{"gene":"MIIP","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2003,"finding":"IIp45 (MIIP) protein binds directly to IGFBP-2 through the thyroglobulin-RGD region of the C terminus of IGFBP-2, as identified by yeast two-hybrid screen, and inhibits IGFBP-2-stimulated glioma cell invasion in vitro and in xenograft models. IIp45 consistently inhibited expression of invasion-associated genes including NFκB and its downstream target ICAM-1.","method":"Yeast two-hybrid screen, functional invasion assays (in vitro and xenograft), gene expression profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional assays in vitro and in vivo, single lab, multiple methods","pmids":["14617774"],"is_preprint":false},{"year":2009,"finding":"IIp45/MIIP physically interacts with HDAC6 (requiring both catalytic domains of HDAC6 for binding), inhibits HDAC6 enzymatic activity, reduces HDAC6 protein stability, increases acetylated α-tubulin levels, and thereby inhibits cell migration. Knockdown of HDAC6 reversed the increased migration caused by MIIP siRNA knockdown.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, HDAC activity assay, protein turnover assay, siRNA epistasis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, GST pulldown, CoIP, enzymatic assay, domain mapping, epistasis) in single rigorous study","pmids":["20008322"],"is_preprint":false},{"year":2010,"finding":"MIIP interacts directly with Cdc20 and inhibits APC/C-mediated degradation of cyclin B1, thereby attenuating mitotic transition and increasing mitotic catastrophe. This mechanism contributes to inhibition of glioma development in a mouse model.","method":"Co-immunoprecipitation, in vitro interaction assay, mouse glial-specific model, colony formation and cell growth assays, siRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction with Cdc20 shown by CoIP with downstream APC/C substrate readout, single lab","pmids":["20418911"],"is_preprint":false},{"year":2005,"finding":"A tumor-specific alternatively spliced isoform of IIp45 (IIp45S), resulting from exclusion of exon 7 and encoding a frameshifted C-terminus, is expressed in 60% of GBM tissue samples and 100% of GBM cell lines but not in normal organs. The IIp45S protein is undetectable despite mRNA expression because it is rapidly degraded by the ubiquitin-proteasome mechanism.","method":"RT-PCR, sequencing, proteasome inhibitor experiments, western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic characterization of isoform instability via proteasome inhibitor experiments, single lab with multiple methods","pmids":["15867349"],"is_preprint":false},{"year":2016,"finding":"MIIP attenuates Rac1 signaling in endometrial cancer by competing with Rac1-GTP for binding to the p21-binding domain of PAK1. MIIP and PAK1 bind each other through a C-terminal polyproline domain of MIIP, and deletion of this PAK1-binding domain reduces MIIP's cell migration-inhibiting activity. Elevated MIIP expression reduces lamellipodia formation.","method":"Co-immunoprecipitation, Rac1 activity assay, serial deletion constructs, immunofluorescence (F-actin), transwell migration assay","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with deletion constructs, CoIP, functional rescue assay, single lab","pmids":["27760566"],"is_preprint":false},{"year":2016,"finding":"MIIP haploinsufficiency inhibits topoisomerase II (Topo II) activity and induces chromosomal missegregation, and also alters stability of APC/CCdc20 downstream proteins securin and cyclin B1, thereby acting as a chromosomal instability suppressor in colorectal cancer.","method":"Zinc finger nuclease-mediated gene deletion (haploinsufficiency), spectral karyotyping, topoisomerase II activity assay, western blot, in vivo xenograft","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion model plus biochemical assay for Topo II activity, single lab","pmids":["27741356"],"is_preprint":false},{"year":2016,"finding":"MIIP overexpression reduces steady-state EGFR protein levels in lung cancer cells by accelerating EGFR protein turnover through both proteasomal degradation in the endoplasmic reticulum and lysosomal degradation after endocytic trafficking, leading to inhibition of downstream Ras/MEK signaling and cell proliferation.","method":"Pulse-chase with 35S-methionine, proteasome and lysosome inhibitor experiments, western blot, overexpression/knockdown, downstream signaling assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — pulse-chase metabolic labeling plus pharmacological inhibitor experiments, single lab","pmids":["26824318"],"is_preprint":false},{"year":2017,"finding":"EGF stimulation induces PKCε-dependent phosphorylation of MIIP at Ser303. This phosphorylation promotes MIIP interaction with RelA/p65 in the nucleus, where MIIP prevents HDAC6-mediated deacetylation of RelA, thereby enhancing RelA transcriptional activity and facilitating tumor metastasis. PP1 phosphatase mediates dephosphorylation of MIIP-S303.","method":"Phosphorylation assays, co-immunoprecipitation, nuclear fractionation, PKCε kinase assay, PP1 phosphatase assay, loss-of-function and gain-of-function studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — kinase identification (PKCε), phosphatase identification (PP1), nuclear interaction with RelA, HDAC6-mediated deacetylation mechanism, multiple orthogonal methods in single rigorous study","pmids":["29038521"],"is_preprint":false},{"year":2018,"finding":"MIIP suppresses HDAC6 deacetylase activity to promote acetylation and subsequent degradation of HIF-1α, thereby impairing HIF-1α accumulation in pancreatic cancer cells. Conversely, HIF-1α indirectly downregulates MIIP at the post-transcriptional level by activating transcription of miR-646, which targets MIIP mRNA coding sequence and impairs its stability.","method":"ChIP, luciferase reporter assay, miRNA array, overexpression/knockdown, HDAC activity assay, co-immunoprecipitation, xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter for regulatory mechanism, HDAC activity assay for