{"gene":"MAT2B","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2013,"finding":"MAT2B (both V1 and V2 variants) directly interacts with GIT1, MEK1, and ERK2, forming a scaffold complex that recruits and activates MEK1/ERK to promote cell growth and tumorigenesis in liver and colon cancer. MAT2B directly promotes binding of GIT1 and ERK2 to MEK1 in pull-down assays, and overexpression of V1, V2, or GIT1 raises cyclin D1 levels and increases growth.","method":"Co-immunoprecipitation, in vitro translated and recombinant protein pull-down assays, transient knockdown/overexpression, in-solution proteomics, immunohistochemistry, orthotopic liver cancer model","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP plus in vitro reconstitution with recombinant proteins, multiple orthogonal methods, functional rescue experiments","pmids":["23325601"],"is_preprint":false},{"year":2001,"finding":"The MAT2B gene promoter is regulated by Sp3 (not Sp1) binding at an Sp1 site at +9 and a TATA element at -32. Down-regulation of MAT2B beta subunit expression causes a 6–10-fold increase in intracellular AdoMet levels, establishing MAT2B as a regulatory subunit controlling S-adenosylmethionine synthesis.","method":"Promoter deletion analysis, chromatin immunoprecipitation, supershift assays, mutation of Sp1/TATA sites, in vitro and in vivo reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, ChIP, and functional reporter assays establishing both promoter regulation and metabolic consequence","pmids":["11337507"],"is_preprint":false},{"year":2024,"finding":"MAT2B, despite lacking catalytic activity, binds and stabilizes MAT2A in an NADP+-dependent manner. Disruption of cellular NADP+ remodels MAT2A protein levels. The pentose phosphate pathway regulates MAT2A protein levels through NADP+/MAT2B interaction. MAT2B-MAT2A interaction also regulates mRNA m6A modification and stability. In liver tumors, restricted NADP+ decreases MAT2A protein despite elevated mRNA. Blocking MAT2B-MAT2A interaction (e.g., by ketogenic diet) suppresses liver tumor growth.","method":"Co-IP, protein stability assays, NADP+ manipulation, m6A sequencing, genetic disruption of MAT2B-MAT2A interaction, in vivo tumor models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, metabolic manipulation, m6A profiling, in vivo models) in a single focused study","pmids":["39353892"],"is_preprint":false},{"year":2016,"finding":"MAT2B promotes porcine intramuscular preadipocyte differentiation and adipogenesis by modulating intracellular SAMe levels and activating AKT/ERK1/2 signaling. Co-IP experiments showed MAT2B directly interacts with AKT. Overexpression of MAT2B activated phosphorylation of AKT and ERK1/2; knockdown blocked AKT signaling. MAT2B overexpression partially rescued LY294002-mediated inhibition of AKT and ERK1/2.","method":"Co-immunoprecipitation, overexpression/knockdown, flow cytometry, EdU-labeling, SAMe measurement, phosphorylation assays, PI3K inhibitor rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for direct AKT interaction plus multiple functional readouts, single lab","pmids":["26940012"],"is_preprint":false},{"year":2019,"finding":"MAT2B silencing suppresses HCC cell migration and invasion, and inhibits metastasis in xenograft zebrafish and nude mouse lung metastasis models. Silencing MAT2B reduces phosphorylation of AKT, EGFR, Src family kinases, FAK, STAT3, and ERK, placing MAT2B upstream of the EGFR signaling pathway in HCC invasion and metastasis.","method":"Stable lentiviral shRNA knockdown, phospho-kinase array, immunoblotting, zebrafish xenograft model, nude mouse lung metastasis model","journal":"Clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular and in vivo phenotype plus phospho-kinase profiling, single lab","pmids":["31493275"],"is_preprint":false},{"year":2008,"finding":"MAT2B knockdown in hepatocellular carcinoma cells increases intracellular SAMe levels, induces apoptosis, and inhibits growth by downregulating cyclin D1 and bcl-xL while upregulating bcl-xS. Normal liver cells are not affected, suggesting tumor-selective dependence.","method":"Lentivirus-mediated shRNA knockdown, MTT and [3H]thymidine proliferation assays, flow cytometry apoptosis assay, SAMe measurement, western blot","journal":"World journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — clean functional KD with multiple orthogonal readouts, metabolic and protein-level measurements, single lab","pmids":["18698677"],"is_preprint":false},{"year":2019,"finding":"MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma. Microarray and validation confirmed EGFR and PCNA as downstream targets of MAT2B, with MAT2B silencing