{"gene":"MT2A","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2015,"finding":"HMBOX1 physically interacts with MT2A (identified by yeast two-hybrid and confirmed by co-immunoprecipitation), and this interaction elevates intracellular free zinc levels; knockdown of MT2A abolishes HMBOX1-mediated zinc elevation, anti-apoptotic, and pro-autophagic effects in vascular endothelial cells.","method":"Yeast two-hybrid, co-immunoprecipitation, MT2A knockdown with phenotypic readout, zinc chelation rescue experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirms interaction, multiple orthogonal functional assays, single lab","pmids":["26456220"],"is_preprint":false},{"year":2017,"finding":"XAF1 directly interacts with MT2A and facilitates its lysosomal degradation, leading to elevation of free intracellular zinc, subsequent p53 activation, and XIAP inactivation, thereby switching stress response toward apoptosis. A MT2A-binding-deficient XAF1 mutant fails to elevate free zinc, confirming the interaction is required for this mechanism. Conversely, MT2A destabilizes XAF1 via the lysosomal pathway under cytostatic stress, establishing mutual antagonism.","method":"Co-immunoprecipitation, domain-mutant XAF1 (binding-deficient), lysosomal degradation assays, intracellular zinc measurement, xenograft models, loss-of-function experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional interaction confirmed by Co-IP and mutagenesis, multiple orthogonal methods, mechanistic pathway fully delineated in single rigorous study","pmids":["28507149"],"is_preprint":false},{"year":2006,"finding":"Recombinant human MT2A expressed in E. coli retains intact metal-binding ability, hydroxyl radical scavenging ability, and protective activity against DNA damage caused by UVC radiation, establishing these as intrinsic biochemical activities of the protein.","method":"In vitro biochemical assays: metal-binding, hydroxyl radical scavenging, DNA damage protection assay with UVC-irradiated purified recombinant protein","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro enzymatic/functional assays with purified recombinant protein, single lab, single study","pmids":["17224279"],"is_preprint":false},{"year":2014,"finding":"EOLA1 interacts with MT2A (identified by yeast two-hybrid screening), and MT2A plays a key role in LPS-induced IL-6 expression in HUVECs; EOLA1 acts as a negative regulator of LPS response by regulating MT2A activity.","method":"Yeast two-hybrid, knockdown of EOLA1 and MT2A with IL-6 and apoptosis readouts in HUVECs","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid interaction plus functional knockdown phenotypes, interaction not confirmed by Co-IP in this paper, single lab","pmids":["24916366"],"is_preprint":false},{"year":2015,"finding":"EOLA1 association with MT2A negatively regulates LPS-induced VCAM-1 expression in ECV304 endothelial cells; MT2A knockdown reduces LPS-induced VCAM-1 production, placing MT2A as a positive regulator of VCAM-1 in this inflammatory pathway.","method":"Knockdown of EOLA1 and MT2A, overexpression of EOLA1, VCAM-1 measurement in LPS-stimulated ECV304 cells","journal":"International journal of inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional knockdown with phenotypic readout but interaction not confirmed by direct biochemical method in this paper; single lab, single study","pmids":["26881174"],"is_preprint":false},{"year":2020,"finding":"MT2A interacts with BARD1 and BRCA1 (confirmed by co-immunoprecipitation and co-localization by immunofluorescence) and positively regulates BARD1/BRCA1 levels; BARD1 overexpression partially restores Oxaliplatin resistance lost upon MT2A knockdown in colorectal cancer cells, placing MT2A upstream of BARD1/BRCA1 in chemoresistance.","method":"Co-immunoprecipitation, immunofluorescence co-localization, MT2A knockdown and overexpression with viability/resistance readouts, BARD1 rescue experiment","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms interaction, epistasis rescue experiment places MT2A upstream of BARD1/BRCA1, single lab","pmids":["32638210"],"is_preprint":false},{"year":2022,"finding":"MT2A overexpression promotes phosphorylation of MST1, LATS2, and YAP1, thereby activating the Hippo signaling pathway and inhibiting colorectal cancer cell proliferation and liver metastasis; specific MST1/2 inhibitors abolish this phosphorylation and rescue proliferation, placing MT2A upstream of the MST1/LATS2/YAP1 axis.","method":"Western blotting for Hippo pathway phosphorylation, MT2A overexpression and knockdown in cells, xenograft and liver metastasis animal models, MST1/2 inhibitor rescue experiment, immunohistochemistry","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo assays with epistasis rescue, single lab","pmids":["35642057"],"is_preprint":false},{"year":2021,"finding":"MT2A overexpression in HL60 AML cells induces apoptosis and G2/M cell cycle arrest associated with downregulation of p-IκB-α and cyclin D1 and upregulation of IκB-α, placing MT2A as a negative regulator of the NF-κB pathway; MT2A knockdown conversely increases proliferation.","method":"Lentiviral MT2A overexpression, shRNA knockdown, flow cytometry, Western blotting for NF-κB pathway components, cell viability assays in HL60 cells","journal":"International journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean loss- and gain-of-function with defined pathway readout, single lab, single study","pmids":["34220318"],"is_preprint":false},{"year":2022,"finding":"CD69 inhibits activin A-induced erythroid differentiation via MT2A; activin A reduces MT2A expression through p38MAPK, and MT2A knockdown reduces CD69's ability to suppress erythroid marker expression and sensitization to imatinib in K562 CML cells, placing MT2A downstream of CD69 in this differentiation pathway.","method":"MT2A knockdown, CD69 overexpression, p38MAPK inhibition (SB203580), erythroid marker expression, growth inhibition and apoptosis assays in K562 and BCR-ABL+ CD34+ cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by knockdown and pathway inhibitors with multiple orthogonal readouts, single lab","pmids":["35643179"],"is_preprint":false},{"year":2023,"finding":"HSF1 binds the MT2A promoter to transcriptionally activate MT2A; RING1 (an