{"gene":"MTMR3","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2001,"finding":"MTMR3 is an inositol lipid 3-phosphatase that hydrolyzes both PtdIns3P and PtdIns(3,5)P2 in vitro and in S. cerevisiae, and provides the first defined cellular route for production of PtdIns5P. Overexpression of catalytically dead MTMR3 (C413S) in mammalian cells induces striking vacuolar compartments enriched in mutant protein.","method":"In vitro phosphatase assay, heterologous expression in S. cerevisiae, active-site mutagenesis (C413S), overexpression in mammalian cells","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with defined substrates, active-site mutagenesis, and in vivo yeast validation in a single rigorous study","pmids":["11676921"],"is_preprint":false},{"year":2000,"finding":"FYVE-DSP1 (MTMR3) is a dual-specificity phosphatase containing a C-terminal FYVE domain; recombinant protein partitions in both cytosolic and membrane fractions, dephosphorylates proteins phosphorylated on Ser, Thr, and Tyr residues, and is inactivated by mutation of the catalytic cysteinyl residue. Three isoforms from alternate RNA splicing are expressed.","method":"Molecular cloning, subcellular fractionation, in vitro phosphatase assay with phosphoprotein and pNPP substrates, active-site mutagenesis, inhibitor characterization (sodium vanadate/pervanadate), RT-PCR tissue distribution","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic characterization and mutagenesis in a single study; recombinant-protein fractionation shows membrane association but functional link not deeply resolved","pmids":["10733931"],"is_preprint":false},{"year":2005,"finding":"The FYVE domain of MTMR3 is atypical: it neither confers endosomal localization nor binds PtdIns3P, and is not required for in vitro phosphatase activity. In contrast, the N-terminal PH-GRAM domain binds phosphoinositides with preference for PtdIns5P as an allosteric regulator, is required for in vitro activity, and mediates plasma-membrane translocation in response to ectopically produced PtdIns5P. Combined PH-GRAM deletion with an active-site mutation localizes MTMR3 to the Golgi complex.","method":"Lipid-binding assays, in vitro phosphatase assay with deletion/point mutants, ectopic expression of bacterial phosphatase IpgD, live-cell fluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assays with domain deletion/mutagenesis and direct localization experiments in a single study with multiple orthogonal methods","pmids":["15840652"],"is_preprint":false},{"year":2010,"finding":"MTMR3 negatively regulates autophagosome formation and size by locally depleting PtdIns3P at autophagosome formation sites. Overexpression of phosphatase-dead MTMR3 partially localizes to autophagosomes and causes accumulation of PtdIns3P and PtdIns3P-binding proteins DFCP1 and WIPI-1α there. Knockdown of MTMR3 increases autophagosome formation; wild-type MTMR3 overexpression reduces autophagosome size and overall autophagic activity.","method":"Dominant-negative overexpression, siRNA knockdown, fluorescence microscopy (GFP-DFCP1, GFP-WIPI-1α reporters), autophagosome quantification","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain-of-function and loss-of-function with defined molecular readouts (PtdIns3P reporters, autophagosome markers) replicated across conditions","pmids":["20059746"],"is_preprint":false},{"year":2012,"finding":"MTMR3, together with the lipid kinase PIKfyve, constitutes a phosphoinositide loop that produces PtdIns5P via PtdIns(3,5)P2, and this PtdIns5P production promotes cell migration. Class III PI3K activity was upstream, and depletion of MTMR3 (or PIKfyve) decreased fibroblast migration; exogenous PtdIns5P or a PtdIns5P-producing bacterial enzyme directly stimulated migration.","method":"siRNA knockdown, cell migration screen, exogenous lipid supplementation, bacterial enzyme expression, Drosophila in vivo migration model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (knockdown, exogenous lipid, bacterial enzyme, in vivo model) consistently demonstrate pathway placement","pmids":["23154468"],"is_preprint":false},{"year":2014,"finding":"PIKfyve and MTMR3 regulate cancer cell migration and invasion through activation of the Rho-family GTPase Rac1. Depletion of MTMR3 or inhibition of PIKfyve enzymatic activity reduces cell velocity in multiple cancer cell lines, and