reducing their expression.","method":"Lentivirus-mediated shRNA, microarray analysis, RT-qPCR, western blot, in vivo xenograft","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — downstream targets identified by microarray and confirmed by expression analysis only, no direct mechanistic link established, single lab","pmids":["30942439"],"is_preprint":false},{"year":2024,"finding":"JX24120, a chlorpromazine derivative, directly binds MAT2B (Kd = 4.724 μM) and inhibits SAMe synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism, and apoptosis in endometrial cancer. Gene editing confirmed tumor growth suppression is MAT2B-dependent in vivo.","method":"Drug binding affinity assay (Kd measurement), patient-derived organoid drug screening, gene editing, in vivo/in vitro functional assays, mTORC1 signaling assessment","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding measured, genetic dependency confirmed, pathway effects measured, single lab","pmids":["39293586"],"is_preprint":false},{"year":2022,"finding":"MAT2B protein directly interacts with BAG3 protein in renal cell carcinoma cells, and this interaction influences proliferation, invasion, and apoptosis downstream of the lncRNA CYTOR/miR-136-5p/MAT2B axis.","method":"Co-immunoprecipitation, dual luciferase reporter assay, RNA pulldown, functional cell assays, in vivo experiments","journal":"Toxicology and applied pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for MAT2B-BAG3 interaction, limited mechanistic follow-up on this specific interaction, single lab","pmids":["35597301"],"is_preprint":false},{"year":2025,"finding":"FMO4 facilitates the physical interaction between MAT2A and MAT2B, promoting cysteine generation from methionine, which boosts glutathione production and protects lung adenocarcinoma cells against ferroptosis. Loss of FMO4 destabilizes the MAT2A/MAT2B complex and promotes ferroptosis.","method":"Proteomic analysis, in vivo FMO4 deletion in KRAS-driven lung adenocarcinoma mice, in vitro ferroptosis induction assays, interaction/complex analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, mechanistic detail on MAT2A/MAT2B complex disruption inferred from proteomic and functional data, not yet peer-reviewed","pmids":["bio_10.1101_2025.03.31.646284"],"is_preprint":true},{"year":2024,"finding":"IGF2BP3 directly regulates the translation of MAT2B (the regulatory subunit of the methionine adenosyltransferase complex), increasing MAT2B levels, which promotes SAM production and increases m6A modifications on RNA, forming a positive feedback loop in leukemia.","method":"Translation regulation assays, metabolic flux analysis, m6A profiling, functional manipulation of IGF2BP3 in leukemia cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, mechanistic link between IGF2BP3 and MAT2B translation is asserted but abstract does not detail specific binding/pull-down evidence for direct regulation","pmids":["bio_10.1101_2024.10.31.621399"],"is_preprint":true},{"year":2018,"finding":"miR-21-3p directly targets MAT2B mRNA, suppressing its expression in brain microvascular endothelial cells. Downregulation of miR-21-3p increased MAT2B expression and alleviated blood-brain barrier damage by reducing apoptosis and NF-κB-mediated inflammation after traumatic brain injury.","method":"Luciferase reporter assay, MAT2B-silenced shRNA vector, antagomir transfection, in vivo intracerebroventricular infusion, Evans Blue extravasation assay","journal":"Journal of neurotrauma","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — luciferase reporter confirms direct miR-21-3p/MAT2B targeting, functional rescue with MAT2B silencing, in vivo validation, single lab","pmids":["29695199"],"is_preprint":false}],"current_model":"MAT2B encodes a regulatory beta subunit of methionine adenosyltransferase II that lacks intrinsic catalytic activity but stabilizes MAT2A in an NADP+-dependent manner to control S-adenosylmethionine (SAM) synthesis; MAT2B also acts as a scaffold protein that directly interacts with GIT1, MEK1, ERK2, and AKT to activate MEK/ERK and AKT/ERK signaling cascades promoting cell growth, and its expression is transcriptionally controlled by Sp3 binding at its promoter, with downstream effects on cyclin D1, Bcl-xL/S, EGFR signaling, mRNA m6A modification, and cellular metabolism."