatin recruitment determinants not mapped"]},{"year":2022,"claim":"Clarified spatiotemporal control of the lesion complex, showing CIP2A is actively exported from interphase nuclei and only accesses chromatin at nuclear envelope breakdown to assemble with MDC1 and TOPBP1 at mitotic double-strand breaks.","evidence":"Co-IP, live imaging, fractionation, nuclear export inhibition, foci quantification","pmids":["35842428"],"confidence":"High","gaps":["Nuclear export signal/receptor not defined","Order of assembly among CIP2A, MDC1, TOPBP1 unresolved"]},{"year":2023,"claim":"Delivered the molecular mechanism of PP2A inhibition, showing CIP2A displaces the PP2A-A subunit to form a pseudotrimer and blocks the B56α substrate pocket, validated by CRISPR head-domain mutagenesis abrogating tumor growth.","evidence":"Structural biology, CRISPR single-residue mutagenesis, phosphatase assays, xenograft","pmids":["36854761"],"confidence":"High","gaps":["Generality of pseudotrimer model to other B56 isoforms not fully tested","Did not address PP2A-independent functions"]},{"year":2024,"claim":"Identified a metabolic role, showing CIP2A directly binds PKM2 to drive its tetramerization and mitochondrial relocalization, promoting oxidative phosphorylation in NSCLC.","evidence":"Co-IP, tetramer formation assays, PKM2-S287 mutagenesis, fractionation, in vivo metabolic assays","pmids":["38321019"],"confidence":"High","gaps":["Single lab","Kinase responsible for PKM2-S287 and Bcl2-T69 phosphorylation not identified"]},{"year":null,"claim":"It remains unresolved how CIP2A's distinct activities—PP2A pseudotrimer formation, Plk1 stabilization, mitotic TOPBP1 recruitment, and PKM2 tetramerization—are coordinated or partitioned across the cell cycle and tissue contexts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the full-length protein or of the mitotic CIP2A-TOPBP1-MDC1 complex","Mechanism switching CIP2A between PP2A-dependent and PP2A-independent modes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,5,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6,14]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,9]},{"term_id":"R-HSA-1640170","term_label":"Cell 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Promotes anchorage-independent cell growth and tumor formation by preventing dephosphorylation of MYC, thereby stabilizing MYC in human malignancies (PubMed:17632056). Together with TOPBP1, plays an essential role in the response to genome instability generated by the presence of acentric chromosome fragments derived from shattered chromosomes within micronuclei (PubMed:35121901, PubMed:35842428, PubMed:37165191, PubMed:37316668). Micronuclei, which are frequently found in cancer cells, consist of chromatin surrounded by their own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, the CIP2A-TOPBP1 complex tethers chromosome fragments during mitosis to ensure clustered segregation of the fragments to a single daughter cell nucleus, facilitating re-ligation with limited chromosome scattering and loss (PubMed:37165191, PubMed:37316668)","subcellular_location":"Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8TCG1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIP2A","classification":"Not 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membrane","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Overexpression of CIP2A transforms human cells, demonstrating direct oncogenic activity.\",\n      \"method\": \"Direct interaction shown by co-immunoprecipitation; PP2A activity assays; cell transformation assays; in vivo tumor formation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — foundational paper with multiple orthogonal methods (Co-IP, phosphatase assays, transformation, in vivo), widely replicated across subsequent studies\",\n      \"pmids\": [\"17632056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIP2A forms homodimers, as confirmed by crystal structure of the N-terminal fragment (amino acids 1-560) at 3.0 Å resolution and structure-based mutational analyses. The CIP2A dimer interacts with PP2A subunits B56α and B56γ via a conserved N-terminal region; dimerization promotes B56 binding. Inhibition of either CIP2A dimerization or B56α/γ expression destabilizes CIP2A.