PtdIns5P is implicated in Rac1 activation downstream of these enzymes.","method":"siRNA knockdown, enzymatic inhibitor (YM201636), cell tracking software, Rac1 activation assay, invasion assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown and pharmacological inhibition with Rac1 activation readout; single lab, two orthogonal perturbation methods","pmids":["24840251"],"is_preprint":false},{"year":2015,"finding":"MTMR3 decreases PRR-induced PtdIns3P and autophagy levels in human macrophages, thereby increasing caspase-1 activation, autocrine IL-1β secretion, and NF-κB signaling. This regulation requires the N-terminal PH-GRAM domain and the catalytic Cys413 residue. In MTMR3-deficient macrophages, reducing enhanced autophagy or restoring NF-κB signaling rescues PRR-induced cytokines.","method":"siRNA knockdown, domain-deletion and point mutants (Cys413), PtdIns3P measurement, autophagy assays, caspase-1 activation assay, NF-κB signaling assays, cytokine secretion measurements, epistasis with autophagy inhibitors","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (domain mutants, KD, chemical epistasis) with defined molecular pathway in a single rigorous study","pmids":["26240347"],"is_preprint":false},{"year":2015,"finding":"MTMR3 physically interacts with mTORC1 and suppresses its kinase activity. The N-terminal half of MTMR3 (containing PH-G and phosphatase domains) is necessary and sufficient for mTORC1 binding and suppression. Phosphatase-deficient MTMR3 provides more robust mTORC1 suppression than wild-type and, together with the phosphatase domain alone, localizes to the Golgi.","method":"Co-immunoprecipitation, overexpression of wild-type and phosphatase-dead MTMR3 constructs, domain-deletion analysis, mTORC1 activity assays (S6K phosphorylation), fluorescence microscopy","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and functional mTORC1 activity readout; single lab","pmids":["26787466"],"is_preprint":false},{"year":2019,"finding":"MTMR3 and MTMR4 together regulate STING trafficking and innate immune responses to cytoplasmic DNA. Double knockout (DKO) of MTMR3/MTMR4 in macrophages enhanced type I interferon production and IRF3 phosphorylation after ISD stimulation and HSV-1 infection, caused rapid STING translocation from ER to Golgi, and led to STING accumulation in enlarged PtdIns3P-positive cytosolic puncta, consistent with MTMR3/4 dephosphorylating PtdIns3P to control these compartments.","method":"CRISPR/Cas9 double knockout, ISD stimulation and HSV-1 infection, type I IFN and IRF3 phosphorylation measurement, fluorescence microscopy for STING/PtdIns3P colocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean DKO with mechanistically defined readouts (PtdIns3P, STING trafficking, IRF3); single lab but multiple readouts","pmids":["30944173"],"is_preprint":false},{"year":2023,"finding":"MTMR3 enhances Toll-like receptor 9-induced IgA production in a manner dependent on its phosphatidylinositol 3-phosphate binding domain. Mtmr3-knockout mice show defective TLR9-induced IgA production, reduced glomerular IgA deposition, and reduced mesangial cell proliferation; RNA-seq revealed an impaired intestinal immune network for IgA production in KO animals.","method":"Mtmr3 knockout mice, TLR9 stimulation, serum IgA measurement, glomerular IgA deposition histology, domain-binding mutant in vitro studies, RNA-seq pathway analysis","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with mechanistic domain requirement validated in vitro; single lab","pmids":["37414396"],"is_preprint":false}],"current_model":"MTMR3 is a PtdIns3P/PtdIns(3,5)P2 3-phosphatase whose catalytic activity (requiring Cys413 in the phosphatase domain) and PH-GRAM domain-mediated PtdIns5P sensing together control local phosphoinositide pools to regulate autophagosome formation and size, mTORC1 activity, STING trafficking and innate immune signaling, TLR9-induced IgA production, and cell migration/invasion—the last function achieved through a PIKfyve–MTMR3 enzymatic loop that generates PtdIns5P to activate Rac1."