},"narrative":{"mechanistic_narrative":"MAT2B is the regulatory beta subunit of methionine adenosyltransferase II that lacks intrinsic catalytic activity but governs cellular S-adenosylmethionine (SAM/AdoMet) output and serves as a signaling scaffold to drive cell growth [PMID:11337507, PMID:23325601]. It controls SAM synthesis by binding and stabilizing the catalytic MAT2A subunit in an NADP+-dependent manner, coupling the pentose phosphate pathway to MAT2A protein levels; this MAT2B–MAT2A interaction also regulates RNA m6A modification, and disrupting it lowers MAT2A and suppresses liver tumor growth [PMID:39353892]. Consistent with its role as a metabolic brake, lowering MAT2B raises intracellular AdoMet several-fold [PMID:11337507, PMID:18698677]. Independent of catalysis, MAT2B acts as an adaptor that directly binds GIT1, MEK1, and ERK2 to assemble and activate a MEK/ERK module, and directly binds AKT to activate AKT/ERK1/2 signaling, raising cyclin D1 and promoting proliferation [PMID:23325601, PMID:26940012]. Its expression is transcriptionally driven by Sp3 acting at an Sp1 site and TATA element in its promoter [PMID:11337507]. Through these activities MAT2B supports tumor cell proliferation and survival and restrains apoptosis — knockdown downregulates cyclin D1 and Bcl-xL, upregulates Bcl-xS, and induces apoptosis selectively in hepatocellular carcinoma cells while sparing normal liver, and silencing suppresses HCC migration, invasion, and metastasis by reducing EGFR-pathway signaling [PMID:18698677, PMID:31493275]. MAT2B is itself a tractable drug target: the small molecule JX24120 directly binds MAT2B and inhibits SAMe synthesis, suppressing mTORC1 signaling and inducing apoptosis in a MAT2B-dependent manner [PMID:39293586].","teleology":[{"year":2001,"claim":"Established that MAT2B is a regulatory subunit constraining SAM synthesis and identified the transcription factor controlling its expression, defining its metabolic role.","evidence":"Promoter deletion, ChIP, supershift, site mutagenesis and reporter assays; AdoMet measurement after knockdown","pmids":["11337507"],"confidence":"High","gaps":["Did not define how the beta subunit mechanistically limits catalytic flux","No structural basis for MAT2A regulation"]},{"year":2008,"claim":"Showed MAT2B is a tumor-selective dependency, linking its loss to elevated SAMe, apoptosis, and growth arrest via cyclin D1 and Bcl-xL/S.","evidence":"shRNA knockdown in HCC cells with proliferation, apoptosis, SAMe and western readouts; normal liver cells as control","pmids":["18698677"],"confidence":"Medium","gaps":["Mechanism connecting MAT2B to cyclin D1/Bcl-x regulation not resolved","Whether effects are SAM-dependent or scaffold-dependent unclear"]},{"year":2013,"claim":"Revealed a catalysis-independent scaffold function: MAT2B directly assembles GIT1/MEK1/ERK2 to activate MEK/ERK and drive growth and tumorigenesis.","evidence":"Reciprocal Co-IP, recombinant/in vitro-translated pull-downs, overexpression/knockdown, in-solution proteomics, orthotopic liver cancer model","pmids":["23325601"],"confidence":"High","gaps":["Structural basis of the scaffold complex not defined","Relative contribution of scaffold vs metabolic role to tumorigenesis not separated"]},{"year":2016,"claim":"Extended the scaffold model to a direct AKT interaction, showing MAT2B activates AKT/ERK1/2 signaling in a developmental (adipogenic) context.","evidence":"Co-IP, overexpression/knockdown, SAMe measurement, phosphorylation assays, PI3K inhibitor rescue in porcine preadipocytes","pmids":["26940012"],"confidence":"Medium","gaps":["Direct AKT binding not confirmed by reciprocal/in vitro reconstitution","Whether AKT activation requires SAM changes unresolved"]},{"year":2019,"claim":"Placed MAT2B upstream of broad receptor-kinase signaling, showing it is required for HCC invasion and metastasis via EGFR-pathway phosphorylation.","evidence":"Stable shRNA knockdown, phospho-kinase array, zebrafish and nude mouse metastasis models","pmids":["31493275"],"confidence":"Medium","gaps":["Direct vs indirect control of EGFR/Src/FAK/STAT3 not distinguished","No biochemical link to the receptor module"]},{"year":2024,"claim":"Defined the molecular logic of MAT2B's metabolic role: NADP+-dependent binding stabilizes MAT2A, coupling the pentose phosphate pathway to SAM output and RNA m6A.","evidence":"Co-IP, protein stability assays, NADP+ manipulation, m6A-seq, genetic interaction disruption, in vivo liver tumor models including ketogenic diet","pmids":["39353892"],"confidence":"High","gaps":["Structural detail of NADP+-dependent interface not resolved","Direct enzyme(s) writing m6A downstream not mapped"]},{"year":2024,"claim":"Demonstrated MAT2B is directly druggable, with a small molecule that binds it and inhibits SAMe synthesis to suppress mTORC1 and induce apoptosis.","evidence":"Kd binding measurement, patient-derived organoid screening, gene editing, mTORC1 signaling and in vivo assays in endometrial