E3 ubiquitin ligase) binds HSF1 and induces its proteasome-dependent degradation, thereby suppressing MT2A transcription and causing cell cycle arrest and apoptosis in breast cancer cells. Ectopic MT2A expression rescues the anti-proliferative effects of RING1, placing MT2A downstream of the RING1-HSF1 axis.","method":"Co-immunoprecipitation (RING1-HSF1), ChIP (HSF1 on MT2A promoter), proteasome inhibitor experiments, MT2A ectopic overexpression rescue, xenograft models, Western blotting","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including Co-IP, ChIP, rescue experiment and in vivo validation, single lab","pmids":["37797799"],"is_preprint":false},{"year":2025,"finding":"Artesunate (AS) directly binds MT2A (validated by HuProt 20K human proteome microarray and surface plasmon resonance), upregulates MT2A in astrocytes, reduces intracellular Cu2+ levels, and inhibits cuproptosis (FDX1, CTR1, lip-DLAT regulation); MT2A-Lys-31 is identified as a key functional site. MT2A knockdown abolishes AS-mediated neuroprotection and copper reduction.","method":"Human proteome microarray (HuProt 20K), surface plasmon resonance (SPR), MT2A knockdown, site-directed mutagenesis (Lys-31), copper ion measurements, cuproptosis marker assessment, in vivo 6-OHDA Parkinson's disease model","journal":"Pharmacological research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding validated by orthogonal biophysical methods (microarray + SPR), functional site identified by mutagenesis, loss-of-function rescue, single lab but multiple orthogonal methods","pmids":["40754045"],"is_preprint":false},{"year":2025,"finding":"Under hypoxia, MT2A translocates to mitochondria in a copper-ion-dependent manner and interacts with the tetrameric form of PKM2 to maintain PKM2 enzymatic activity, thereby promoting glycolysis and oxidative phosphorylation in breast cancer cells.","method":"Mitochondrial proteomics, co-immunoprecipitation (MT2A-PKM2 tetrameric form), subcellular fractionation, copper ion manipulation, glycolysis and OXPHOS functional assays, MT2A knockdown with tumor growth readout","journal":"Cell insight","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP identifies interaction with tetrameric PKM2 and functional metabolic assays support the mechanism, single lab, single study","pmids":["41211480"],"is_preprint":false},{"year":2025,"finding":"MT2A overexpression in HUVECs alleviates copper overload (CPO)-induced mitochondrial dysfunction and cytotoxicity; in a rat chronic ischemia model, MT2A overexpression reduces DLAT accumulation and mitochondrial abnormalities and promotes angiogenesis, establishing a copper-mitochondria regulatory mechanism for MT2A in ischemic angiogenesis.","method":"MT2A overexpression in HUVECs (in vitro copper overload model), rat 2VO+EMS in vivo model, mitochondrial morphology and activity assays, CD31 immunostaining, cuproptosis marker analysis (DLAT, FDX1, SDHB), cerebral blood perfusion measurement","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo gain-of-function experiments with multiple mechanistic readouts, single lab","pmids":["39915841"],"is_preprint":false},{"year":2024,"finding":"MT2A overexpression in hypoxia-exposed dorsal root ganglion neurons inhibits apoptosis by inactivating p38 MAPK, and MT2A co-localizes with neurons (but not microglia or astrocytes) in rat DRG tissues, establishing MT2A as a neuronal anti-apoptotic regulator acting through the p38 MAPK pathway in neurogenic intermittent claudication.","method":"Lentivirus-mediated MT2A overexpression in primary neurons, hypoxia-induced cell damage model, co-localization immunostaining, apoptosis assays, p38 MAPK activation measurements, rat cauda equina compression model","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined pathway (p38 MAPK) and localization data, in vitro and in vivo, single lab","pmids":["38546949"],"is_preprint":false},{"year":2019,"finding":"TUG1 lncRNA recruits EZH2 to the MT2A promoter to epigenetically suppress MT2A transcription; ChIP experiments confirmed EZH2 binding to the MT2A promoter, and TUG1 knockdown reduced this binding, de-repressing MT2A expression. [NOTE: This paper was subsequently retracted (PMID:34992381), so this finding should be treated with caution.]","method":"RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), TUG1 knockdown, MT2A expression analysis","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 2 / Weak — mechanistic ChIP and RIP data, but paper was retracted; confidence severely diminished by retraction","pmids":["30787623"],"is_preprint":false},{"year":2023,"finding":"GHET1 lncRNA recruits EZH2 and LSD1 to the MT2A promoter, reducing H3K27me3 and H3K4me2 occupancy to epigenetically suppress MT2A transcription; MT2A knockdown reverses GHET1 inhibition of trophoblast phenotypes, establishing MT2A as a downstream effector of GHET1 in extravillous trophoblast biology.","method":"RNA immunoprecipitation (RIP), RNA pull-down, chromatin immunoprecipitation (ChIP) for histone marks, MT2A knockdown rescue experiments, proliferation and migration assays","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods (RIP, pull-down, ChIP) with functional rescue, single lab","pmids":["37548351"],"is_preprint":false}],"current_model":"MT2A is a cysteine-rich metal-binding protein that sequesters zinc and copper ions intracellularly; it acts as a zinc/copper buffer whose interaction partners (XAF1, HMBOX1, EOLA1, BARD1/BRCA1, PKM2) determine cell fate by modulating free intracellular metal levels, with downstream consequences for p53 activation, XIAP stability, NF-κB and p38 MAPK signaling, Hippo pathway activation, glycolysis/OXPHOS, and cuproptosis, while its transcription is regulated epigenetically by EZH2/LSD1 recruitment and by the RING1-HSF1 ubiquitination axis."