},"narrative":{"mechanistic_narrative":"MTMR3 is a myotubularin-related inositol lipid 3-phosphatase that hydrolyzes PtdIns3P and PtdIns(3,5)P2, controlling local phosphoinositide pools to regulate membrane trafficking, autophagy, and innate immune signaling [PMID:11676921]. Its catalytic activity depends on an active-site cysteine (Cys413), and overexpression of the catalytically dead C413S mutant produces enlarged vacuolar compartments enriched in the mutant protein [PMID:11676921]. Substrate access and localization are governed by an N-terminal PH-GRAM domain that binds phosphoinositides with a preference for PtdIns5P as an allosteric activator, is required for catalytic activity, and drives plasma-membrane translocation in response to PtdIns5P; in contrast its FYVE domain is atypical, neither binding PtdIns3P nor conferring endosomal localization, and combined PH-GRAM loss with active-site mutation redirects the protein to the Golgi [PMID:15840652]. Through local PtdIns3P depletion at autophagosome formation sites, MTMR3 negatively regulates autophagosome formation and size, opposing the PtdIns3P-binding effectors DFCP1 and WIPI-1α [PMID:20059746]. Acting in a PIKfyve–MTMR3 enzymatic loop downstream of class III PI3K, it generates PtdIns5P to promote cell migration and invasion via activation of the Rho-family GTPase Rac1 [PMID:23154468, PMID:24840251]. In innate immunity it restrains PRR-induced autophagy and PtdIns3P in macrophages to tune caspase-1, IL-1β, and NF-κB signaling [PMID:26240347], cooperates with MTMR4 to control STING trafficking from ER to Golgi and limit type I interferon responses to cytoplasmic DNA [PMID:30944173], and supports TLR9-induced IgA production in vivo [PMID:37414396]. It additionally binds and suppresses mTORC1 through its N-terminal half [PMID:26787466].","teleology":[{"year":2000,"claim":"Established MTMR3 (FYVE-DSP1) as a dual-specificity phosphatase bearing a C-terminal FYVE domain, defining the catalytic activity and a candidate membrane-targeting module.","evidence":"Molecular cloning, subcellular fractionation, in vitro phosphatase assays on phosphoproteins and pNPP, active-site mutagenesis","pmids":["10733931"],"confidence":"Medium","gaps":["Physiological lipid substrate not yet defined","Membrane-association mechanism not resolved","FYVE domain function not tested"]},{"year":2001,"claim":"Identified the physiological substrates as PtdIns3P and PtdIns(3,5)P2 and positioned MTMR3 as the first defined cellular route to PtdIns5P, with Cys413 as the catalytic residue.","evidence":"In vitro phosphatase assay with defined lipid substrates, yeast heterologous expression, C413S mutagenesis, mammalian overexpression","pmids":["11676921"],"confidence":"High","gaps":["Cellular pathway controlled by the lipid product unknown","Spatial regulation of activity undefined"]},{"year":2005,"claim":"Resolved domain logic: the PH-GRAM domain, not the atypical FYVE domain, senses PtdIns5P, is required for activity, and controls membrane targeting.","evidence":"Lipid-binding assays, deletion/point-mutant phosphatase assays, IpgD ectopic expression, live-cell microscopy","pmids":["15840652"],"confidence":"High","gaps":["Endogenous trigger of PH-GRAM-driven translocation in vivo unclear","Significance of Golgi pool not defined"]},{"year":2010,"claim":"Placed MTMR3 as a negative regulator of autophagosome formation and size by locally depleting PtdIns3P at formation sites.","evidence":"Reciprocal overexpression/knockdown with GFP-DFCP1 and GFP-WIPI-1α PtdIns3P reporters and autophagosome quantification","pmids":["20059746"],"confidence":"High","gaps":["Recruitment mechanism to formation sites unknown","Relationship to other myotubularins at autophagosomes unresolved"]},{"year":2012,"claim":"Defined a PIKfyve–MTMR3 loop that converts PtdIns(3,5)P2 to PtdIns5P downstream of class III PI3K to drive cell migration.","evidence":"siRNA migration screen, exogenous PtdIns5P and bacterial enzyme supplementation, Drosophila in vivo migration model","pmids":["23154468"],"confidence":"High","gaps":["Direct PtdIns5P effector in migration not identified at this stage","Spatial organization of the loop unclear"]},{"year":2014,"claim":"Connected the PIKfyve–MTMR3 loop to Rac1 activation as the effector arm driving cancer cell migration and invasion.","evidence":"siRNA knockdown, PIKfyve inhibitor (YM201636), cell tracking, Rac1 activation and invasion assays in cancer lines","pmids":["24840251"],"confidence":"Medium","gaps":["Mechanism linking PtdIns5P to Rac1 GEF/GAP activity not defined","Single-lab finding with two perturbation modalities"]},{"year":2015,"claim":"Showed MTMR3 restrains PRR-induced autophagy and PtdIns3P in