\",\n      \"method\": \"Yeast two-hybrid, crystal structure determination, structure-based mutagenesis, co-immunoprecipitation validation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus orthogonal binding assays in a single rigorous study\",\n      \"pmids\": [\"28174209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CIP2A inhibits PP2A-B56α by displacing the PP2A-A subunit and hijacking both B56α and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. CIP2A also competes with B56α substrates by blocking the LxxIxE-motif substrate binding pocket on B56α. The N-terminal head domain mediates interaction with B56α and stabilizes CIP2A protein. CRISPR/Cas9 single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation and abrogated triple-negative breast cancer tumor growth in vivo.\",\n      \"method\": \"Structural biology, CRISPR/Cas9 mutagenesis, phosphatase activity assays, in vivo xenograft tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural mechanism plus functional CRISPR mutagenesis plus in vivo validation in a single study\",\n      \"pmids\": [\"36854761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIP2A is cytoplasmic during interphase but accumulates at DNA lesions in mitosis as part of a complex with TOPBP1. CIP2A deficiency does not cause replication-associated DNA lesions but leads to lethal mis-segregation of acentric chromosomes in BRCA-deficient cells. Physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient tumors, establishing CIP2A as a synthetic lethal target in BRCA1/2-mutated cancers.\",\n      \"method\": \"Genome-scale CRISPR-Cas9 synthetic lethality screens in isogenic BRCA1/2-deficient cells, live-cell imaging, co-immunoprecipitation, functional chromosome segregation assays\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale CRISPR screen plus mechanistic follow-up with multiple orthogonal methods, independently replicated concept\",\n      \"pmids\": [\"35121901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIP2A is actively exported from the cell nucleus during interphase but, upon nuclear envelope breakdown at mitosis onset, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DNA double-strand breaks. Loss of CIP2A causes increased radio-sensitivity, micronuclei formation, and chromosomal instability.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, subcellular fractionation, nuclear export inhibition experiments, gamma-H2AX/TOPBP1 foci quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including live imaging and fractionation with functional consequence, consistent with independent PMID:35121901\",\n      \"pmids\": [\"35842428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, enhancing mTORC1-dependent growth signaling and inhibiting autophagy. Under nutrient deprivation, CIP2A undergoes ubiquitination and p62/SQSTM1-dependent autophagic degradation, which reverses mTORC1 activation and destabilizes c-Myc.\",\n      \"method\": \"RNAi screen, co-immunoprecipitation (CIP2A-mTORC1 association), PP2A activity assays, autophagy flux assays, ubiquitination assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi screen discovery plus reciprocal Co-IP plus mechanistic assays in multiple cell models\",\n      \"pmids\": [\"24590173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CIP2A translocates from the cytoplasm to the nucleus at mitotic entry, enriching at spindle poles. CIP2A directly interacts with the polo-box domain of Plk1 during mitosis, maintaining Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis and enhancing Plk1 kinase activity. CIP2A depletion delays mitotic progression and causes mitotic abnormalities independently of PP2A activity.\",\n      \"method\": \"Subcellular fractionation and immunofluorescence (localization), co-immunoprecipitation (CIP2A-Plk1 interaction), Plk1 kinase activity assays, APC/C-Cdh1 ubiquitination assays, siRNA depletion with mitotic phenotype readout\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP of CIP2A-Plk1 polo-box domain interaction, kinase activity assays, and localization with functional consequence, all in single study\",\n      \"pmids\": [\"23983103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A micropeptide CIP2A-BP encoded by LINC00665 directly binds CIP2A and replaces the PP2A B56γ subunit, thereby releasing PP2A activity, which inhibits the PI3K/AKT/NFκB pathway and decreases expression of MMP-2, MMP-9, and Snail. TGF-β suppresses CIP2A-BP translation via Smad-induced 4E-BP1 upregulation.