functional mechanism, multiple orthogonal methods, single lab","pmids":["29343850"],"is_preprint":false},{"year":2019,"finding":"MIIP interacts with PP1α via its C-terminal part and facilitates PP1-mediated AKT dephosphorylation, thereby inhibiting AKT-mTOR signaling and prostate cancer cell growth. A C-terminal deletion mutant of MIIP (MIIPΔC) that cannot interact with PP1α loses this inhibitory function, and silencing PP1α reverses MIIP's inhibitory effect on AKT phosphorylation.","method":"Co-immunoprecipitation, immunofluorescence co-localization, western blot, deletion mutagenesis, siRNA knockdown, xenograft model","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal CoIP, domain deletion mutagenesis with functional rescue, multiple orthogonal methods, single lab","pmids":["31092266"],"is_preprint":false},{"year":2021,"finding":"MIIP promotes HSP90 acetylation and impairs its chaperone function toward HIF-2α in clear cell renal cell carcinoma, leading to RACK1 binding HIF-2α and causing its ubiquitination and proteasomal degradation, consequently decreasing transcription of the HIF-2α target CYR61 and inhibiting proliferation and angiogenesis.","method":"Co-immunoprecipitation, ubiquitination assay, RNA-sequencing, overexpression/knockdown, xenograft model, western blot, ELISA","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP with ubiquitination assay and functional rescue, multiple orthogonal methods, single lab","pmids":["34931765"],"is_preprint":false},{"year":2022,"finding":"MIIP directly interacts with integrin β3 (ITGB3) through its RGD motif, suppresses ITGB3 downstream signaling, elevates ubiquitin-mediated β-catenin degradation, reduces VEGFA production, and inhibits EMT, thereby suppressing angiogenesis and tumorigenesis in triple-negative breast cancer.","method":"Co-immunoprecipitation, RGD-mutant functional assays, ubiquitination assay, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP with domain mutagenesis (RGD) and functional readouts, single lab","pmids":["36130933"],"is_preprint":false},{"year":2024,"finding":"MIIP interacts with the lipid mobilization factor AZGP1 and regulates its N-glycosylation by interfering with its association with the glycosyltransferase STT3A. MIIP downregulation promotes STT3A-mediated N-glycosylation and oversecretion of AZGP1, which then induces adipocyte browning and lipolysis through the cAMP-PKA pathway in colorectal cancer.","method":"Co-immunoprecipitation, glycosylation assays, in vitro co-culture model, in vivo allograft model, western blot","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP with glycosylation mechanistic follow-up and in vivo validation, single lab","pmids":["38245780"],"is_preprint":false},{"year":2024,"finding":"MIIP localizes between microtubule triplets at the A-C linker of centrioles, forming a complex with CCDC77 and WDR67. Depletion of A-C linker components including MIIP disrupts microtubule triplet cohesion, causing breakage at the proximal end of centrioles. The A-C linker (including MIIP) also plays a role in centriole duplication through torus regulation.","method":"Ultrastructure expansion microscopy, protein depletion (siRNA/knockdown), co-localization studies","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, localization and depletion phenotype shown but direct interaction/complex membership not confirmed by CoIP in this abstract","pmids":["bio_10.1101_2024.10.04.616628"],"is_preprint":true}],"current_model":"MIIP (IIp45) is a multifunctional tumor suppressor that inhibits cell migration, invasion, and mitotic progression through several distinct mechanisms: it binds IGFBP-2 to antagonize invasion signaling; it physically interacts with and inhibits HDAC6 deacetylase activity, increasing α-tubulin acetylation and stabilizing microtubules; it binds Cdc20 to suppress APC/C activity and attenuate mitotic transition; it competes with Rac1-GTP for PAK1 binding to remodel the cytoskeleton; it facilitates PP1α-mediated AKT dephosphorylation to suppress AKT-mTOR signaling; it interacts with ITGB3 via its RGD motif to suppress β-catenin and VEGFA; it promotes HSP90 acetylation to destabilize HIF-2α; and its nuclear activity is regulated by PKCε-mediated phosphorylation at Ser303, which determines whether MIIP prevents HDAC6-mediated deacetylation of RelA/p65 to modulate NF-κB transcriptional output."},"narrative":{"mechanistic_narrative":"MIIP (IIp45) is a multifunctional tumor suppressor that restrains cell invasion, migration, mitotic progression, and oncogenic signaling across multiple cancer types [PMID:14617774, PMID:20008322, PMID:20418911]. It was first identified as a direct binding partner of IGFBP-2 through the latter's thyroglobulin-RGD region, antagonizing IGFBP-2-stimulated glioma invasion and downregulating invasion-associated genes including NFκB targets [PMID:14617774]. A central mechanism is its physical interaction with and inhibition of the deacetylase HDAC6: MIIP binds HDAC6, suppresses its enzymatic activity and stability, increases α-tubulin acetylation, and thereby inhibits migration [PMID:20008322]. This HDAC6 axis is reused in distinct contexts — MIIP promotes acetylation-dependent degradation of HIF-1α [PMID:29343850], and EGF-triggered PKCε phosphorylation of MIIP at Ser303 drives its nuclear interaction with RelA/p65, where it blocks HDAC6-mediated RelA deacetylation to tune NF-κB output, with PP1 reversing this phosphorylation [PMID:29038521]. MIIP also controls mitotic and chromosomal fidelity by binding Cdc20 to inhibit APC/C-mediated cyclin B1 degradation [PMID:20418911] and by suppressing topoisomerase II activity, with haploinsufficiency producing chromosomal instability [PMID:27741356]. Through dedicated C-terminal and RGD/polyproline motifs, MIIP additionally competes with Rac1-GTP for PAK1 to remodel the actin cytoskeleton [PMID:27760566], facilitates PP1α-mediated AKT dephosphorylation to suppress AKT-mTOR signaling [PMID:31092266], and engages integrin β3 to drive β-catenin degradation and reduce