macrophages, thereby promoting caspase-1/IL-1β and NF-κB output, dependent on PH-GRAM and Cys413.","evidence":"siRNA knockdown, PH-GRAM/Cys413 mutants, PtdIns3P and autophagy assays, caspase-1, NF-κB, cytokine readouts, chemical epistasis","pmids":["26240347"],"confidence":"High","gaps":["In vivo immune phenotype not tested here","PRR receptor specificity not fully mapped"]},{"year":2015,"claim":"Identified a physical interaction with mTORC1 and suppression of its kinase activity by the N-terminal half of MTMR3.","evidence":"Co-immunoprecipitation, domain-deletion constructs, wild-type vs phosphatase-dead MTMR3, S6K phosphorylation readout, microscopy","pmids":["26787466"],"confidence":"Medium","gaps":["Reciprocal/endogenous interaction not shown","Mechanism of mTORC1 suppression (lipid-dependent vs scaffolding) unresolved","Single lab"]},{"year":2019,"claim":"Demonstrated that MTMR3 and MTMR4 jointly control STING trafficking and dampen cytosolic-DNA-induced type I interferon by regulating PtdIns3P-positive compartments.","evidence":"CRISPR/Cas9 MTMR3/4 double knockout macrophages, ISD/HSV-1 stimulation, IFN/IRF3 readouts, STING/PtdIns3P colocalization microscopy","pmids":["30944173"],"confidence":"Medium","gaps":["Individual contribution of MTMR3 vs MTMR4 not separated","Direct dephosphorylation event inferred, not biochemically isolated"]},{"year":2023,"claim":"Established an in vivo role for MTMR3 in TLR9-induced IgA production dependent on its PtdIns3P-binding domain, with relevance to glomerular IgA deposition.","evidence":"Mtmr3-knockout mice, TLR9 stimulation, serum/glomerular IgA assays, domain-binding mutant in vitro, RNA-seq","pmids":["37414396"],"confidence":"Medium","gaps":["Cell-type responsible for the IgA phenotype not pinpointed","Direct lipid substrate event in this pathway not demonstrated","Human disease causality not established"]},{"year":null,"claim":"How MTMR3's distinct molecular roles—PtdIns3P depletion, PtdIns5P generation, and mTORC1 binding—are spatially and temporally partitioned among autophagy, migration, and immune compartments remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate selection vs allosteric PtdIns5P sensing","Mechanism coupling PtdIns5P to Rac1 unresolved","Determinants of compartment-specific recruitment unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,7]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,7]}],"complexes":[],"partners":["PIKFYVE","MTMR4","MTOR","STING1","RAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13615","full_name":"Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR3","aliases":["FYVE domain-containing dual specificity protein phosphatase 1","FYVE-DSP1","Myotubularin-related protein 3","Phosphatidylinositol-3,5-bisphosphate 3-phosphatase","Phosphatidylinositol-3-phosphate phosphatase","Zinc finger FYVE domain-containing protein 10"],"length_aa":1198,"mass_kda":133.6,"function":"Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate (PubMed:10733931, PubMed:11302699, PubMed:11676921, PubMed:12646134). Decreases the levels of phosphatidylinositol 3-phosphate, a phospholipid found in cell membranes where it acts as key regulator of both cell signaling and intracellular membrane traffic (PubMed:11302699, PubMed:11676921, PubMed:12646134). Could also have a molecular sequestering/adapter activity and regulate biological processes independently of its phosphatase activity. It includes the regulation of midbody abscission during mitotic cytokinesis (PubMed:25659891)","subcellular_location":"Cytoplasm, cytosol; Membrane","url":"https://www.uniprot.org/uniprotkb/Q13615/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTMR3","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTMR3","total_profiled":1310},"omim":[{"mim_id":"603559","title":"MYOTUBULARIN-RELATED PROTEIN 4; MTMR4","url":"https://www.omim.org/entry/603559"},{"mim_id":"603558","title":"MYOTUBULARIN-RELATED PROTEIN 3; MTMR3","url":"https://www.omim.org/entry/603558"},{"mim_id":"300415","title":"MYOTUBULARIN; MTM1","url":"https://www.omim.org/entry/300415"},{"mim_id":"300171","title":"MYOTUBULARIN-RELATED PROTEIN 1; MTMR1","url":"https://www.omim.org/entry/300171"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":77.1}],"url":"https://www.proteinatlas.org/search/MTMR3"},"hgnc":{"alias_symbol":["KIAA0371","ZFYVE10","FYVE-DSP1"],"prev_symbol":[]},"alphafold":{"accession":"Q13615","domains":[{"cath_id":"2.30.29.30","chopping":"15-120","consensus_level":"high","plddt":92.1108,"start":15,"end":120},{"cath_id":"3.90.190.10","chopping":"156-269_310-577","consensus_level":"high","plddt":94.722,"start":156,"end":577},{"cath_id":"3.30.40.10","chopping":"1120-1179","consensus_level":"high","plddt":89.8178,"start":1120,"end":1179}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13615","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13615-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13615-F1-predicted_aligned_error_v6.png","plddt_mean":65.