\",\n      \"method\": \"Co-immunoprecipitation (CIP2A-BP with CIP2A and B56γ), PP2A activity assays, Western blot, in vivo MMTV-PyMT model with CIP2A-BP gene introduction or direct peptide injection\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, biochemical PP2A release assay, and in vivo rescue experiment providing multiple orthogonal lines of evidence\",\n      \"pmids\": [\"31755573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CIP2A physically associates with H-Ras in cervical cancer cells, leading to activation of the MEK/ERK signaling pathway and promoting epithelial-to-mesenchymal transition (EMT) and cervical cancer progression.\",\n      \"method\": \"Pull-down assay, mass spectrometry peptide sequencing, bilateral co-immunoprecipitation\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP and MS identification, but single lab and limited mechanistic follow-up on the H-Ras interaction\",\n      \"pmids\": [\"25458953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CIP2A negatively regulates Akt-related PP2A activity in hepatocellular carcinoma cells; ectopic expression of CIP2A decreased Akt-related PP2A activity and upregulated phospho-Akt, while silencing CIP2A increased PP2A activity toward Akt.\",\n      \"method\": \"siRNA knockdown, CIP2A overexpression, PP2A phosphatase activity assays specific to Akt substrate, Western blot, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with PP2A activity assay, single lab but two complementary approaches\",\n      \"pmids\": [\"20729919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIP2A overexpression in neurons causes PP2A inhibition, driving tau/APP hyperphosphorylation at multiple sites, increased APP β-cleavage and Aβ production, tau mislocalization to dendrites and spines, synaptic degeneration, and cognitive deficits. AAV-CIP2A hippocampal injection in mice induced AD-like cognitive deficits and impaired LTP.\",\n      \"method\": \"AAV-mediated CIP2A overexpression in mouse hippocampus, PP2A activity assays, Western blot for phospho-tau/APP, LTP electrophysiology, behavioral cognitive assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo AAV gain-of-function with multiple orthogonal readouts (phosphorylation, electrophysiology, behavior) establishing causal mechanism\",\n      \"pmids\": [\"30021167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Chk1 activity is elevated in AD brains and Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Chk1 inhibition decreases CIP2A expression and restores PP2A activity.\",\n      \"method\": \"AAV-GFAP-ChK1 in vivo brain injection, Chk1 inhibitor (GDC0575) treatment in AD cell models and APP/PS1 mice, Western blot, PP2A activity assays, behavioral tests\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and cell model data with gain/loss-of-function, single lab\",\n      \"pmids\": [\"35286657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"H. pylori CagA protein upregulates CIP2A expression in gastric cells via the Src and MEK/ERK (Ras/MEK/ERK) signaling pathways, and CIP2A upregulation is dependent on CagA phosphorylation. CIP2A depletion partially attenuated H. pylori infection-induced Myc stabilization.\",\n      \"method\": \"Plasmid-mediated CagA expression in gastric cell lines, H. pylori infection, signal inhibitors (Src inhibitor, MEK inhibitor), immunoblotting, CIP2A siRNA depletion\",\n      \"journal\": \"Journal of medical microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitors plus genetic knockdown, single lab, two orthogonal approaches\",\n      \"pmids\": [\"19959630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CIP2A depletion inhibits JNK2 expression and transwell migration independently of MYC, whereas MYC depletion does not affect JNK2 expression or migration. PP2A inhibition reverses CIP2A siRNA-elicited inhibition of colony growth and activation of MYC-repressed genes.\",\n      \"method\": \"siRNA depletion of CIP2A vs. MYC, JNK2 expression analysis, transwell migration assay, PP2A inhibitor rescue experiment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via double knockdown and pharmacological rescue, single lab\",\n      \"pmids\": [\"22249265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CIP2A promotes primary cilia disassembly through activation of Aurora A kinase; CIP2A depletion increases ciliated cell frequency and cilia length. CIP2A is localized in the centrosome. CIP2A depletion also shifts cellular metabolism toward the glycolytic pathway independently of cilia assembly.