VEGFA [PMID:36130933]. Further reported activities include accelerated EGFR turnover [PMID:26824318], HSP90 acetylation-driven HIF-2α destabilization [PMID:34931765], and regulation of AZGP1 N-glycosylation [PMID:38245780].","teleology":[{"year":2003,"claim":"Established MIIP's founding identity as an IGFBP-2 binding protein that suppresses invasion, answering what cellular process this uncharacterized protein controls.","evidence":"Yeast two-hybrid screen with in vitro and xenograft invasion assays and gene expression profiling in glioma","pmids":["14617774"],"confidence":"Medium","gaps":["Mechanism by which IGFBP-2 binding translates to NFκB/ICAM-1 downregulation not resolved","Binding interface on MIIP itself not mapped"]},{"year":2005,"claim":"Showed that a tumor-specific frameshifted splice isoform (IIp45S) is rapidly proteasomally degraded, explaining how MIIP function may be lost in glioblastoma despite mRNA expression.","evidence":"RT-PCR, sequencing, proteasome inhibitor experiments and western blot in GBM tissues and cell lines","pmids":["15867349"],"confidence":"Medium","gaps":["Functional consequence of isoform loss not directly tested","Degradation machinery targeting IIp45S not identified"]},{"year":2009,"claim":"Defined the HDAC6 axis, showing MIIP binds and inhibits HDAC6 to raise α-tubulin acetylation, providing a concrete molecular mechanism for migration suppression.","evidence":"Yeast two-hybrid, GST pulldown, co-IP, HDAC activity assay, domain mapping, protein turnover and siRNA epistasis","pmids":["20008322"],"confidence":"High","gaps":["How MIIP both inhibits activity and reduces HDAC6 stability mechanistically distinct or linked is unclear","No structural model of the MIIP-HDAC6 interface"]},{"year":2010,"claim":"Linked MIIP to mitotic control by showing it binds Cdc20 and inhibits APC/C-mediated cyclin B1 degradation, establishing a cell-cycle tumor-suppressive role.","evidence":"Co-IP, in vitro interaction assay, glial-specific mouse model and growth/colony assays","pmids":["20418911"],"confidence":"Medium","gaps":["Whether MIIP competes with substrates or alters Cdc20 conformation not resolved","Cdc20-binding region of MIIP not mapped"]},{"year":2016,"claim":"Expanded MIIP's mechanistic repertoire across cytoskeletal, chromosomal, and receptor pathways, showing PAK1/Rac1 competition, Topo II inhibition with chromosomal instability suppression, and accelerated EGFR turnover.","evidence":"Co-IP, Rac1 activity and deletion-construct mapping; ZFN haploinsufficiency model with karyotyping and Topo II assay; pulse-chase and inhibitor experiments for EGFR","pmids":["27760566","27741356","26824318"],"confidence":"Medium","gaps":["Whether these are independent activities or share an upstream trigger is unknown","Direct Topo II interaction versus indirect modulation not distinguished","Mechanism routing EGFR to both proteasomal and lysosomal degradation unclear"]},{"year":2017,"claim":"Revealed signal-dependent regulation of MIIP, showing EGF/PKCε-driven Ser303 phosphorylation switches MIIP into a nuclear RelA-stabilizing factor, redefining MIIP as a context-dependent modulator rather than a purely inhibitory protein.","evidence":"Phosphorylation and kinase/phosphatase assays, nuclear fractionation, co-IP, and gain/loss-of-function studies","pmids":["29038521"],"confidence":"High","gaps":["How Ser303 phosphorylation directs nuclear localization not detailed","Reconciliation of pro-metastatic RelA stabilization with MIIP's tumor-suppressive activities not resolved"]},{"year":2018,"claim":"Connected the HDAC6 axis to hypoxia signaling and established a feedback loop, showing MIIP promotes HIF-1α acetylation/degradation while HIF-1α represses MIIP via miR-646.","evidence":"ChIP, luciferase reporter, miRNA array, HDAC activity assay and co-IP with xenografts in pancreatic cancer","pmids":["29343850"],"confidence":"Medium","gaps":["Whether HIF-1α acetylation is the direct consequence of HDAC6 inhibition not formally separated from other effects","miR-646 regulation tested in a single tumor context"]},{"year":2019,"claim":"Identified the PP1α-AKT mechanism, showing MIIP's C-terminus recruits PP1α to dephosphorylate AKT and suppress AKT-mTOR signaling.","evidence":"Reciprocal co-IP, co-localization, deletion mutagenesis with functional rescue and siRNA in prostate cancer with xenografts","pmids":["31092266"],"confidence":"Medium","gaps":["Whether MIIP acts as a scaffold or allosteric activator of PP1α not resolved","Substrate selectivity of the MIIP-PP1α module not defined"]},{"year":2021,"claim":"Extended HSP90-chaperone control of HIF, showing MIIP promotes HSP90 acetylation to release HIF-2α for RACK1-mediated ubiquitination and degradation in renal carcinoma.","evidence":"Co-IP, ubiquitination assay, RNA-seq and xenograft models","pmids":["34931765"],"confidence":"Medium","gaps":["How MIIP enhances HSP90 acetylation mechanistically (via HDAC6 or other) not stated","Direct versus indirect MIIP-HSP90 engagement unclear"]},{"year":2022,"claim":"Defined an integrin-based mechanism, showing MIIP's RGD motif binds ITGB3 to drive β-catenin degradation and reduce VEGFA, linking MIIP to angiogenesis suppression.","evidence":"Co-IP, RGD-mutant functional assays, ubiquitination assay and in vitro/in vivo assays in triple-negative breast cancer","pmids":["36130933"],"confidence":"Medium","gaps":["Downstream signaling steps from ITGB3 to β-catenin not fully mapped","Whether RGD engagement competes with ECM ligands not tested"]},{"year":2024,"claim":"Uncovered a metabolic role, showing MIIP regulates AZGP1 N-glycosylation by interfering with STT3A, controlling AZGP1 secretion and adipocyte browning/lipolysis.","evidence":"Co-IP, glycosylation assays, co-culture and allograft models in colorectal cancer","pmids":["38245780"],"confidence":"Medium","gaps":["How MIIP physically blocks the AZGP1-STT3A association not detailed","Tested in colorectal context only"]},{"year":2024,"claim":"Proposed a structural/centriolar role, localizing MIIP to the