cancer","pmids":["39293586"],"confidence":"Medium","gaps":["Binding site on MAT2B not mapped","Whether inhibition acts via metabolic or scaffold function unclear"]},{"year":null,"claim":"How MAT2B's two distinct activities — SAM-controlling MAT2A stabilization and the kinase-scaffolding function — are coordinated, and whether structural interfaces and partners (e.g. BAG3, FMO4, IGF2BP3) generalize beyond single reports, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of MAT2B in its scaffold complex","Scaffold vs metabolic contributions to phenotypes not genetically separated","Several reported partners rest on single Co-IP or preprint evidence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]}],"complexes":["methionine adenosyltransferase II (MAT2A/MAT2B)"],"partners":["MAT2A","GIT1","MEK1","ERK2","AKT","BAG3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZL9","full_name":"Methionine adenosyltransferase 2 subunit beta","aliases":["Methionine adenosyltransferase II beta","MAT II beta","Putative dTDP-4-keto-6-deoxy-D-glucose 4-reductase"],"length_aa":334,"mass_kda":37.6,"function":"Regulatory subunit of S-adenosylmethionine synthetase 2, an enzyme that catalyzes the formation of S-adenosylmethionine from methionine and ATP. Regulates MAT2A catalytic activity by changing its kinetic properties, increasing its affinity for L-methionine (PubMed:10644686, PubMed:23189196, PubMed:25075345). Can bind NADP (in vitro) (PubMed:23189196, PubMed:23425511)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NZL9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAT2B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAT2B","total_profiled":1310},"omim":[{"mim_id":"605527","title":"METHIONINE ADENOSYLTRANSFERASE II, BETA; MAT2B","url":"https://www.omim.org/entry/605527"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAT2B"},"hgnc":{"alias_symbol":["MATIIbeta","SDR23E1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NZL9","domains":[{"cath_id":"3.40.50.720","chopping":"28-189_222-254_289-310","consensus_level":"high","plddt":97.2351,"start":28,"end":310}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZL9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZL9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZL9-F1-predicted_aligned_error_v6.png","plddt_mean":94.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAT2B","jax_strain_url":"https://www.jax.org/strain/search?query=MAT2B"},"sequence":{"accession":"Q9NZL9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZL9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZL9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZL9"}},"corpus_meta":[{"pmid":"31004447","id":"PMC_31004447","title":"Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma Through the miR-338-3p/PKM2 Axis Under Hypoxic Stress.","date":"2019","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/31004447","citation_count":242,"is_preprint":false},{"pmid":"23325601","id":"PMC_23325601","title":"MAT2B-GIT1 interplay activates MEK1/ERK 1 and 2 to induce growth in human liver and colon cancer.","date":"2013","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/23325601","citation_count":72,"is_preprint":false},{"pmid":"29695199","id":"PMC_29695199","title":"Increased miR-21-3p in Injured Brain Microvascular Endothelial Cells after Traumatic Brain Injury Aggravates Blood-Brain Barrier Damage by Promoting Cellular Apoptosis and Inflammation through Targeting MAT2B.","date":"2018","source":"Journal of neurotrauma","url":"https://pubmed.ncbi.nlm.nih.gov/29695199","citation_count":63,"is_preprint":false},{"pmid":"11337507","id":"PMC_11337507","title":"Regulation of the human MAT2B gene encoding the regulatory beta subunit of methionine adenosyltransferase, MAT II.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11337507","citation_count":49,"is_preprint":false},{"pmid":"32467667","id":"PMC_32467667","title":"Circular RNA circ-MAT2B facilitates glycolysis and growth of gastric cancer through regulating the miR-515-5p/HIF-1α axis.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32467667","citation_count":43,"is_preprint":false},{"pmid":"31686458","id":"PMC_31686458","title":"Adipose-derived mesenchymal stem cells attenuate ischemic brain injuries in rats by modulating miR-21-3p/MAT2B signaling transduction.","date":"2019","source":"Croatian medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/31686458","citation_count":32,"is_preprint":false},{"pmid":"26940012","id":"PMC_26940012","title":"MAT2B promotes adipogenesis by modulating SAMe levels and activating AKT/ERK pathway during porcine intramuscular preadipocyte differentiation.","date":"2016","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26940012","citation_count":24,"is_preprint":false},{"pmid":"35597301","id":"PMC_35597301","title":"Long non-coding RNA CYTOR modulates cancer progression through miR-136-5p/MAT2B axis in renal cell carcinoma.","date":"2022","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35597301","citation_count":18,"is_preprint":false},{"pmid":"32848465","id":"PMC_32848465","title":"Circular RNA MAT2B Induces Colorectal Cancer Proliferation via Sponging miR-610, Resulting in an Increased E2F1 Expression.