\",\n      \"method\": \"Immunofluorescence localization, CIP2A overexpression and siRNA depletion, Aurora A kinase activity measurement, cilia length quantification, glycolysis metabolic assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiment tied to functional phenotypes, gain- and loss-of-function, single lab\",\n      \"pmids\": [\"29491003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CIP2A binds to PKM2 and induces PKM2 tetramer formation, with serine 287 identified as a novel phosphorylation site essential for PKM2 dimer-tetramer switching. CIP2A redirects PKM2 to the mitochondrion, leading to Bcl2 upregulation via phosphorylation of Bcl2 at threonine 69, thereby promoting oxidative phosphorylation and inhibiting glycolysis in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation (CIP2A-PKM2 interaction), biochemical tetramer formation assays, site-directed mutagenesis of PKM2-S287, subcellular fractionation, Western blot for Bcl2-T69 phosphorylation, in vitro and in vivo metabolic assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical reconstitution of tetramer formation, mutagenesis of key residue, organelle localization, in vivo validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38321019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In spermatogonial progenitor cells, CIP2A is co-expressed with PLZF and ki-67. CIP2A mutant mice show reduced PLZF-positive spermatogonial progenitor cell numbers and reduced sperm counts. Spermatogonia-specific restoration of CIP2A expression rescues PLZF expression and sperm production defects, establishing a physiological role for CIP2A in maintaining spermatogonial progenitor cells upstream of PLZF.\",\n      \"method\": \"CIP2A mutant mouse model, genetic rescue with spermatogonia-specific CIP2A re-expression, qRT-PCR for Plzf/Oct-4/Nanog, sperm count, PLZF IHC\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue in vivo establishes epistatic relationship, single lab\",\n      \"pmids\": [\"22461891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CIP2A promotes T-cell activation during adaptive immune response; CIP2A-deficient mice show decreased frequency of CD4+ and CD8+ effector T-cells upon Listeria monocytogenes infection. CIP2A expression is induced during T-cell activation in a Zap70 activity-dependent manner.\",\n      \"method\": \"CIP2A-deficient mouse (CIP2AHOZ) model, Listeria infection challenge, T-cell frequency analysis by flow cytometry, Zap70 inhibitor treatment, cell-autonomous T-cell activation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model plus cell-autonomous confirmation, single lab\",\n      \"pmids\": [\"27100879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIP2A negatively regulates IL-17 production by Th17 cells; CIP2A-deficient Th17 cells show increased strength and duration of STAT3 phosphorylation. CIP2A regulates the strength of interaction between AGK (Acylglycerol Kinase) and STAT3, thereby modulating STAT3 phosphorylation and IL-17 expression.\",\n      \"method\": \"CIP2A-deficient mouse/human Th17 differentiation assays, phospho-STAT3 measurement, phospho-STAT3 interactome analysis by MS, genome-wide gene expression profiling, co-immunoprecipitation of AGK-STAT3\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome MS plus genetic KO plus gene expression profiling, single lab\",\n      \"pmids\": [\"32171124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIP2A directly interacts with TopBP1 (a DNA repair scaffold protein) and this interaction is required for DNA damage-induced mitotic checkpoint function and survival of HR-defective BLBC cells. CIP2A inhibition results in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. CIP2A drives MYC and E2F1 proliferative signaling in basal-like TNBC cells.\",\n      \"method\": \"Co-immunoprecipitation (CIP2A-TopBP1 direct interaction), CRISPR/Cas9 CIP2A knockout in isogenic cell pairs, chromatin fractionation for TopBP1/RAD51, BLBC mouse tumor initiation model, patient-derived xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP, genetic KO with functional phenotype, in vivo tumor model, consistent with PMID:35121901\",\n      \"pmids\": [\"34145035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In meiosis I oocytes, CIP2A forms a complex with MDC1 and TOPBP1 at spindle poles; upon DSB induction, the CIP2A-MDC1-TOPBP1 complex is transported from spindle poles to chromosomes via microtubules (kinetochore/centromere as structural hub). This transport requires CENP-A and HEC1 and is regulated by PLK1 but not ATM. This mechanism allows oocytes to repair DSBs during meiosis.