A-C linker of centrioles in a complex with CCDC77 and WDR67 required for triplet cohesion and duplication.","evidence":"Ultrastructure expansion microscopy and depletion phenotyping (preprint)","pmids":["bio_10.1101_2024.10.04.616628"],"confidence":"Low","gaps":["Direct interaction/complex membership not confirmed by co-IP","Relationship between centriolar role and cytoplasmic tumor-suppressive functions unknown","Single preprint, not peer-reviewed"]},{"year":null,"claim":"How MIIP's many distinct interaction modules (HDAC6, Cdc20, PAK1, PP1α, ITGB3, HSP90, AZGP1, centriolar partners) are coordinated, prioritized, or spatially partitioned within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated model reconciling cytoskeletal, mitotic, signaling, and centriolar roles","No high-resolution structure of MIIP or its complexes","Endogenous stoichiometry and context-dependent partner selection undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,8,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,9,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,10]}],"complexes":["APC/C (via Cdc20 interaction)","centriolar A-C linker (with CCDC77, WDR67)"],"partners":["IGFBP2","HDAC6","CDC20","PAK1","PPP1CA","ITGB3","RELA","AZGP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5JXC2","full_name":"Migration and invasion-inhibitory protein","aliases":["IGFBP2-binding protein","Invasion-inhibitory protein 45","IIp45"],"length_aa":388,"mass_kda":42.8,"function":"Inhibits glioma cells invasion and down-regulates adhesion- and motility-associated genes such as NFKB2 and ICAM1. Exhibits opposing effects to IGFBP2 on cell invasion","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5JXC2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MIIP","classification":"Not Classified","n_dependent_lines":87,"n_total_lines":1208,"dependency_fraction":0.07201986754966887},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MIIP","total_profiled":1310},"omim":[{"mim_id":"621444","title":"TBC1 DOMAIN FAMILY, MEMBER 31; TBC1D31","url":"https://www.omim.org/entry/621444"},{"mim_id":"608772","title":"MIGRATION AND INVASION INHIBITORY PROTEIN; MIIP","url":"https://www.omim.org/entry/608772"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MIIP"},"hgnc":{"alias_symbol":["FLJ12438","IIp45"],"prev_symbol":[]},"alphafold":{"accession":"Q5JXC2","domains":[{"cath_id":"1.20.5","chopping":"2-27","consensus_level":"medium","plddt":91.5262,"start":2,"end":27}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JXC2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JXC2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JXC2-F1-predicted_aligned_error_v6.png","plddt_mean":56.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MIIP","jax_strain_url":"https://www.jax.org/strain/search?query=MIIP"},"sequence":{"accession":"Q5JXC2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5JXC2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5JXC2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JXC2"}},"corpus_meta":[{"pmid":"14617774","id":"PMC_14617774","title":"IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/14617774","citation_count":76,"is_preprint":false},{"pmid":"20008322","id":"PMC_20008322","title":"IIp45 inhibits cell migration through inhibition of HDAC6.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20008322","citation_count":49,"is_preprint":false},{"pmid":"29343850","id":"PMC_29343850","title":"MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29343850","citation_count":48,"is_preprint":false},{"pmid":"29038521","id":"PMC_29038521","title":"PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29038521","citation_count":41,"is_preprint":false},{"pmid":"20418911","id":"PMC_20418911","title":"Inhibition of gliomagenesis and attenuation of mitotic transition by MIIP.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20418911","citation_count":37,"is_preprint":false},{"pmid":"32195032","id":"PMC_32195032","title":"MIIP inhibits EMT and cell invasion in prostate cancer through miR-181a/b-5p-KLF17 axis.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32195032","citation_count":24,"is_preprint":false},{"pmid":"15867349","id":"PMC_15867349","title":"Inactivation of the invasion inhibitory gene IIp45 by alternative splicing in gliomas.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15867349","citation_count":23,"is_preprint":false},{"pmid":"27760566","id":"PMC_27760566","title":"MIIP remodels Rac1-mediated cytoskeleton structure in suppression of endometrial cancer metastasis.","date":"2016","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27760566","citation_count":23,"is_preprint":false},{"pmid":"21190522","id":"PMC_21190522","title":"MIIP, a cytoskeleton regulator that blocks cell migration and invasion, delays mitosis, and suppresses tumorogenesis.","date":"2011","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/21190522","citation_count":22,"is_preprint":false},{"pmid":"26824318","id":"PMC_26824318","title":"MIIP accelerates epidermal growth factor receptor protein turnover and attenuates proliferation in non-small cell lung cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26824318","citation_count":17,"is_preprint":false},{"pmid":"27741356","id":"PMC_27741356","title":"MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer.","date":"2016","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27741356","citation_count":16,"is_preprint":false},{"pmid":"20103646","id":"PMC_20103646","title":"Definition of a functional single nucleotide polymorphism in the cell migration inhibitory gene MIIP that affects the risk of breast cancer.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20103646","citation_count":16,"is_preprint":false},{"pmid":"31092266","id":"PMC_31092266","title":"MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling.","date":"2019","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/31092266","citation_count":13,"is_preprint":false},{"pmid":"36130933","id":"PMC_36130933","title":"MIIP functions as a novel ligand for ITGB3 to inhibit angiogenesis and tumorigenesis of triple-negative breast cancer.