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32848465","citation_count":18,"is_preprint":false},{"pmid":"31493275","id":"PMC_31493275","title":"MAT2B mediates invasion and metastasis by regulating EGFR signaling pathway in hepatocellular carcinoma.","date":"2019","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31493275","citation_count":12,"is_preprint":false},{"pmid":"34288814","id":"PMC_34288814","title":"Circular RNA MAT2B promotes migration, invasion and epithelial-mesenchymal transition of non-small cell lung cancer cells by sponging miR-431.","date":"2021","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/34288814","citation_count":11,"is_preprint":false},{"pmid":"30942439","id":"PMC_30942439","title":"MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma by targeting epidermal growth factor receptor and proliferating cell nuclear antigen.","date":"2019","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30942439","citation_count":11,"is_preprint":false},{"pmid":"18698677","id":"PMC_18698677","title":"Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocelluar carcinoma.","date":"2008","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/18698677","citation_count":9,"is_preprint":false},{"pmid":"27573889","id":"PMC_27573889","title":"Lentivirus-mediated downregulation of MAT2B inhibits cell proliferation and induces apoptosis in melanoma.","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27573889","citation_count":7,"is_preprint":false},{"pmid":"39353892","id":"PMC_39353892","title":"MAT2B regulates the protein level of MAT2A to preserve RNA N6-methyladenosine.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39353892","citation_count":6,"is_preprint":false},{"pmid":"39293586","id":"PMC_39293586","title":"Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B.","date":"2024","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/39293586","citation_count":4,"is_preprint":false},{"pmid":"40499634","id":"PMC_40499634","title":"miR-142 regulates the function of microvascular endothelial cells through MAT2B.","date":"2025","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40499634","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.31.646284","title":"FMO4 drives lung adenocarcinoma by stabilizing the MAT2A/MAT2B complex and hindering ferroptosis","date":"2025-04-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.646284","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.31.621399","title":"Metabolic regulation of RNA methylation by the m6A-reader IGF2BP3","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.31.621399","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12400,"output_tokens":3174,"usd":0.042405,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10668,"output_tokens":2836,"usd":0.06212,"stage2_stop_reason":"end_turn"},"total_usd":0.104525,"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\": 2013,\n      \"finding\": \"MAT2B (both V1 and V2 variants) directly interacts with GIT1, MEK1, and ERK2, forming a scaffold complex that recruits and activates MEK1/ERK to promote cell growth and tumorigenesis in liver and colon cancer. MAT2B directly promotes binding of GIT1 and ERK2 to MEK1 in pull-down assays, and overexpression of V1, V2, or GIT1 raises cyclin D1 levels and increases growth.\",\n      \"method\": \"Co-immunoprecipitation, in vitro translated and recombinant protein pull-down assays, transient knockdown/overexpression, in-solution proteomics, immunohistochemistry, orthotopic liver cancer model\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP plus in vitro reconstitution with recombinant proteins, multiple orthogonal methods, functional rescue experiments\",\n      \"pmids\": [\"23325601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The MAT2B gene promoter is regulated by Sp3 (not Sp1) binding at an Sp1 site at +9 and a TATA element at -32. Down-regulation of MAT2B beta subunit expression causes a 6–10-fold increase in intracellular AdoMet levels, establishing MAT2B as a regulatory subunit controlling S-adenosylmethionine synthesis.