\",\n      \"method\": \"Immunofluorescence imaging, microtubule depolymerization experiments, CIP2A depletion (p-MDC1 and p-TOPBP1 recruitment assay), CENP-A/HEC1 depletion, PLK1 and ATM inhibition\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging plus genetic/pharmacological perturbations, single lab, novel context\",\n      \"pmids\": [\"36999590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A CIP2A splicing variant called NOCIVA (novel CIP2A variant) contains CIP2A exons 1-13 fused to 349 nucleotides from CIP2A intron 13 encoding a unique 13-amino acid tail. NOCIVA retains capacity to bind B56α but, unlike cytoplasmic CIP2A, translocates to the nucleus. NOCIVA overexpression is characteristic of myeloid malignancies and predicts tyrosine kinase inhibitor resistance in CML.\",\n      \"method\": \"5' and 3' RACE for variant characterization, structural and molecular biology binding assays, nuclear/cytoplasmic fractionation, clinical cohort analysis for TKI resistance\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization of variant plus localization, single lab, clinical validation adds support\",\n      \"pmids\": [\"33674272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CIP2A promotes p27Kip1 phosphorylation at Ser10 via inhibiting Akt-associated PP2A activity, causing p27Kip1 cytoplasmic relocalization and degradation. CIP2A also recruits c-Myc to mediate transcriptional inhibition of p27Kip1, resulting in cell cycle progression in TNBC cells.\",\n      \"method\": \"CIP2A siRNA knockdown, CIP2A overexpression, PP2A activity assay, Western blot for p27Kip1-Ser10 phosphorylation, nuclear/cytoplasmic fractionation, ChIP for c-Myc at p27Kip1 promoter, xenograft growth\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays including ChIP and fractionation with PP2A activity measurement, single lab\",\n      \"pmids\": [\"27694903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin. CIP2A physically interacts with β-catenin (confirmed by co-immunoprecipitation and immunofluorescence co-localization), and this interaction enhances β-catenin stability and FN-induced proliferation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, cycloheximide chase assay for β-catenin stability, CIP2A siRNA depletion, in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus cycloheximide chase plus in vivo, single lab\",\n      \"pmids\": [\"28521777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HDAC1 controls CIP2A transcription; HDAC1 inhibition by a small molecule or specific siRNA downregulates CIP2A transcription in colorectal cancer cells, restoring PP2A activity, which dephosphorylates pGSK-3β(Ser9), leading to β-catenin phosphorylation, cytosolic retention, degradation, and decreased c-Myc/cyclin D1 expression.\",\n      \"method\": \"HDAC1 siRNA, pharmacological HDAC1 inhibitor, CIP2A mRNA/protein measurement, PP2A activity assay, β-catenin phosphorylation Western blot, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological HDAC1 inhibition with PP2A activity assay establishing regulatory axis, single lab\",\n      \"pmids\": [\"27029072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Oct4 positively regulates CIP2A expression in testicular cancer cell lines and embryonic stem cells; Oct4 and CIP2A are co-expressed in CD24-positive side-population of patient-derived HNSCC cell lines and cooperate in radioresistance.\",\n      \"method\": \"Oct4 overexpression/knockdown with CIP2A mRNA/protein measurement, luciferase reporter assays, cell line radioresistance assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional regulation suggested by reporter assays and expression correlation, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"25474139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXB13 protein binds to the CIP2A gene locus (chromatin binding demonstrated) and functionally promotes CIP2A transcription; ectopic expression of HOXB13 stimulates prostate cancer cell growth and migration in a CIP2A-dependent manner.\",\n      \"method\": \"ChIP assay showing HOXB13 chromatin binding at CIP2A locus, CIP2A mRNA/protein measurement after HOXB13 overexpression, functional cell growth/migration assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence plus functional validation, single lab\",\n      \"pmids\": [\"30181389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Estradiol increases CIP2A expression at the translational level in a c-MYC-independent manner via EGFR activation of MAPK and PI3K pathways converging on p70 S6 kinase (S6K), which phosphorylates eIF4B to increase CIP2A translation.