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36130933","citation_count":12,"is_preprint":false},{"pmid":"31078343","id":"PMC_31078343","title":"Upregulation of MIIP regulates human breast cancer proliferation, invasion and migration by mediated by IGFBP2.","date":"2019","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/31078343","citation_count":12,"is_preprint":false},{"pmid":"38245780","id":"PMC_38245780","title":"MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose tissue browning.","date":"2024","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/38245780","citation_count":10,"is_preprint":false},{"pmid":"25873164","id":"PMC_25873164","title":"Altered expression and loss of heterozygosity of the migration and invasion inhibitory protein (MIIP) gene in breast cancer.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25873164","citation_count":10,"is_preprint":false},{"pmid":"34931765","id":"PMC_34931765","title":"MIIP inhibits clear cell renal cell carcinoma proliferation and angiogenesis via negative modulation of the HIF-2α-CYR61 axis.","date":"2021","source":"Cancer biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34931765","citation_count":9,"is_preprint":false},{"pmid":"32065215","id":"PMC_32065215","title":"idenPC-MIIP: identify protein complexes from weighted PPI networks using mutual important interacting partner relation.","date":"2021","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/32065215","citation_count":8,"is_preprint":false},{"pmid":"38372808","id":"PMC_38372808","title":"VNP20009-Abvec-Igκ-MIIP suppresses ovarian cancer progression by modulating Ras/MEK/ERK signaling pathway.","date":"2024","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38372808","citation_count":6,"is_preprint":false},{"pmid":"26825982","id":"PMC_26825982","title":"MIIP expression predicts outcomes of surgically resected esophageal squamous cell carcinomas.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26825982","citation_count":5,"is_preprint":false},{"pmid":"32196585","id":"PMC_32196585","title":"MIIP inhibits malignant progression of hepatocellular carcinoma through regulating AKT.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32196585","citation_count":5,"is_preprint":false},{"pmid":"26626200","id":"PMC_26626200","title":"DNA studies of newly synthesized heteroleptic platinum(II) complexes [Pt(bpy)(iip)](2+) and [Pt(bpy)(miip)](2.).","date":"2015","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26626200","citation_count":5,"is_preprint":false},{"pmid":"30588008","id":"PMC_30588008","title":"MIIP is downregulated in gastric cancer and its forced expression inhibits proliferation and invasion of gastric cancer cells in vitro and in vivo.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30588008","citation_count":4,"is_preprint":false},{"pmid":"29860763","id":"PMC_29860763","title":"[Expression and clinical significance of MIIP and PAK1 in endometrial carcinoma].","date":"2018","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/29860763","citation_count":1,"is_preprint":false},{"pmid":"33986600","id":"PMC_33986600","title":"Erratum: MIIP is Downregulated in Gastric Cancer and Its Forced Expression Inhibits Proliferation and Invasion of Gastric Cancer Cells in vitro and in vivo [Corrigendum].","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33986600","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.04.616628","title":"The A-C Linker controls centriole cohesion and duplication","date":"2024-10-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.04.616628","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15835,"output_tokens":3716,"usd":0.051623,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11458,"output_tokens":4411,"usd":0.083782,"stage2_stop_reason":"end_turn"},"total_usd":0.135405,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"IIp45 (MIIP) protein binds directly to IGFBP-2 through the thyroglobulin-RGD region of the C terminus of IGFBP-2, as identified by yeast two-hybrid screen, and inhibits IGFBP-2-stimulated glioma cell invasion in vitro and in xenograft models. IIp45 consistently inhibited expression of invasion-associated genes including NFκB and its downstream target ICAM-1.\",\n      \"method\": \"Yeast two-hybrid screen, functional invasion assays (in vitro and xenograft), gene expression profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional assays in vitro and in vivo, single lab, multiple methods\",\n      \"pmids\": [\"14617774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IIp45/MIIP physically interacts with HDAC6 (requiring both catalytic domains of HDAC6 for binding), inhibits HDAC6 enzymatic activity, reduces HDAC6 protein stability, increases acetylated α-tubulin levels, and thereby inhibits cell migration. Knockdown of HDAC6 reversed the increased migration caused by MIIP siRNA knockdown.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, HDAC activity assay, protein turnover assay, siRNA epistasis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, GST pulldown, CoIP, enzymatic assay, domain mapping, epistasis) in single rigorous study\",\n      \"pmids\": [\"20008322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MIIP interacts directly with Cdc20 and inhibits APC/C-mediated degradation of cyclin B1, thereby attenuating mitotic transition and increasing mitotic catastrophe. This mechanism contributes to inhibition of glioma development in a mouse model.\",\n      \"method\": \"Co-immunoprecipitation, in vitro interaction assay, mouse glial-specific model, colony formation and cell growth assays, siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction with Cdc20 shown by CoIP with downstream APC/C substrate readout, single lab\",\n      \"pmids\": [\"20418911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A tumor-specific alternatively spliced isoform of IIp45 (IIp45S), resulting from exclusion of exon 7 and encoding a frameshifted C-terminus, is expressed in 60% of GBM tissue samples and 100% of GBM cell lines but not in normal organs. The IIp45S protein is undetectable despite mRNA expression because it is rapidly degraded by the ubiquitin-proteasome mechanism.