\",\n      \"method\": \"Promoter deletion analysis, chromatin immunoprecipitation, supershift assays, mutation of Sp1/TATA sites, in vitro and in vivo reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, ChIP, and functional reporter assays establishing both promoter regulation and metabolic consequence\",\n      \"pmids\": [\"11337507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAT2B, despite lacking catalytic activity, binds and stabilizes MAT2A in an NADP+-dependent manner. Disruption of cellular NADP+ remodels MAT2A protein levels. The pentose phosphate pathway regulates MAT2A protein levels through NADP+/MAT2B interaction. MAT2B-MAT2A interaction also regulates mRNA m6A modification and stability. In liver tumors, restricted NADP+ decreases MAT2A protein despite elevated mRNA. Blocking MAT2B-MAT2A interaction (e.g., by ketogenic diet) suppresses liver tumor growth.\",\n      \"method\": \"Co-IP, protein stability assays, NADP+ manipulation, m6A sequencing, genetic disruption of MAT2B-MAT2A interaction, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, metabolic manipulation, m6A profiling, in vivo models) in a single focused study\",\n      \"pmids\": [\"39353892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAT2B promotes porcine intramuscular preadipocyte differentiation and adipogenesis by modulating intracellular SAMe levels and activating AKT/ERK1/2 signaling. Co-IP experiments showed MAT2B directly interacts with AKT. Overexpression of MAT2B activated phosphorylation of AKT and ERK1/2; knockdown blocked AKT signaling. MAT2B overexpression partially rescued LY294002-mediated inhibition of AKT and ERK1/2.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, flow cytometry, EdU-labeling, SAMe measurement, phosphorylation assays, PI3K inhibitor rescue\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for direct AKT interaction plus multiple functional readouts, single lab\",\n      \"pmids\": [\"26940012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAT2B silencing suppresses HCC cell migration and invasion, and inhibits metastasis in xenograft zebrafish and nude mouse lung metastasis models. Silencing MAT2B reduces phosphorylation of AKT, EGFR, Src family kinases, FAK, STAT3, and ERK, placing MAT2B upstream of the EGFR signaling pathway in HCC invasion and metastasis.\",\n      \"method\": \"Stable lentiviral shRNA knockdown, phospho-kinase array, immunoblotting, zebrafish xenograft model, nude mouse lung metastasis model\",\n      \"journal\": \"Clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular and in vivo phenotype plus phospho-kinase profiling, single lab\",\n      \"pmids\": [\"31493275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAT2B knockdown in hepatocellular carcinoma cells increases intracellular SAMe levels, induces apoptosis, and inhibits growth by downregulating cyclin D1 and bcl-xL while upregulating bcl-xS. Normal liver cells are not affected, suggesting tumor-selective dependence.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, MTT and [3H]thymidine proliferation assays, flow cytometry apoptosis assay, SAMe measurement, western blot\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — clean functional KD with multiple orthogonal readouts, metabolic and protein-level measurements, single lab\",\n      \"pmids\": [\"18698677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma. Microarray and validation confirmed EGFR and PCNA as downstream targets of MAT2B, with MAT2B silencing reducing their expression.\",\n      \"method\": \"Lentivirus-mediated shRNA, microarray analysis, RT-qPCR, western blot, in vivo xenograft\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — downstream targets identified by microarray and confirmed by expression analysis only, no direct mechanistic link established, single lab\",\n      \"pmids\": [\"30942439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JX24120, a chlorpromazine derivative, directly binds MAT2B (Kd = 4.724 μM) and inhibits SAMe synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism, and apoptosis in endometrial cancer. Gene editing confirmed tumor growth suppression is MAT2B-dependent in vivo.\",\n      \"method\": \"Drug binding affinity assay (Kd measurement), patient-derived organoid drug screening, gene editing, in vivo/in vitro functional assays, mTORC1 signaling assessment\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding measured, genetic dependency confirmed, pathway effects measured, single lab\",\n      \"pmids\": [\"39293586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAT2B protein directly interacts with BAG3 protein in renal cell carcinoma cells, and this interaction influences proliferation, invasion, and apoptosis downstream of the lncRNA CYTOR/miR-136-5p/MAT2B axis.