\",\n      \"method\": \"Pharmacological inhibitors of EGFR, MEK, PI3K, and S6K; eIF4B phosphorylation Western blot; polysome profiling (translational regulation); cycloheximide chase; siRNA knockdown of S6K\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitors and mechanistic assays converging on translational mechanism, single lab\",\n      \"pmids\": [\"24280132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lapatinib inhibits CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter, and an erlotinib derivative TD52 also downregulates CIP2A transcription via Elk1; these transcription factor-CIP2A promoter interactions mediate drug-induced apoptosis through the CIP2A/PP2A/Akt axis.\",\n      \"method\": \"ChIP assay for Elk1 binding to CIP2A promoter, CIP2A mRNA measurement, PP2A activity assay, in vivo xenograft\",\n      \"journal\": \"Oncotarget / European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay demonstrating Elk1-CIP2A promoter interaction plus functional validation, replicated in two separate studies\",\n      \"pmids\": [\"26824320\", \"28027514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TP53TG1 lncRNA interacts with CIP2A protein and triggers its ubiquitination-mediated degradation, resulting in inhibition of the PI3K/AKT pathway.\",\n      \"method\": \"Co-immunoprecipitation (TP53TG1-CIP2A interaction), ubiquitination assay, CIP2A protein stability assay, Western blot for AKT signaling\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with functional readout, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"36114757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHK1 overexpression/constitutive activity positively regulates CIP2A gene expression, and pSTAT3 and CIP2A form a recursively wired transcriptional circuit in glioblastoma; perturbing CIP2A expression induces GBM cell senescence and retards tumor growth in vitro and in vivo.\",\n      \"method\": \"siRNA and pharmacological CHK1 inhibitors with CIP2A mRNA/protein measurement, pSTAT3 inhibition, luciferase reporter assays, in vivo GBM model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitors and reporter assays defining transcriptional circuit, single lab with in vivo validation\",\n      \"pmids\": [\"32079743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MycN and CIP2A are co-expressed in the neural plate but excluded from the adjacent neural crest domain; ectopic expression of either MycN or CIP2A in the neural crest biases cells toward CNS-like neural stem cells expressing Sox2, suggesting a cell-fate regulatory function for CIP2A.\",\n      \"method\": \"In ovo electroporation of CIP2A and MycN in chick neural crest, immunofluorescence for neural identity markers (Sox2), lineage tracing\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo gain-of-function in embryo with defined cell-fate readout, single lab\",\n      \"pmids\": [\"30021854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CIP2A promotes multidrug resistance in cervical adenocarcinoma by enhancing P-glycoprotein (P-gp) expression through the transcription factor E2F1; CIP2A knockdown decreases P-gp expression at the transcriptional level and reduces P-gp efflux activity.\",\n      \"method\": \"CIP2A siRNA and overexpression, P-gp expression (Western blot, RT-PCR), Rhodamine 123 efflux assay for P-gp activity, E2F1 regulation analysis, drug sensitivity assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect transcriptional mechanism via E2F1 with limited mechanistic detail on direct interaction\",\n      \"pmids\": [\"26404133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SFXN1 (sideroflexin-1) promotes TNBC progression by inhibiting the autophagy receptor TOLLIP-mediated autophagic degradation of CIP2A, thereby maintaining CIP2A protein levels and activating the CIP2A/PP2A/p-AKT pathway.\",\n      \"method\": \"Label-free quantitative proteomics/LC-MS to identify SFXN1 targets, immunoblotting for CIP2A autophagy flux, immunofluorescence for co-localization, RT-qPCR, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomic screen plus mechanistic follow-up, but TOLLIP-CIP2A interaction and selective autophagy mechanism need further direct biochemical validation; single lab\",\n      \"pmids\": [\"38849012\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIP2A is an oncoprotein that inhibits the tumor suppressor PP2A heterotrimer (particularly PP2A-B56α) by displacing the PP2A-A subunit and forming a CIP2A-B56α-PP2Ac pseudotrimer that also blocks substrate access to the B56α LxxIxE-binding pocket; structurally, CIP2A forms homodimers required for efficient B56 binding and its