\",\n      \"method\": \"RT-PCR, sequencing, proteasome inhibitor experiments, western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic characterization of isoform instability via proteasome inhibitor experiments, single lab with multiple methods\",\n      \"pmids\": [\"15867349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIIP attenuates Rac1 signaling in endometrial cancer by competing with Rac1-GTP for binding to the p21-binding domain of PAK1. MIIP and PAK1 bind each other through a C-terminal polyproline domain of MIIP, and deletion of this PAK1-binding domain reduces MIIP's cell migration-inhibiting activity. Elevated MIIP expression reduces lamellipodia formation.\",\n      \"method\": \"Co-immunoprecipitation, Rac1 activity assay, serial deletion constructs, immunofluorescence (F-actin), transwell migration assay\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with deletion constructs, CoIP, functional rescue assay, single lab\",\n      \"pmids\": [\"27760566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIIP haploinsufficiency inhibits topoisomerase II (Topo II) activity and induces chromosomal missegregation, and also alters stability of APC/CCdc20 downstream proteins securin and cyclin B1, thereby acting as a chromosomal instability suppressor in colorectal cancer.\",\n      \"method\": \"Zinc finger nuclease-mediated gene deletion (haploinsufficiency), spectral karyotyping, topoisomerase II activity assay, western blot, in vivo xenograft\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion model plus biochemical assay for Topo II activity, single lab\",\n      \"pmids\": [\"27741356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIIP overexpression reduces steady-state EGFR protein levels in lung cancer cells by accelerating EGFR protein turnover through both proteasomal degradation in the endoplasmic reticulum and lysosomal degradation after endocytic trafficking, leading to inhibition of downstream Ras/MEK signaling and cell proliferation.\",\n      \"method\": \"Pulse-chase with 35S-methionine, proteasome and lysosome inhibitor experiments, western blot, overexpression/knockdown, downstream signaling assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — pulse-chase metabolic labeling plus pharmacological inhibitor experiments, single lab\",\n      \"pmids\": [\"26824318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EGF stimulation induces PKCε-dependent phosphorylation of MIIP at Ser303. This phosphorylation promotes MIIP interaction with RelA/p65 in the nucleus, where MIIP prevents HDAC6-mediated deacetylation of RelA, thereby enhancing RelA transcriptional activity and facilitating tumor metastasis. PP1 phosphatase mediates dephosphorylation of MIIP-S303.\",\n      \"method\": \"Phosphorylation assays, co-immunoprecipitation, nuclear fractionation, PKCε kinase assay, PP1 phosphatase assay, loss-of-function and gain-of-function studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — kinase identification (PKCε), phosphatase identification (PP1), nuclear interaction with RelA, HDAC6-mediated deacetylation mechanism, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"29038521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MIIP suppresses HDAC6 deacetylase activity to promote acetylation and subsequent degradation of HIF-1α, thereby impairing HIF-1α accumulation in pancreatic cancer cells. Conversely, HIF-1α indirectly downregulates MIIP at the post-transcriptional level by activating transcription of miR-646, which targets MIIP mRNA coding sequence and impairs its stability.\",\n      \"method\": \"ChIP, luciferase reporter assay, miRNA array, overexpression/knockdown, HDAC activity assay, co-immunoprecipitation, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter for regulatory mechanism, HDAC activity assay for functional mechanism, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29343850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MIIP interacts with PP1α via its C-terminal part and facilitates PP1-mediated AKT dephosphorylation, thereby inhibiting AKT-mTOR signaling and prostate cancer cell growth. A C-terminal deletion mutant of MIIP (MIIPΔC) that cannot interact with PP1α loses this inhibitory function, and silencing PP1α reverses MIIP's inhibitory effect on AKT phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, western blot, deletion mutagenesis, siRNA knockdown, xenograft model\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal CoIP, domain deletion mutagenesis with functional rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31092266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MIIP promotes HSP90 acetylation and impairs its chaperone function toward HIF-2α in clear cell renal cell carcinoma, leading to RACK1 binding HIF-2α and causing its ubiquitination and proteasomal degradation, consequently decreasing transcription of the HIF-2α target CYR61 and inhibiting proliferation and angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RNA-sequencing, overexpression/knockdown, xenograft model, western blot, ELISA\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP with ubiquitination assay and functional rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34931765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MIIP directly interacts with integrin β3 (ITGB3) through its RGD motif, suppresses ITGB3 downstream signaling, elevates ubiquitin-mediated β-catenin degradation, reduces VEGFA production, and inhibits EMT, thereby suppressing angiogenesis and tumorigenesis in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, RGD-mutant functional assays, ubiquitination assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP with domain mutagenesis (RGD) and functional