\",\n      \"method\": \"Co-immunoprecipitation, dual luciferase reporter assay, RNA pulldown, functional cell assays, in vivo experiments\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for MAT2B-BAG3 interaction, limited mechanistic follow-up on this specific interaction, single lab\",\n      \"pmids\": [\"35597301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FMO4 facilitates the physical interaction between MAT2A and MAT2B, promoting cysteine generation from methionine, which boosts glutathione production and protects lung adenocarcinoma cells against ferroptosis. Loss of FMO4 destabilizes the MAT2A/MAT2B complex and promotes ferroptosis.\",\n      \"method\": \"Proteomic analysis, in vivo FMO4 deletion in KRAS-driven lung adenocarcinoma mice, in vitro ferroptosis induction assays, interaction/complex analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, mechanistic detail on MAT2A/MAT2B complex disruption inferred from proteomic and functional data, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.31.646284\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 directly regulates the translation of MAT2B (the regulatory subunit of the methionine adenosyltransferase complex), increasing MAT2B levels, which promotes SAM production and increases m6A modifications on RNA, forming a positive feedback loop in leukemia.\",\n      \"method\": \"Translation regulation assays, metabolic flux analysis, m6A profiling, functional manipulation of IGF2BP3 in leukemia cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, mechanistic link between IGF2BP3 and MAT2B translation is asserted but abstract does not detail specific binding/pull-down evidence for direct regulation\",\n      \"pmids\": [\"bio_10.1101_2024.10.31.621399\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-21-3p directly targets MAT2B mRNA, suppressing its expression in brain microvascular endothelial cells. Downregulation of miR-21-3p increased MAT2B expression and alleviated blood-brain barrier damage by reducing apoptosis and NF-κB-mediated inflammation after traumatic brain injury.\",\n      \"method\": \"Luciferase reporter assay, MAT2B-silenced shRNA vector, antagomir transfection, in vivo intracerebroventricular infusion, Evans Blue extravasation assay\",\n      \"journal\": \"Journal of neurotrauma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — luciferase reporter confirms direct miR-21-3p/MAT2B targeting, functional rescue with MAT2B silencing, in vivo validation, single lab\",\n      \"pmids\": [\"29695199\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAT2B encodes a regulatory beta subunit of methionine adenosyltransferase II that lacks intrinsic catalytic activity but stabilizes MAT2A in an NADP+-dependent manner to control S-adenosylmethionine (SAM) synthesis; MAT2B also acts as a scaffold protein that directly interacts with GIT1, MEK1, ERK2, and AKT to activate MEK/ERK and AKT/ERK signaling cascades promoting cell growth, and its expression is transcriptionally controlled by Sp3 binding at its promoter, with downstream effects on cyclin D1, Bcl-xL/S, EGFR signaling, mRNA m6A modification, and cellular metabolism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAT2B is the regulatory beta subunit of methionine adenosyltransferase II that lacks intrinsic catalytic activity but governs cellular S-adenosylmethionine (SAM/AdoMet) output and serves as a signaling scaffold to drive cell growth [#1, #0]. It controls SAM synthesis by binding and stabilizing the catalytic MAT2A subunit in an NADP+-dependent manner, coupling the pentose phosphate pathway to MAT2A protein levels; this MAT2B–MAT2A interaction also regulates RNA m6A modification, and disrupting it lowers MAT2A and suppresses liver tumor growth [#2]. Consistent with its role as a metabolic brake, lowering MAT2B raises intracellular AdoMet several-fold [#1, #5]. Independent of catalysis, MAT2B acts as an adaptor that directly binds GIT1, MEK1, and ERK2 to assemble and activate a MEK/ERK module, and directly binds AKT to activate AKT/ERK1/2 signaling, raising cyclin D1 and promoting proliferation [#0, #3]. Its expression is transcriptionally driven by Sp3 acting at an Sp1 site and TATA element in its promoter [#1]. Through these activities MAT2B supports tumor cell proliferation and survival and restrains apoptosis — knockdown downregulates cyclin D1 and Bcl-xL, upregulates Bcl-xS, and induces apoptosis selectively in hepatocellular carcinoma cells while sparing normal liver, and silencing suppresses HCC migration, invasion, and metastasis by reducing EGFR-pathway signaling [#5, #4]. MAT2B is itself a tractable drug target: the small molecule JX24120 directly binds MAT2B and inhibits SAMe synthesis, suppressing mTORC1 signaling and inducing apoptosis in a MAT2B-dependent manner [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that MAT2B is a regulatory subunit constraining SAM synthesis and identified the transcription factor controlling its expression, defining its metabolic role.