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTMR3","jax_strain_url":"https://www.jax.org/strain/search?query=MTMR3"},"sequence":{"accession":"Q13615","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13615.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13615/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13615"}},"corpus_meta":[{"pmid":"20059746","id":"PMC_20059746","title":"Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy.","date":"2010","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/20059746","citation_count":163,"is_preprint":false},{"pmid":"11676921","id":"PMC_11676921","title":"Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity.","date":"2001","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/11676921","citation_count":140,"is_preprint":false},{"pmid":"32531321","id":"PMC_32531321","title":"Exosomal miR-1910-3p promotes proliferation, metastasis, and autophagy of breast cancer cells by targeting MTMR3 and activating the NF-κB signaling pathway.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/32531321","citation_count":135,"is_preprint":false},{"pmid":"33198772","id":"PMC_33198772","title":"Circular RNA MCTP2 inhibits cisplatin resistance in gastric cancer by miR-99a-5p-mediated induction of MTMR3 expression.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33198772","citation_count":85,"is_preprint":false},{"pmid":"23154468","id":"PMC_23154468","title":"Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration.","date":"2012","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/23154468","citation_count":63,"is_preprint":false},{"pmid":"15840652","id":"PMC_15840652","title":"Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3.","date":"2005","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15840652","citation_count":63,"is_preprint":false},{"pmid":"26240347","id":"PMC_26240347","title":"MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26240347","citation_count":44,"is_preprint":false},{"pmid":"24840251","id":"PMC_24840251","title":"PIKfyve, MTMR3 and their product PtdIns5P regulate cancer cell migration and invasion through activation of Rac1.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24840251","citation_count":40,"is_preprint":false},{"pmid":"24943867","id":"PMC_24943867","title":"Brief Report: identification of MTMR3 as a novel susceptibility gene for lupus nephritis in northern Han Chinese by shared-gene analysis with IgA nephropathy.","date":"2014","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/24943867","citation_count":40,"is_preprint":false},{"pmid":"28447759","id":"PMC_28447759","title":"miR-181a modulates proliferation, migration and autophagy in AGS gastric cancer cells and downregulates MTMR3.","date":"2017","source":"Molecular medicine 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international","url":"https://pubmed.ncbi.nlm.nih.gov/37414396","citation_count":17,"is_preprint":false},{"pmid":"31485632","id":"PMC_31485632","title":"MTMR3 is upregulated in patients with breast cancer and regulates proliferation, cell cycle progression and autophagy in breast cancer cells.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31485632","citation_count":17,"is_preprint":false},{"pmid":"36045954","id":"PMC_36045954","title":"miR-100-5p Promotes Epidermal Stem Cell Proliferation through Targeting MTMR3 to Activate PIP3/AKT and ERK Signaling Pathways.","date":"2022","source":"Stem cells international","url":"https://pubmed.ncbi.nlm.nih.gov/36045954","citation_count":16,"is_preprint":false},{"pmid":"37014739","id":"PMC_37014739","title":"miR-100-5p is upregulated in multiple myeloma and involves in the pathogenesis of multiple myeloma through targeting