readouts, single lab\",\n      \"pmids\": [\"36130933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MIIP interacts with the lipid mobilization factor AZGP1 and regulates its N-glycosylation by interfering with its association with the glycosyltransferase STT3A. MIIP downregulation promotes STT3A-mediated N-glycosylation and oversecretion of AZGP1, which then induces adipocyte browning and lipolysis through the cAMP-PKA pathway in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, glycosylation assays, in vitro co-culture model, in vivo allograft model, western blot\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP with glycosylation mechanistic follow-up and in vivo validation, single lab\",\n      \"pmids\": [\"38245780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MIIP localizes between microtubule triplets at the A-C linker of centrioles, forming a complex with CCDC77 and WDR67. Depletion of A-C linker components including MIIP disrupts microtubule triplet cohesion, causing breakage at the proximal end of centrioles. The A-C linker (including MIIP) also plays a role in centriole duplication through torus regulation.\",\n      \"method\": \"Ultrastructure expansion microscopy, protein depletion (siRNA/knockdown), co-localization studies\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, localization and depletion phenotype shown but direct interaction/complex membership not confirmed by CoIP in this abstract\",\n      \"pmids\": [\"bio_10.1101_2024.10.04.616628\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MIIP (IIp45) is a multifunctional tumor suppressor that inhibits cell migration, invasion, and mitotic progression through several distinct mechanisms: it binds IGFBP-2 to antagonize invasion signaling; it physically interacts with and inhibits HDAC6 deacetylase activity, increasing α-tubulin acetylation and stabilizing microtubules; it binds Cdc20 to suppress APC/C activity and attenuate mitotic transition; it competes with Rac1-GTP for PAK1 binding to remodel the cytoskeleton; it facilitates PP1α-mediated AKT dephosphorylation to suppress AKT-mTOR signaling; it interacts with ITGB3 via its RGD motif to suppress β-catenin and VEGFA; it promotes HSP90 acetylation to destabilize HIF-2α; and its nuclear activity is regulated by PKCε-mediated phosphorylation at Ser303, which determines whether MIIP prevents HDAC6-mediated deacetylation of RelA/p65 to modulate NF-κB transcriptional output.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MIIP (IIp45) is a multifunctional tumor suppressor that restrains cell invasion, migration, mitotic progression, and oncogenic signaling across multiple cancer types [#0, #1, #2]. It was first identified as a direct binding partner of IGFBP-2 through the latter's thyroglobulin-RGD region, antagonizing IGFBP-2-stimulated glioma invasion and downregulating invasion-associated genes including NF\\u03baB targets [#0]. A central mechanism is its physical interaction with and inhibition of the deacetylase HDAC6: MIIP binds HDAC6, suppresses its enzymatic activity and stability, increases \\u03b1-tubulin acetylation, and thereby inhibits migration [#1]. This HDAC6 axis is reused in distinct contexts \\u2014 MIIP promotes acetylation-dependent degradation of HIF-1\\u03b1 [#8], and EGF-triggered PKC\\u03b5 phosphorylation of MIIP at Ser303 drives its nuclear interaction with RelA/p65, where it blocks HDAC6-mediated RelA deacetylation to tune NF-\\u03baB output, with PP1 reversing this phosphorylation [#7]. MIIP also controls mitotic and chromosomal fidelity by binding Cdc20 to inhibit APC/C-mediated cyclin B1 degradation [#2] and by suppressing topoisomerase II activity, with haploinsufficiency producing chromosomal instability [#5]. Through dedicated C-terminal and RGD/polyproline motifs, MIIP additionally competes with Rac1-GTP for PAK1 to remodel the actin cytoskeleton [#4], facilitates PP1\\u03b1-mediated AKT dephosphorylation to suppress AKT-mTOR signaling [#9], and engages integrin \\u03b23 to drive \\u03b2-catenin degradation and reduce VEGFA [#11]. Further reported activities include accelerated EGFR turnover [#6], HSP90 acetylation-driven HIF-2\\u03b1 destabilization [#10], and regulation of AZGP1 N-glycosylation [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established MIIP's founding identity as an IGFBP-2 binding protein that suppresses invasion, answering what cellular process this uncharacterized protein controls.\",\n      \"evidence\": \"Yeast two-hybrid screen with in vitro and xenograft invasion assays and gene expression profiling in glioma\",\n      \"pmids\": [\"14617774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IGFBP-2 binding translates to NF\\u03baB/ICAM-1 downregulation not resolved\", \"Binding interface on MIIP itself not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that a tumor-specific frameshifted splice isoform (IIp45S) is rapidly proteasomally degraded, explaining how MIIP function may be lost in glioblastoma despite mRNA expression.\",\n      \"evidence\": \"RT-PCR, sequencing, proteasome inhibitor experiments and western blot in GBM tissues and cell lines\",\n      \"pmids\": [\"15867349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of isoform loss not directly tested\", \"Degradation machinery targeting IIp45S not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the HDAC6 axis, showing MIIP binds and inhibits HDAC6 to raise \\u03b1-tubulin acetylation, providing a concrete molecular mechanism for migration suppression.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-IP, HDAC activity assay, domain mapping, protein turnover and siRNA epistasis\",\n      \"pmids\": [\"20008322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MIIP both inhibits activity and reduces HDAC6 stability mechanistically distinct or linked is unclear\", \"No structural model of the MIIP-HDAC6 interface\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked MIIP to mitotic control by showing it binds Cdc20 and inhibits APC/C-mediated cyclin B1 degradation, establishing a cell-cycle tumor-suppressive role.