},"narrative":{"mechanistic_narrative":"MT2A is a cysteine-rich metal-binding protein that buffers intracellular zinc and copper and, through these metal pools and a set of protein partners, governs cell-fate decisions of survival, apoptosis, differentiation, and metabolism [PMID:28507149, PMID:17224279]. The purified protein intrinsically binds metal, scavenges hydroxyl radicals, and protects DNA against UVC damage, establishing its core cytoprotective biochemistry [PMID:17224279]. Its free-zinc-buffering role is set by competing partners: XAF1 binds MT2A and routes it to lysosomal degradation, raising free zinc, activating p53, and inactivating XIAP to drive apoptosis, while MT2A reciprocally destabilizes XAF1, creating a mutual antagonism that titrates the stress response [PMID:28507149]; HMBOX1 binding instead elevates free zinc to support anti-apoptotic and pro-autophagic outcomes in endothelial cells [PMID:26456220]. MT2A also acts in copper handling and cuproptosis: it limits intracellular Cu2+ and suppresses cuproptosis markers (FDX1, CTR1, DLAT), with Lys-31 identified as a functional site and direct small-molecule (artesunate) binding demonstrated [PMID:40754045], and it protects mitochondria from copper-overload toxicity in endothelial and ischemic-angiogenesis models [PMID:39915841]. Under hypoxia MT2A translocates to mitochondria in a copper-dependent manner and binds tetrameric PKM2 to sustain its activity and promote glycolysis and OXPHOS [PMID:41211480]. Through partner and pathway control, MT2A engages BARD1/BRCA1 in chemoresistance [PMID:32638210], the MST1/LATS2/YAP1 Hippo axis [PMID:35642057], NF-κB [PMID:34220318], and p38 MAPK signaling [PMID:35643179, PMID:38546949], the latter underlying neuronal anti-apoptotic protection [PMID:38546949]. MT2A transcription is controlled by an HSF1 promoter-binding activator that is itself destabilized by the RING1 E3 ligase [PMID:37797799] and by lncRNA-directed recruitment of EZH2/LSD1 chromatin-modifying activity to its promoter [PMID:37548351].","teleology":[{"year":2006,"claim":"Established that MT2A's protective activities are intrinsic to the protein, defining its core biochemistry of metal binding, radical scavenging, and DNA protection rather than dependence on cellular context.","evidence":"In vitro metal-binding, hydroxyl radical scavenging, and UVC DNA-damage protection assays with purified recombinant human protein","pmids":["17224279"],"confidence":"Medium","gaps":["Single-lab in vitro study","Does not address which metals dominate in vivo or stoichiometry under physiological conditions"]},{"year":2014,"claim":"Linked MT2A to inflammatory signaling by identifying EOLA1 as an interactor and showing MT2A is required for LPS-induced IL-6 in endothelial cells.","evidence":"Yeast two-hybrid screen plus EOLA1/MT2A knockdown with IL-6 and apoptosis readouts in HUVECs","pmids":["24916366"],"confidence":"Medium","gaps":["Interaction not confirmed by Co-IP in this study","Molecular mechanism connecting MT2A to IL-6 transcription not defined"]},{"year":2015,"claim":"Showed that partner identity tunes MT2A's free-zinc output toward survival, with HMBOX1 binding raising zinc to drive anti-apoptotic and pro-autophagic effects, and extended the EOLA1 axis to VCAM-1.","evidence":"Yeast two-hybrid, reciprocal Co-IP, MT2A knockdown with zinc chelation rescue (HMBOX1); knockdown/overexpression with VCAM-1 readout (EOLA1) in endothelial cells","pmids":["26456220","26881174"],"confidence":"Medium","gaps":["VCAM-1 finding is Low confidence with no biochemical interaction validation","Structural basis of HMBOX1-driven zinc elevation unknown"]},{"year":2017,"claim":"Defined the mechanism by which MT2A-controlled zinc dictates apoptosis versus survival, showing XAF1 degrades MT2A to release zinc and activate p53/XIAP, with reciprocal MT2A destabilization of XAF1.","evidence":"Co-IP, binding-deficient XAF1 mutant, lysosomal degradation and zinc-measurement assays, and xenograft loss-of-function models","pmids":["28507149"],"confidence":"High","gaps":["Does not resolve how cells choose between XAF1-driven degradation and HMBOX1-driven stabilization","Lysosomal targeting machinery for MT2A not identified"]},{"year":2019,"claim":"Proposed epigenetic silencing of MT2A via lncRNA-directed EZH2 recruitment to its promoter.","evidence":"RIP, ChIP for EZH2 on the MT2A promoter, and TUG1 knockdown (paper subsequently retracted)","pmids":["30787623"],"confidence":"Low","gaps":["Paper was retracted, so the finding cannot be relied upon","Independent confirmation of TUG1-EZH2-MT2A axis lacking"]},{"year":2020,"claim":"Placed MT2A upstream of the BARD1/BRCA1 module in chemoresistance, expanding its role beyond metal buffering into DNA-repair-associated drug response.","evidence":"Co-IP, immunofluorescence co-localization, and BARD1 rescue of Oxaliplatin resistance in MT2A-knockdown colorectal cancer cells","pmids":["32638210"],"confidence":"Medium","gaps":["Mechanism by which MT2A stabilizes BARD1/BRCA1 not defined","Whether metal binding is required for this interaction untested"]},{"year":2021,"claim":"Identified MT2A as a negative regulator of NF-κB driving apoptosis and G2/M arrest in AML cells, broadening its tumor-suppressive signaling repertoire.","evidence":"Lentiviral overexpression and shRNA knockdown with flow cytometry and Western blotting of NF-κB components in HL60 cells","pmids":["34220318"],"confidence":"Medium","gaps":["Direct molecular link between MT2A and IκB-α/NF-κB not established","Single cell line"]},{"year":2022,"claim":"Connected MT2A to Hippo and erythroid-differentiation pathways, showing it activates the MST1/LATS2/YAP1 axis to suppress tumor growth and acts downstream of CD69 via p38MAPK regulation.","evidence":"Overexpression/knockdown with Hippo phosphorylation Westerns and MST1/2 inhibitor rescue plus xenografts (Hippo); MT2A knockdown with p38MAPK inhibition and erythroid readouts (CD69)","pmids":["35642057","35643179"],"confidence":"Medium","gaps":["How MT2A activates upstream Hippo kinases is unknown","Whether metal buffering mediates these signaling effects untested"]},{"year":2023,"claim":"Resolved transcriptional control of MT2A, establishing an HSF1 activating input opposed by RING1-mediated HSF1 degradation, and a parallel GHET1-EZH2/LSD1 chromatin-silencing route.","evidence":"Co-IP, ChIP for HSF1 on MT2A promoter, proteasome inhibition and MT2A rescue (RING1-HSF1); RIP, pull-down, histone-mark ChIP, knockdown rescue (GHET1)","pmids":["37797799","37548351"],"confidence":"Medium","gaps":["Signals that toggle these activating versus silencing inputs unknown","Single-lab studies in distinct cell contexts"]},{"year":2025,"claim":"Defined MT2A's role in copper handling and