MTMR3.","date":"2023","source":"Hematology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/37014739","citation_count":12,"is_preprint":false},{"pmid":"31780315","id":"PMC_31780315","title":"Three SNPs of FCRL3 and one SNP of MTMR3 are associated with immunoglobulin A nephropathy risk.","date":"2019","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31780315","citation_count":5,"is_preprint":false},{"pmid":"37910386","id":"PMC_37910386","title":"Breast cancer risk is associated with the HULC rs7763881, MTMR3 rs12537 polymorphisms, and serum levels of HULC and MTMR3 in Egyptian patients.","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37910386","citation_count":3,"is_preprint":false},{"pmid":"40433045","id":"PMC_40433045","title":"Association of MTMR3 rs12537 at miR-181a Binding Site with Ischemic Stroke in Southern Chinese Han Population.","date":"2025","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40433045","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13637,"output_tokens":3055,"usd":0.043368,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10330,"output_tokens":3792,"usd":0.073225,"stage2_stop_reason":"end_turn"},"total_usd":0.116593,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MTMR3 is an inositol lipid 3-phosphatase that hydrolyzes both PtdIns3P and PtdIns(3,5)P2 in vitro and in S. cerevisiae, and provides the first defined cellular route for production of PtdIns5P. Overexpression of catalytically dead MTMR3 (C413S) in mammalian cells induces striking vacuolar compartments enriched in mutant protein.\",\n      \"method\": \"In vitro phosphatase assay, heterologous expression in S. cerevisiae, active-site mutagenesis (C413S), overexpression in mammalian cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with defined substrates, active-site mutagenesis, and in vivo yeast validation in a single rigorous study\",\n      \"pmids\": [\"11676921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FYVE-DSP1 (MTMR3) is a dual-specificity phosphatase containing a C-terminal FYVE domain; recombinant protein partitions in both cytosolic and membrane fractions, dephosphorylates proteins phosphorylated on Ser, Thr, and Tyr residues, and is inactivated by mutation of the catalytic cysteinyl residue. Three isoforms from alternate RNA splicing are expressed.\",\n      \"method\": \"Molecular cloning, subcellular fractionation, in vitro phosphatase assay with phosphoprotein and pNPP substrates, active-site mutagenesis, inhibitor characterization (sodium vanadate/pervanadate), RT-PCR tissue distribution\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic characterization and mutagenesis in a single study; recombinant-protein fractionation shows membrane association but functional link not deeply resolved\",\n      \"pmids\": [\"10733931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The FYVE domain of MTMR3 is atypical: it neither confers endosomal localization nor binds PtdIns3P, and is not required for in vitro phosphatase activity. In contrast, the N-terminal PH-GRAM domain binds phosphoinositides with preference for PtdIns5P as an allosteric regulator, is required for in vitro activity, and mediates plasma-membrane translocation in response to ectopically produced PtdIns5P. Combined PH-GRAM deletion with an active-site mutation localizes MTMR3 to the Golgi complex.\",\n      \"method\": \"Lipid-binding assays, in vitro phosphatase assay with deletion/point mutants, ectopic expression of bacterial phosphatase IpgD, live-cell fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assays with domain deletion/mutagenesis and direct localization experiments in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"15840652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MTMR3 negatively regulates autophagosome formation and size by locally depleting PtdIns3P at autophagosome formation sites. Overexpression of phosphatase-dead MTMR3 partially localizes to autophagosomes and causes accumulation of PtdIns3P and PtdIns3P-binding proteins DFCP1 and WIPI-1α there. Knockdown of MTMR3 increases autophagosome formation; wild-type MTMR3 overexpression reduces autophagosome size and overall autophagic activity.