own stability. Through PP2A inhibition, CIP2A stabilizes c-Myc (by blocking PP2A-mediated dephosphorylation of c-Myc-S62), activates AKT and mTORC1 signaling, and allosterically inhibits mTORC1-associated PP2A to enhance growth signaling and suppress autophagy. Beyond PP2A inhibition, CIP2A directly binds the polo-box domain of Plk1 to maintain Plk1 stability and kinase activity during mitosis, and forms a mitosis-specific complex with TOPBP1 (and MDC1) that is actively excluded from the nucleus during interphase but gains chromatin access upon nuclear envelope breakdown to facilitate TOPBP1 recruitment to mitotic DNA lesions, preventing lethal chromosome mis-segregation—a function that is selectively essential in BRCA1/2-deficient cells. CIP2A also directly binds PKM2 to induce its tetramerization and redirect it to mitochondria, promoting oxidative phosphorylation in lung cancer cells. CIP2A undergoes p62/SQSTM1-dependent autophagic degradation upon mTORC1 inhibition, creating a feedback circuit that links nutrient status to c-Myc stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIP2A is an oncoprotein whose central activity is the inhibition of the tumor-suppressor phosphatase PP2A, through which it stabilizes c-Myc and drives proliferative signaling in multiple cancers [#0]. Structurally, CIP2A forms homodimers via a conserved N-terminal region required for efficient binding to the PP2A B56 regulatory subunits, and dimerization or B56 binding is needed for CIP2A's own stability [#1]. It inhibits PP2A-B56\\u03b1 by displacing the PP2A-A scaffold subunit and hijacking B56\\u03b1 and the catalytic PP2Ac subunit into a CIP2A-B56\\u03b1-PP2Ac pseudotrimer, while simultaneously occluding the LxxIxE substrate-binding pocket of B56\\u03b1; targeted mutation of the N-terminal head domain blunts MYC expression and MEK phosphorylation and abrogates triple-negative breast cancer growth in vivo [#2]. By suppressing PP2A activity toward c-Myc-S62, Akt, and p27Kip1, CIP2A sustains growth and cell-cycle progression [#0, #9, #22]. CIP2A additionally associates with mTORC1 as an allosteric inhibitor of mTORC1-associated PP2A, enhancing growth signaling and suppressing autophagy, and is itself subject to p62/SQSTM1-dependent autophagic degradation upon nutrient deprivation, forming a feedback circuit that couples nutrient status to c-Myc stability [#5]. Beyond phosphatase inhibition, CIP2A performs PP2A-independent mitotic functions: it binds the polo-box domain of Plk1 to block APC/C-Cdh1-mediated proteolysis and maintain Plk1 activity [#6], and it forms a mitosis-specific complex with TOPBP1 and MDC1 that is nuclear-excluded during interphase but accesses chromatin upon nuclear envelope breakdown to recruit TOPBP1 to mitotic DNA lesions and prevent lethal chromosome mis-segregation\\u2014a function selectively essential in BRCA1/2-deficient cancers, establishing CIP2A as a synthetic-lethal target [#3, #4, #19]. CIP2A also directly binds PKM2 to induce its tetramerization and mitochondrial relocalization, promoting oxidative phosphorylation in lung cancer cells [#15]. CIP2A levels are controlled transcriptionally by factors including HDAC1, HOXB13, and Elk1 [#24, #26, #28] and contribute to physiological roles in spermatogonial progenitor maintenance and T-cell activation [#16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established CIP2A's founding identity: it was unknown how c-Myc escaped PP2A-mediated turnover, and this work showed CIP2A binds c-Myc, inhibits PP2A toward c-Myc-S62, and is itself transforming.\",\n      \"evidence\": \"Co-IP, PP2A activity assays, cell transformation and in vivo tumor assays\",\n      \"pmids\": [\"17632056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of PP2A inhibition\", \"Did not distinguish direct versus indirect c-Myc binding mechanism\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended PP2A inhibition to Akt signaling, addressing whether CIP2A acts beyond c-Myc by showing it suppresses Akt-directed PP2A activity to elevate phospho-Akt.\",\n      \"evidence\": \"siRNA and overexpression with Akt-substrate PP2A activity assays and xenograft in hepatocellular carcinoma\",\n      \"pmids\": [\"20729919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not define which PP2A holoenzyme mediates the Akt effect\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a PP2A-independent mitotic role, answering how CIP2A affects mitosis: it binds the Plk1 polo-box domain to block APC/C-Cdh1 degradation and sustain Plk1 activity.