cuproptosis, identifying a druggable site (Lys-31), copper-dependent mitochondrial translocation, and a tetrameric-PKM2 interaction linking metal buffering to metabolic and protective outcomes.","evidence":"HuProt microarray and SPR with site mutagenesis and Parkinson's model (artesunate/Lys-31); mitochondrial proteomics and Co-IP with PKM2; copper-overload and ischemia gain-of-function models","pmids":["40754045","41211480","39915841"],"confidence":"High","gaps":["How copper ions trigger mitochondrial translocation mechanistically unresolved","Relationship between zinc and copper buffering functions of the same protein unclear"]},{"year":null,"claim":"It remains unresolved how a single metal-buffering protein integrates its many partner-specific and pathway-specific outputs into a unified rule governing cell fate across tissues.","evidence":"No single study reconciles the zinc- versus copper-centric mechanisms or the competing partner interactions","pmids":[],"confidence":"Low","gaps":["No structural model of MT2A in complex with any partner","No unified accounting of when MT2A is pro- versus anti-apoptotic","Quantitative contribution of metal buffering versus direct protein interactions undefined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11,12]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,11,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,7,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,8]}],"complexes":[],"partners":["XAF1","HMBOX1","EOLA1","BARD1","BRCA1","PKM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02795","full_name":"Metallothionein-2","aliases":["Metallothionein-2A","Metallothionein-II","MT-II"],"length_aa":61,"mass_kda":6.0,"function":"Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P02795/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MT2A","classification":"Common Essential","n_dependent_lines":594,"n_total_lines":1090,"dependency_fraction":0.544954128440367},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MT2A","total_profiled":1310},"omim":[{"mim_id":"617288","title":"SERINE PEPTIDASE INHIBITOR, KAZAL-TYPE, 7; SPINK7","url":"https://www.omim.org/entry/617288"},{"mim_id":"616508","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 11; SLC39A11","url":"https://www.omim.org/entry/616508"},{"mim_id":"609882","title":"METAL-REGULATORY TRANSCRIPTION FACTOR 2; MTF2","url":"https://www.omim.org/entry/609882"},{"mim_id":"606206","title":"METALLOTHIONEIN 4; MT4","url":"https://www.omim.org/entry/606206"},{"mim_id":"301009","title":"P ANTIGEN FAMILY, MEMBER 5; PAGE5","url":"https://www.omim.org/entry/301009"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":15847.5}],"url":"https://www.proteinatlas.org/search/MT2A"},"hgnc":{"alias_symbol":[],"prev_symbol":["MT2"]},"alphafold":{"accession":"P02795","domains":[{"cath_id":"4.10.10.10","chopping":"1-30","consensus_level":"medium","plddt":77.718,"start":1,"end":30},{"cath_id":"-","chopping":"33-61","consensus_level":"medium","plddt":84.1845,"start":33,"end":61}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02795","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02795-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02795-F1-predicted_aligned_error_v6.png","plddt_mean":80.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MT2A","jax_strain_url":"https://www.jax.org/strain/search?query=MT2A"},"sequence":{"accession":"P02795","fasta_url":"https://rest.uniprot.org/uniprotkb/P02795.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02795/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02795"}},"corpus_meta":[{"pmid":"16518702","id":"PMC_16518702","title":"Novel -209A/G MT2A polymorphism in old patients with type 2 diabetes and atherosclerosis: relationship with inflammation (IL-6) and zinc.","date":"2005","source":"Biogerontology","url":"https://pubmed.ncbi.nlm.nih.gov/16518702","citation_count":71,"is_preprint":false},{"pmid":"26456220","id":"PMC_26456220","title":"HMBOX1 interacts with MT2A to regulate autophagy and apoptosis in vascular endothelial cells.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26456220","citation_count":59,"is_preprint":false},{"pmid":"17622311","id":"PMC_17622311","title":"The +838 C/G MT2A polymorphism, metals, and the inflammatory/immune response in carotid artery stenosis in elderly people.","date":"2007","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/17622311","citation_count":46,"is_preprint":false},{"pmid":"30612060","id":"PMC_30612060","title":"Arsenic metabolites; selenium; and AS3MT, MTHFR, AQP4, AQP9, SELENOP, INMT, and MT2A polymorphisms in Croatian-Slovenian population from PHIME-CROME study.","date":"2018","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/30612060","citation_count":34,"is_preprint":false},{"pmid":"30787623","id":"PMC_30787623","title":"Overexpressed long noncoding RNA TUG1 affects the cell cycle, proliferation, and apoptosis of pancreatic cancer partly through suppressing RND3 and MT2A.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30787623","citation_count":33,"is_preprint":false},{"pmid":"28507149","id":"PMC_28507149","title":"Identification of XAF1-MT2A mutual antagonism as a molecular switch in cell-fate decisions under stressful conditions.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28507149","citation_count":30,"is_preprint":false},{"pmid":"35642057","id":"PMC_35642057","title":"Metallothionein 2A (MT2A) controls cell proliferation and liver metastasis by controlling the MST1/LATS2/YAP1 signaling pathway in colorectal cancer.","date":"2022","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/35642057","citation_count":29,"is_preprint":false},{"pmid":"21277639","id":"PMC_21277639","title":"Distributions of interleukin-6 (IL-6) promoter and metallothionein 2A (MT2A) core promoter region gene polymorphisms and their associations with aging in Turkish population.","date":"2011","source":"Archives of gerontology and geriatrics","url":"https://pubmed.ncbi.nlm.nih.gov/21277639","citation_count":24,"is_preprint":false},{"pmid":"37713131","id":"PMC_37713131","title":"Single-cell transcriptome analysis revealing the intratumoral heterogeneity of ccRCC and validation of MT2A in pathogenesis.","date":"2023","source":"Functional & integrative 