\",\n      \"method\": \"Dominant-negative overexpression, siRNA knockdown, fluorescence microscopy (GFP-DFCP1, GFP-WIPI-1α reporters), autophagosome quantification\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain-of-function and loss-of-function with defined molecular readouts (PtdIns3P reporters, autophagosome markers) replicated across conditions\",\n      \"pmids\": [\"20059746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MTMR3, together with the lipid kinase PIKfyve, constitutes a phosphoinositide loop that produces PtdIns5P via PtdIns(3,5)P2, and this PtdIns5P production promotes cell migration. Class III PI3K activity was upstream, and depletion of MTMR3 (or PIKfyve) decreased fibroblast migration; exogenous PtdIns5P or a PtdIns5P-producing bacterial enzyme directly stimulated migration.\",\n      \"method\": \"siRNA knockdown, cell migration screen, exogenous lipid supplementation, bacterial enzyme expression, Drosophila in vivo migration model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (knockdown, exogenous lipid, bacterial enzyme, in vivo model) consistently demonstrate pathway placement\",\n      \"pmids\": [\"23154468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIKfyve and MTMR3 regulate cancer cell migration and invasion through activation of the Rho-family GTPase Rac1. Depletion of MTMR3 or inhibition of PIKfyve enzymatic activity reduces cell velocity in multiple cancer cell lines, and PtdIns5P is implicated in Rac1 activation downstream of these enzymes.\",\n      \"method\": \"siRNA knockdown, enzymatic inhibitor (YM201636), cell tracking software, Rac1 activation assay, invasion assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown and pharmacological inhibition with Rac1 activation readout; single lab, two orthogonal perturbation methods\",\n      \"pmids\": [\"24840251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MTMR3 decreases PRR-induced PtdIns3P and autophagy levels in human macrophages, thereby increasing caspase-1 activation, autocrine IL-1β secretion, and NF-κB signaling. This regulation requires the N-terminal PH-GRAM domain and the catalytic Cys413 residue. In MTMR3-deficient macrophages, reducing enhanced autophagy or restoring NF-κB signaling rescues PRR-induced cytokines.\",\n      \"method\": \"siRNA knockdown, domain-deletion and point mutants (Cys413), PtdIns3P measurement, autophagy assays, caspase-1 activation assay, NF-κB signaling assays, cytokine secretion measurements, epistasis with autophagy inhibitors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (domain mutants, KD, chemical epistasis) with defined molecular pathway in a single rigorous study\",\n      \"pmids\": [\"26240347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MTMR3 physically interacts with mTORC1 and suppresses its kinase activity. The N-terminal half of MTMR3 (containing PH-G and phosphatase domains) is necessary and sufficient for mTORC1 binding and suppression. Phosphatase-deficient MTMR3 provides more robust mTORC1 suppression than wild-type and, together with the phosphatase domain alone, localizes to the Golgi.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of wild-type and phosphatase-dead MTMR3 constructs, domain-deletion analysis, mTORC1 activity assays (S6K phosphorylation), fluorescence microscopy\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and functional mTORC1 activity readout; single lab\",\n      \"pmids\": [\"26787466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTMR3 and MTMR4 together regulate STING trafficking and innate immune responses to cytoplasmic DNA. Double knockout (DKO) of MTMR3/MTMR4 in macrophages enhanced type I interferon production and IRF3 phosphorylation after ISD stimulation and HSV-1 infection, caused rapid STING translocation from ER to Golgi, and led to STING accumulation in enlarged PtdIns3P-positive cytosolic puncta, consistent with MTMR3/4 dephosphorylating PtdIns3P to control these compartments.\",\n      \"method\": \"CRISPR/Cas9 double knockout, ISD stimulation and HSV-1 infection, type I IFN and IRF3 phosphorylation measurement, fluorescence microscopy for STING/PtdIns3P colocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean DKO with mechanistically defined readouts (PtdIns3P, STING trafficking, IRF3); single lab but multiple readouts\",\n      \"pmids\": [\"30944173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MTMR3 enhances Toll-like receptor 9-induced IgA production in a manner dependent on its phosphatidylinositol 3-phosphate binding domain. Mtmr3-knockout mice show defective TLR9-induced IgA production, reduced glomerular IgA deposition, and reduced mesangial cell proliferation; RNA-seq revealed an impaired intestinal immune network for IgA production in KO animals.