\",\n      \"evidence\": \"Co-IP, in vitro interaction assay, glial-specific mouse model and growth/colony assays\",\n      \"pmids\": [\"20418911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MIIP competes with substrates or alters Cdc20 conformation not resolved\", \"Cdc20-binding region of MIIP not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded MIIP's mechanistic repertoire across cytoskeletal, chromosomal, and receptor pathways, showing PAK1/Rac1 competition, Topo II inhibition with chromosomal instability suppression, and accelerated EGFR turnover.\",\n      \"evidence\": \"Co-IP, Rac1 activity and deletion-construct mapping; ZFN haploinsufficiency model with karyotyping and Topo II assay; pulse-chase and inhibitor experiments for EGFR\",\n      \"pmids\": [\"27760566\", \"27741356\", \"26824318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these are independent activities or share an upstream trigger is unknown\", \"Direct Topo II interaction versus indirect modulation not distinguished\", \"Mechanism routing EGFR to both proteasomal and lysosomal degradation unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed signal-dependent regulation of MIIP, showing EGF/PKC\\u03b5-driven Ser303 phosphorylation switches MIIP into a nuclear RelA-stabilizing factor, redefining MIIP as a context-dependent modulator rather than a purely inhibitory protein.\",\n      \"evidence\": \"Phosphorylation and kinase/phosphatase assays, nuclear fractionation, co-IP, and gain/loss-of-function studies\",\n      \"pmids\": [\"29038521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser303 phosphorylation directs nuclear localization not detailed\", \"Reconciliation of pro-metastatic RelA stabilization with MIIP's tumor-suppressive activities not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected the HDAC6 axis to hypoxia signaling and established a feedback loop, showing MIIP promotes HIF-1\\u03b1 acetylation/degradation while HIF-1\\u03b1 represses MIIP via miR-646.\",\n      \"evidence\": \"ChIP, luciferase reporter, miRNA array, HDAC activity assay and co-IP with xenografts in pancreatic cancer\",\n      \"pmids\": [\"29343850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HIF-1\\u03b1 acetylation is the direct consequence of HDAC6 inhibition not formally separated from other effects\", \"miR-646 regulation tested in a single tumor context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the PP1\\u03b1-AKT mechanism, showing MIIP's C-terminus recruits PP1\\u03b1 to dephosphorylate AKT and suppress AKT-mTOR signaling.\",\n      \"evidence\": \"Reciprocal co-IP, co-localization, deletion mutagenesis with functional rescue and siRNA in prostate cancer with xenografts\",\n      \"pmids\": [\"31092266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MIIP acts as a scaffold or allosteric activator of PP1\\u03b1 not resolved\", \"Substrate selectivity of the MIIP-PP1\\u03b1 module not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended HSP90-chaperone control of HIF, showing MIIP promotes HSP90 acetylation to release HIF-2\\u03b1 for RACK1-mediated ubiquitination and degradation in renal carcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, RNA-seq and xenograft models\",\n      \"pmids\": [\"34931765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MIIP enhances HSP90 acetylation mechanistically (via HDAC6 or other) not stated\", \"Direct versus indirect MIIP-HSP90 engagement unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an integrin-based mechanism, showing MIIP's RGD motif binds ITGB3 to drive \\u03b2-catenin degradation and reduce VEGFA, linking MIIP to angiogenesis suppression.\",\n      \"evidence\": \"Co-IP, RGD-mutant functional assays, ubiquitination assay and in vitro/in vivo assays in triple-negative breast cancer\",\n      \"pmids\": [\"36130933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling steps from ITGB3 to \\u03b2-catenin not fully mapped\", \"Whether RGD engagement competes with ECM ligands not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a metabolic role, showing MIIP regulates AZGP1 N-glycosylation by interfering with STT3A, controlling AZGP1 secretion and adipocyte browning/lipolysis.\",\n      \"evidence\": \"Co-IP, glycosylation assays, co-culture and allograft models in colorectal cancer\",\n      \"pmids\": [\"38245780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MIIP physically blocks the AZGP1-STT3A association not detailed\", \"Tested in colorectal context only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed a structural/centriolar role, localizing MIIP to the A-C linker of centrioles in a complex with CCDC77 and WDR67 required for triplet cohesion and duplication.\",\n      \"evidence\": \"Ultrastructure expansion microscopy and depletion phenotyping (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.04.616628\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct interaction/complex membership not confirmed by co-IP\", \"Relationship between centriolar role and cytoplasmic tumor-suppressive functions unknown\", \"Single preprint, not peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MIIP's many distinct interaction modules (HDAC6, Cdc20, PAK1, PP1\\u03b1, ITGB3, HSP90, AZGP1, centriolar partners) are coordinated, prioritized, or spatially partitioned within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated model reconciling cytoskeletal, mitotic, signaling, and centriolar roles\", \"No high-resolution structure of MIIP or its complexes\", \"Endogenous stoichiometry and context-dependent partner selection undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 8, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [\"APC/C (via Cdc20 interaction)\", \"centriolar A-C linker (with CCDC77, WDR67)\"],\n    \"partners\": [\"IGFBP2\", \"HDAC6\", \"CDC20\", \"PAK1\", \"PPP1CA\", \"ITGB3\", \"RELA\", \"AZGP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}