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cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24916366","citation_count":20,"is_preprint":false},{"pmid":"17224279","id":"PMC_17224279","title":"High-yield expression in Escherichia coli of soluble human MT2A with native functions.","date":"2006","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/17224279","citation_count":18,"is_preprint":false},{"pmid":"32765800","id":"PMC_32765800","title":"Polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13 and MT2A do not contribute to breast, lung and colon cancer risk in polish population.","date":"2020","source":"Hereditary cancer in clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/32765800","citation_count":14,"is_preprint":false},{"pmid":"39915841","id":"PMC_39915841","title":"MT2A promotes angiogenesis in chronically ischemic brains through a copper-mitochondria regulatory mechanism.","date":"2025","source":"Journal of translational 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gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/36060520","citation_count":3,"is_preprint":false},{"pmid":"37797799","id":"PMC_37797799","title":"RING induces cell cycle arrest and apoptosis in human breast cancer cells by regulating the HSF1/MT2A axis.","date":"2023","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37797799","citation_count":3,"is_preprint":false},{"pmid":"29231000","id":"PMC_29231000","title":"Time-dependent Expression of MT1A mRNA and MT2A mRNA in the Contused Skeletal Muscle of Rats.","date":"2017","source":"Fa yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/29231000","citation_count":3,"is_preprint":false},{"pmid":"38546949","id":"PMC_38546949","title":"Compensatory upregulation of MT2A alleviates neurogenic intermittent claudication through inhibiting activated p38 MAPK-mediated neuronal apoptosis.","date":"2024","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/38546949","citation_count":3,"is_preprint":false},{"pmid":"20836978","id":"PMC_20836978","title":"[Tea polyphenol inhibits colorectal cancer with microsatellite instability by regulating the expressions of HES1, JAG1, MT2A and MAFA].","date":"2010","source":"Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20836978","citation_count":3,"is_preprint":false},{"pmid":"37548351","id":"PMC_37548351","title":"lncRNA GHET1 regulates extravillous trophoblastic phenotype via EZH2/LSD1-mediated MT2A epigenetic suppression in pre-eclampsia.","date":"2023","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/37548351","citation_count":2,"is_preprint":false},{"pmid":"25218889","id":"PMC_25218889","title":"Interaction study of arsenic (III and V) ions with metallothionein gene (MT2A) fragment.","date":"2014","source":"International journal of biological 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journal of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/33062250","citation_count":0,"is_preprint":false},{"pmid":"34992381","id":"PMC_34992381","title":"Overexpressed Long Noncoding RNA TUG1 Affects the Cell Cycle, Proliferation, and Apoptosis of Pancreatic Cancer Partly Through Suppressing RND3 and MT2A [Retraction].","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34992381","citation_count":0,"is_preprint":false},{"pmid":"16806025","id":"PMC_16806025","title":"[Expression and purification of human MT-2a fusion protein in prokaryotic cells and preparation of its antiserum].","date":"2006","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16806025","citation_count":0,"is_preprint":false},{"pmid":"22145350","id":"PMC_22145350","title":"[Immunogenic properties and molecular-genetic features of native and inactivated Chlamydia trachomatis MT-2A serovariant D strain].","date":"2011","source":"Zhurnal mikrobiologii, epidemiologii i immunobiologii","url":"https://pubmed.ncbi.nlm.nih.gov/22145350","citation_count":0,"is_preprint":false},{"pmid":"18595462","id":"PMC_18595462","title":"[Biological and immunogenic characteristics of Chlamydia trachomatis strain MT-2A (serovar D) and its use for development of experimental inactivated vaccine].","date":"2008","source":"Zhurnal mikrobiologii, epidemiologii i immunobiologii","url":"https://pubmed.ncbi.nlm.nih.gov/18595462","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.03.657705","title":"RNA-seq reveals transcriptomic differences in circadian-related genes of the choroid plexus in a preclinical chronic migraine 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\"Yeast two-hybrid, co-immunoprecipitation, MT2A knockdown with phenotypic readout, zinc chelation rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirms interaction, multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"26456220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"XAF1 directly interacts with MT2A and facilitates its lysosomal degradation, leading to elevation of free intracellular zinc, subsequent p53 activation, and XIAP inactivation, thereby switching stress response toward apoptosis. A MT2A-binding-deficient XAF1 mutant fails to elevate free zinc, confirming the interaction is required for this mechanism. Conversely, MT2A destabilizes XAF1 via the lysosomal pathway under cytostatic stress, establishing mutual antagonism.\",\n      \"method\": \"Co-immunoprecipitation, domain-mutant XAF1 (binding-deficient), lysosomal degradation assays, intracellular zinc measurement, xenograft models, loss-of-function experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional interaction confirmed by Co-IP and mutagenesis, multiple orthogonal methods, mechanistic pathway fully delineated in single rigorous study\",\n      \"pmids\": [\"28507149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Recombinant human MT2A expressed in E. coli retains intact metal-binding ability, hydroxyl radical scavenging ability, and protective activity against DNA damage caused by UVC radiation, establishing these as intrinsic biochemical activities of the protein.\",\n      \"method\": \"In vitro biochemical assays: metal-binding, hydroxyl radical scavenging, DNA damage protection assay with UVC-irradiated purified recombinant protein\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro enzymatic/functional assays with purified recombinant protein, single lab, single study\",\n      \"pmids\": [\"17224279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EOLA1 interacts with MT2A (identified by yeast two-hybrid screening), and MT2A plays a key role in LPS-induced IL-6 expression in HUVECs; EOLA1 acts as a negative regulator of LPS response by regulating MT2A activity.