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP, Plk1 kinase and APC/C-Cdh1 ubiquitination assays, siRNA phenotyping\",\n      \"pmids\": [\"23983103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the Plk1-binding region on CIP2A\", \"Relationship to the later TOPBP1 mitotic complex unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CIP2A to nutrient sensing and autophagy, showing it allosterically inhibits mTORC1-associated PP2A and is degraded via p62-dependent autophagy under starvation, forming a feedback loop to c-Myc.\",\n      \"evidence\": \"RNAi screen, reciprocal Co-IP, PP2A activity, autophagy flux and ubiquitination assays\",\n      \"pmids\": [\"24590173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase for CIP2A ubiquitination not identified\", \"Stoichiometry of CIP2A within mTORC1 unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the structural basis for PP2A engagement: a crystal structure of the N-terminal fragment showed CIP2A homodimerizes and that dimerization is required for B56\\u03b1/\\u03b3 binding and CIP2A stability.\",\n      \"evidence\": \"Yeast two-hybrid, 3.0 \\u00c5 crystal structure, structure-based mutagenesis, Co-IP\",\n      \"pmids\": [\"28174209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure covered only residues 1-560\", \"Did not capture the assembled PP2A-CIP2A complex\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the mitotic DNA-lesion function and a therapeutic vulnerability, showing CIP2A localizes to DNA lesions in mitosis with TOPBP1 and is synthetically lethal in BRCA-deficient cells through prevention of acentric chromosome mis-segregation.\",\n      \"evidence\": \"Genome-scale CRISPR synthetic-lethality screens, live imaging, Co-IP, chromosome segregation assays\",\n      \"pmids\": [\"35121901\", \"34145035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CIP2A senses or marks mitotic lesions unresolved\", \"Direct chromatin recruitment determinants not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Clarified spatiotemporal control of the lesion complex, showing CIP2A is actively exported from interphase nuclei and only accesses chromatin at nuclear envelope breakdown to assemble with MDC1 and TOPBP1 at mitotic double-strand breaks.\",\n      \"evidence\": \"Co-IP, live imaging, fractionation, nuclear export inhibition, foci quantification\",\n      \"pmids\": [\"35842428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear export signal/receptor not defined\", \"Order of assembly among CIP2A, MDC1, TOPBP1 unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Delivered the molecular mechanism of PP2A inhibition, showing CIP2A displaces the PP2A-A subunit to form a pseudotrimer and blocks the B56\\u03b1 substrate pocket, validated by CRISPR head-domain mutagenesis abrogating tumor growth.\",\n      \"evidence\": \"Structural biology, CRISPR single-residue mutagenesis, phosphatase assays, xenograft\",\n      \"pmids\": [\"36854761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of pseudotrimer model to other B56 isoforms not fully tested\", \"Did not address PP2A-independent functions\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a metabolic role, showing CIP2A directly binds PKM2 to drive its tetramerization and mitochondrial relocalization, promoting oxidative phosphorylation in NSCLC.\",\n      \"evidence\": \"Co-IP, tetramer formation assays, PKM2-S287 mutagenesis, fractionation, in vivo metabolic assays\",\n      \"pmids\": [\"38321019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Kinase responsible for PKM2-S287 and Bcl2-T69 phosphorylation not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CIP2A's distinct activities\\u2014PP2A pseudotrimer formation, Plk1 stabilization, mitotic TOPBP1 recruitment, and PKM2 tetramerization\\u2014are coordinated or partitioned across the cell cycle and tissue contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the full-length protein or of the mitotic CIP2A-TOPBP1-MDC1 complex\", \"Mechanism switching CIP2A between PP2A-dependent and PP2A-independent modes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 5, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 4, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"CIP2A-B56\\u03b1-PP2Ac pseudotrimer\",\n      \"CIP2A-TOPBP1-MDC1 mitotic complex\"\n    ],\n    \"partners\": [\n      \"MYC\",\n      \"PPP2R5A\",\n      \"PLK1\",\n      \"TOPBP1\",\n      \"MDC1\",\n      \"PKM2\",\n      \"HRAS\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}