\",\n      \"evidence\": \"Promoter deletion, ChIP, supershift, site mutagenesis and reporter assays; AdoMet measurement after knockdown\",\n      \"pmids\": [\"11337507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how the beta subunit mechanistically limits catalytic flux\", \"No structural basis for MAT2A regulation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed MAT2B is a tumor-selective dependency, linking its loss to elevated SAMe, apoptosis, and growth arrest via cyclin D1 and Bcl-xL/S.\",\n      \"evidence\": \"shRNA knockdown in HCC cells with proliferation, apoptosis, SAMe and western readouts; normal liver cells as control\",\n      \"pmids\": [\"18698677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting MAT2B to cyclin D1/Bcl-x regulation not resolved\", \"Whether effects are SAM-dependent or scaffold-dependent unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a catalysis-independent scaffold function: MAT2B directly assembles GIT1/MEK1/ERK2 to activate MEK/ERK and drive growth and tumorigenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, recombinant/in vitro-translated pull-downs, overexpression/knockdown, in-solution proteomics, orthotopic liver cancer model\",\n      \"pmids\": [\"23325601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the scaffold complex not defined\", \"Relative contribution of scaffold vs metabolic role to tumorigenesis not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the scaffold model to a direct AKT interaction, showing MAT2B activates AKT/ERK1/2 signaling in a developmental (adipogenic) context.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, SAMe measurement, phosphorylation assays, PI3K inhibitor rescue in porcine preadipocytes\",\n      \"pmids\": [\"26940012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AKT binding not confirmed by reciprocal/in vitro reconstitution\", \"Whether AKT activation requires SAM changes unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed MAT2B upstream of broad receptor-kinase signaling, showing it is required for HCC invasion and metastasis via EGFR-pathway phosphorylation.\",\n      \"evidence\": \"Stable shRNA knockdown, phospho-kinase array, zebrafish and nude mouse metastasis models\",\n      \"pmids\": [\"31493275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of EGFR/Src/FAK/STAT3 not distinguished\", \"No biochemical link to the receptor module\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the molecular logic of MAT2B's metabolic role: NADP+-dependent binding stabilizes MAT2A, coupling the pentose phosphate pathway to SAM output and RNA m6A.\",\n      \"evidence\": \"Co-IP, protein stability assays, NADP+ manipulation, m6A-seq, genetic interaction disruption, in vivo liver tumor models including ketogenic diet\",\n      \"pmids\": [\"39353892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of NADP+-dependent interface not resolved\", \"Direct enzyme(s) writing m6A downstream not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated MAT2B is directly druggable, with a small molecule that binds it and inhibits SAMe synthesis to suppress mTORC1 and induce apoptosis.\",\n      \"evidence\": \"Kd binding measurement, patient-derived organoid screening, gene editing, mTORC1 signaling and in vivo assays in endometrial cancer\",\n      \"pmids\": [\"39293586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on MAT2B not mapped\", \"Whether inhibition acts via metabolic or scaffold function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAT2B's two distinct activities — SAM-controlling MAT2A stabilization and the kinase-scaffolding function — are coordinated, and whether structural interfaces and partners (e.g. BAG3, FMO4, IGF2BP3) generalize beyond single reports, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of MAT2B in its scaffold complex\", \"Scaffold vs metabolic contributions to phenotypes not genetically separated\", \"Several reported partners rest on single Co-IP or preprint evidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"methionine adenosyltransferase II (MAT2A/MAT2B)\"],\n    \"partners\": [\"MAT2A\", \"GIT1\", \"MEK1\", \"ERK2\", \"AKT\", \"BAG3\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}