\",\n      \"method\": \"Yeast two-hybrid, knockdown of EOLA1 and MT2A with IL-6 and apoptosis readouts in HUVECs\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid interaction plus functional knockdown phenotypes, interaction not confirmed by Co-IP in this paper, single lab\",\n      \"pmids\": [\"24916366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EOLA1 association with MT2A negatively regulates LPS-induced VCAM-1 expression in ECV304 endothelial cells; MT2A knockdown reduces LPS-induced VCAM-1 production, placing MT2A as a positive regulator of VCAM-1 in this inflammatory pathway.\",\n      \"method\": \"Knockdown of EOLA1 and MT2A, overexpression of EOLA1, VCAM-1 measurement in LPS-stimulated ECV304 cells\",\n      \"journal\": \"International journal of inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional knockdown with phenotypic readout but interaction not confirmed by direct biochemical method in this paper; single lab, single study\",\n      \"pmids\": [\"26881174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MT2A interacts with BARD1 and BRCA1 (confirmed by co-immunoprecipitation and co-localization by immunofluorescence) and positively regulates BARD1/BRCA1 levels; BARD1 overexpression partially restores Oxaliplatin resistance lost upon MT2A knockdown in colorectal cancer cells, placing MT2A upstream of BARD1/BRCA1 in chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, MT2A knockdown and overexpression with viability/resistance readouts, BARD1 rescue experiment\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms interaction, epistasis rescue experiment places MT2A upstream of BARD1/BRCA1, single lab\",\n      \"pmids\": [\"32638210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MT2A overexpression promotes phosphorylation of MST1, LATS2, and YAP1, thereby activating the Hippo signaling pathway and inhibiting colorectal cancer cell proliferation and liver metastasis; specific MST1/2 inhibitors abolish this phosphorylation and rescue proliferation, placing MT2A upstream of the MST1/LATS2/YAP1 axis.\",\n      \"method\": \"Western blotting for Hippo pathway phosphorylation, MT2A overexpression and knockdown in cells, xenograft and liver metastasis animal models, MST1/2 inhibitor rescue experiment, immunohistochemistry\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo assays with epistasis rescue, single lab\",\n      \"pmids\": [\"35642057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MT2A overexpression in HL60 AML cells induces apoptosis and G2/M cell cycle arrest associated with downregulation of p-IκB-α and cyclin D1 and upregulation of IκB-α, placing MT2A as a negative regulator of the NF-κB pathway; MT2A knockdown conversely increases proliferation.\",\n      \"method\": \"Lentiviral MT2A overexpression, shRNA knockdown, flow cytometry, Western blotting for NF-κB pathway components, cell viability assays in HL60 cells\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean loss- and gain-of-function with defined pathway readout, single lab, single study\",\n      \"pmids\": [\"34220318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD69 inhibits activin A-induced erythroid differentiation via MT2A; activin A reduces MT2A expression through p38MAPK, and MT2A knockdown reduces CD69's ability to suppress erythroid marker expression and sensitization to imatinib in K562 CML cells, placing MT2A downstream of CD69 in this differentiation pathway.\",\n      \"method\": \"MT2A knockdown, CD69 overexpression, p38MAPK inhibition (SB203580), erythroid marker expression, growth inhibition and apoptosis assays in K562 and BCR-ABL+ CD34+ cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by knockdown and pathway inhibitors with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"35643179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSF1 binds the MT2A promoter to transcriptionally activate MT2A; RING1 (an E3 ubiquitin ligase) binds HSF1 and induces its proteasome-dependent degradation, thereby suppressing MT2A transcription and causing cell cycle arrest and apoptosis in breast cancer cells. Ectopic MT2A expression rescues the anti-proliferative effects of RING1, placing MT2A downstream of the RING1-HSF1 axis.\",\n      \"method\": \"Co-immunoprecipitation (RING1-HSF1), ChIP (HSF1 on MT2A promoter), proteasome inhibitor experiments, MT2A ectopic overexpression rescue, xenograft models, Western blotting\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including Co-IP, ChIP, rescue experiment and in vivo validation, single lab\",\n      \"pmids\": [\"37797799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Artesunate (AS) directly binds MT2A (validated by HuProt 20K human proteome microarray and surface plasmon resonance), upregulates MT2A in astrocytes, reduces intracellular Cu2+ levels, and inhibits cuproptosis (FDX1, CTR1, lip-DLAT regulation); MT2A-Lys-31 is identified as a key functional site. MT2A knockdown abolishes AS-mediated neuroprotection and copper reduction.\",\n      \"method\": \"Human proteome microarray (HuProt 20K), surface plasmon resonance (SPR), MT2A knockdown, site-directed mutagenesis (Lys-31), copper ion measurements, cuproptosis marker assessment, in vivo 6-OHDA Parkinson's disease model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding validated by orthogonal biophysical methods (microarray + SPR), functional site identified by mutagenesis, loss-of-function rescue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40754045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under hypoxia, MT2A translocates to mitochondria in a copper-ion-dependent manner and interacts with the tetrameric form of PKM2 to maintain PKM2 enzymatic activity, thereby promoting glycolysis and oxidative phosphorylation in breast cancer cells.\",\n      \"method\": \"Mitochondrial proteomics, co-immunoprecipitation (MT2A-PKM2 tetrameric form), subcellular fractionation, copper ion manipulation, glycolysis and OXPHOS functional assays, MT2A knockdown with tumor growth readout\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP identifies interaction with tetrameric PKM2 and functional metabolic assays support the mechanism, single lab, single study\",\n      \"pmids\": [\"41211480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MT2A overexpression in HUVECs alleviates copper overload (CPO)-induced mitochondrial dysfunction and cytotoxicity; in a rat chronic ischemia model, MT2A overexpression reduces DLAT accumulation and mitochondrial abnormalities and promotes angiogenesis, establishing a copper-mitochondria regulatory mechanism for MT2A in ischemic angiogenesis.\",\n      \"method\": \"MT2A overexpression in HUVECs (in vitro copper overload model), rat 2VO+EMS in vivo model, mitochondrial morphology and activity assays, CD31 immunostaining, cuproptosis marker analysis (DLAT, FDX1, SDHB), cerebral blood perfusion measurement\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo gain-of-function experiments with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"39915841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MT2A overexpression in hypoxia-exposed dorsal root ganglion neurons inhibits apoptosis by inactivating p38 MAPK, and MT2A co-localizes with neurons (but not microglia or astrocytes) in rat DRG tissues, establishing MT2A as a neuronal anti-apoptotic regulator acting through the p38 MAPK pathway in neurogenic intermittent claudication.\",\n      \"method\": \"Lentivirus-mediated MT2A overexpression in primary neurons, hypoxia-induced cell damage model, co-localization immunostaining, apoptosis assays, p38 MAPK activation measurements, rat cauda equina compression model\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined pathway (p38 MAPK) and localization data, in vitro and in vivo, single lab\",\n      \"pmids\": [\"38546949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TUG1 lncRNA recruits EZH2 to the MT2A promoter to epigenetically suppress MT2A transcription; ChIP experiments confirmed EZH2 binding to the MT2A promoter, and TUG1 knockdown reduced this binding, de-repressing MT2A expression. [NOTE: This paper was subsequently retracted (PMID:34992381), so this finding should be treated with caution.]\",\n      \"method\": \"RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), TUG1 knockdown, MT2A expression analysis\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic ChIP and RIP data, but paper was retracted; confidence severely diminished by retraction\",\n      \"pmids\": [\"30787623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GHET1 lncRNA recruits EZH2 and LSD1 to the MT2A promoter, reducing H3K27me3 and H3K4me2 occupancy to epigenetically suppress MT2A transcription; MT2A knockdown reverses GHET1 inhibition of trophoblast phenotypes, establishing MT2A as a downstream effector of GHET1 in extravillous trophoblast biology.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pull-down, chromatin immunoprecipitation (ChIP) for histone marks, MT2A knockdown rescue experiments, proliferation and migration assays\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods (RIP, pull-down, ChIP) with functional rescue, single lab\",\n      \"pmids\": [\"37548351\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MT2A is a cysteine-rich metal-binding protein that sequesters zinc and copper ions intracellularly; it acts as a zinc/copper buffer whose interaction partners (XAF1, HMBOX1, EOLA1, BARD1/BRCA1, PKM2) determine cell fate by modulating free intracellular metal levels, with downstream consequences for p53 activation, XIAP stability, NF-κB and p38 MAPK signaling, Hippo pathway activation, glycolysis/OXPHOS, and cuproptosis, while its transcription is regulated epigenetically by EZH2/LSD1 recruitment and by the RING1-HSF1 ubiquitination axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MT2A is a cysteine-rich metal-binding protein that buffers intracellular zinc and copper and, through these metal pools and a set of protein partners, governs cell-fate decisions of survival, apoptosis, differentiation, and metabolism [#1, #2]. The purified protein intrinsically binds metal, scavenges hydroxyl radicals, and protects DNA against UVC damage, establishing its core cytoprotective biochemistry [#2]. Its free-zinc-buffering role is set by competing partners: XAF1 binds MT2A and routes it to lysosomal degradation, raising free zinc, activating p53, and inactivating XIAP to drive apoptosis, while MT2A reciprocally destabilizes XAF1, creating a mutual antagonism that titrates the stress response [#1]; HMBOX1 binding instead elevates free zinc to support anti-apoptotic and pro-autophagic outcomes in endothelial cells [#0]. MT2A also acts in copper handling and cuproptosis: it limits intracellular Cu2+ and suppresses cuproptosis markers (FDX1, CTR1, DLAT), with Lys-31 identified as a functional site and direct small-molecule (artesunate) binding demonstrated [#10], and it protects mitochondria from copper-overload toxicity in endothelial and ischemic-angiogenesis models [#12]. Under hypoxia MT2A translocates to mitochondria in a copper-dependent manner and binds tetrameric PKM2 to sustain its activity and promote glycolysis and OXPHOS [#11]. Through partner and pathway control, MT2A engages BARD1/BRCA1 in chemoresistance [#5], the MST1/LATS2/YAP1 Hippo axis [#6], NF-\\u03baB [#7], and p38 MAPK signaling [#8, #13], the latter underlying neuronal anti-apoptotic protection [#13]. MT2A transcription is controlled by an HSF1 promoter-binding activator that is itself destabilized by the RING1 E3 ligase [#9] and by lncRNA-directed recruitment of EZH2/LSD1 chromatin-modifying activity to its promoter [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that MT2A's protective activities are intrinsic to the protein, defining its core biochemistry of metal binding, radical scavenging, and DNA protection rather than dependence on cellular context.\",\n      \"evidence\": \"In vitro metal-binding, hydroxyl radical scavenging, and UVC DNA-damage protection assays with purified recombinant human protein\",\n      \"pmids\": [\"17224279\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vitro study\", \"Does not address which metals dominate in vivo or stoichiometry under physiological conditions\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked MT2A to inflammatory signaling by identifying EOLA1 as an interactor and showing MT2A is required for LPS-induced IL-6 in endothelial cells.\",\n      \"evidence\": \"Yeast two-hybrid screen plus EOLA1/MT2A knockdown with IL-6 and apoptosis readouts in HUVECs\",\n      \"pmids\": [\"24916366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not confirmed by Co-IP in this study\", \"Molecular mechanism connecting MT2A to IL-6 transcription not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that partner identity tunes MT2A's free-zinc output toward survival, with HMBOX1 binding raising zinc to drive anti-apoptotic and pro-autophagic effects, and extended the EOLA1 axis to VCAM-1.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, MT2A knockdown with zinc chelation rescue (HMBOX1); knockdown/overexpression with VCAM-1 readout (EOLA1) in endothelial cells\",\n      \"pmids\": [\"26456220\", \"26881174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"VCAM-1 finding is Low confidence with no biochemical interaction validation\", \"Structural basis of HMBOX1-driven zinc elevation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the mechanism by which MT2A-controlled zinc dictates apoptosis versus survival, showing XAF1 degrades MT2A to release zinc and activate p53/XIAP, with reciprocal MT2A destabilization of XAF1.\",\n      \"evidence\": \"Co-IP, binding-deficient XAF1 mutant, lysosomal degradation and zinc-measurement assays, and xenograft loss-of-function models\",\n      \"pmids\": [\"28507149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how cells choose between XAF1-driven degradation and HMBOX1-driven stabilization\", \"Lysosomal targeting machinery for MT2A not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Proposed epigenetic silencing of MT2A via lncRNA-directed EZH2 recruitment to its promoter.\",\n      \"evidence\": \"RIP, ChIP for EZH2 on the MT2A promoter, and TUG1 knockdown (paper subsequently retracted)\",\n      \"pmids\": [\"30787623\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Paper was retracted, so the finding cannot be relied upon\", \"Independent confirmation of TUG1-EZH2-MT2A axis lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed MT2A upstream of the BARD1/BRCA1 module in chemoresistance, expanding its role beyond metal buffering into DNA-repair-associated drug response.\",\n      \"evidence\": \"Co-IP, immunofluorescence co-localization, and BARD1 rescue of Oxaliplatin resistance in MT2A-knockdown colorectal cancer cells\",\n      \"pmids\": [\"32638210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MT2A stabilizes BARD1/BRCA1 not defined\", \"Whether metal binding is required for this interaction untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified MT2A as a negative regulator of NF-\\u03baB driving apoptosis and G2/M arrest in AML cells, broadening its tumor-suppressive signaling repertoire.\",\n      \"evidence\": \"Lentiviral overexpression and shRNA knockdown with flow cytometry and Western blotting of NF-\\u03baB components in HL60 cells\",\n      \"pmids\": [\"34220318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between MT2A and I\\u03baB-\\u03b1/NF-\\u03baB not established\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected MT2A to Hippo and erythroid-differentiation pathways, showing it activates the MST1/LATS2/YAP1 axis to suppress tumor growth and acts downstream of CD69 via p38MAPK regulation.\",\n      \"evidence\": \"Overexpression/knockdown with Hippo phosphorylation Westerns and MST1/2 inhibitor rescue plus xenografts (Hippo); MT2A knockdown with p38MAPK inhibition and erythroid readouts (CD69)\",\n      \"pmids\": [\"35642057\", \"35643179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MT2A activates upstream Hippo kinases is unknown\", \"Whether metal buffering mediates these signaling effects untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved transcriptional control of MT2A, establishing an HSF1 activating input opposed by RING1-mediated HSF1 degradation, and a parallel GHET1-EZH2/LSD1 chromatin-silencing route.\",\n      \"evidence\": \"Co-IP, ChIP for HSF1 on MT2A promoter, proteasome inhibition and MT2A rescue (RING1-HSF1); RIP, pull-down, histone-mark ChIP, knockdown rescue (GHET1)\",\n      \"pmids\": [\"37797799\", \"37548351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals that toggle these activating versus silencing inputs unknown\", \"Single-lab studies in distinct cell contexts\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined MT2A's role in copper handling and cuproptosis, identifying a druggable site (Lys-31), copper-dependent mitochondrial translocation, and a tetrameric-PKM2 interaction linking metal buffering to metabolic and protective outcomes.\",\n      \"evidence\": \"HuProt microarray and SPR with site mutagenesis and Parkinson's model (artesunate/Lys-31); mitochondrial proteomics and Co-IP with PKM2; copper-overload and ischemia gain-of-function models\",\n      \"pmids\": [\"40754045\", \"41211480\", \"39915841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How copper ions trigger mitochondrial translocation mechanistically unresolved\", \"Relationship between zinc and copper buffering functions of the same protein unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single metal-buffering protein integrates its many partner-specific and pathway-specific outputs into a unified rule governing cell fate across tissues.\",\n      \"evidence\": \"No single study reconciles the zinc- versus copper-centric mechanisms or the competing partner interactions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of MT2A in complex with any partner\", \"No unified accounting of when MT2A is pro- versus anti-apoptotic\", \"Quantitative contribution of metal buffering versus direct protein interactions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0046872\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 11, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 7, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"XAF1\", \"HMBOX1\", \"EOLA1\", \"BARD1\", \"BRCA1\", \"PKM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}