\",\n      \"method\": \"Mtmr3 knockout mice, TLR9 stimulation, serum IgA measurement, glomerular IgA deposition histology, domain-binding mutant in vitro studies, RNA-seq pathway analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with mechanistic domain requirement validated in vitro; single lab\",\n      \"pmids\": [\"37414396\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTMR3 is a PtdIns3P/PtdIns(3,5)P2 3-phosphatase whose catalytic activity (requiring Cys413 in the phosphatase domain) and PH-GRAM domain-mediated PtdIns5P sensing together control local phosphoinositide pools to regulate autophagosome formation and size, mTORC1 activity, STING trafficking and innate immune signaling, TLR9-induced IgA production, and cell migration/invasion—the last function achieved through a PIKfyve–MTMR3 enzymatic loop that generates PtdIns5P to activate Rac1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTMR3 is a myotubularin-related inositol lipid 3-phosphatase that hydrolyzes PtdIns3P and PtdIns(3,5)P2, controlling local phosphoinositide pools to regulate membrane trafficking, autophagy, and innate immune signaling [#0]. Its catalytic activity depends on an active-site cysteine (Cys413), and overexpression of the catalytically dead C413S mutant produces enlarged vacuolar compartments enriched in the mutant protein [#0]. Substrate access and localization are governed by an N-terminal PH-GRAM domain that binds phosphoinositides with a preference for PtdIns5P as an allosteric activator, is required for catalytic activity, and drives plasma-membrane translocation in response to PtdIns5P; in contrast its FYVE domain is atypical, neither binding PtdIns3P nor conferring endosomal localization, and combined PH-GRAM loss with active-site mutation redirects the protein to the Golgi [#2]. Through local PtdIns3P depletion at autophagosome formation sites, MTMR3 negatively regulates autophagosome formation and size, opposing the PtdIns3P-binding effectors DFCP1 and WIPI-1\\u03b1 [#3]. Acting in a PIKfyve\\u2013MTMR3 enzymatic loop downstream of class III PI3K, it generates PtdIns5P to promote cell migration and invasion via activation of the Rho-family GTPase Rac1 [#4, #5]. In innate immunity it restrains PRR-induced autophagy and PtdIns3P in macrophages to tune caspase-1, IL-1\\u03b2, and NF-\\u03baB signaling [#6], cooperates with MTMR4 to control STING trafficking from ER to Golgi and limit type I interferon responses to cytoplasmic DNA [#8], and supports TLR9-induced IgA production in vivo [#9]. It additionally binds and suppresses mTORC1 through its N-terminal half [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established MTMR3 (FYVE-DSP1) as a dual-specificity phosphatase bearing a C-terminal FYVE domain, defining the catalytic activity and a candidate membrane-targeting module.\",\n      \"evidence\": \"Molecular cloning, subcellular fractionation, in vitro phosphatase assays on phosphoproteins and pNPP, active-site mutagenesis\",\n      \"pmids\": [\"10733931\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physiological lipid substrate not yet defined\", \"Membrane-association mechanism not resolved\", \"FYVE domain function not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the physiological substrates as PtdIns3P and PtdIns(3,5)P2 and positioned MTMR3 as the first defined cellular route to PtdIns5P, with Cys413 as the catalytic residue.\",\n      \"evidence\": \"In vitro phosphatase assay with defined lipid substrates, yeast heterologous expression, C413S mutagenesis, mammalian overexpression\",\n      \"pmids\": [\"11676921\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cellular pathway controlled by the lipid product unknown\", \"Spatial regulation of activity undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved domain logic: the PH-GRAM domain, not the atypical FYVE domain, senses PtdIns5P, is required for activity, and controls membrane targeting.\",\n      \"evidence\": \"Lipid-binding assays, deletion/point-mutant phosphatase assays, IpgD ectopic expression, live-cell microscopy\",\n      \"pmids\": [\"15840652\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Endogenous trigger of PH-GRAM-driven translocation in vivo unclear\", \"Significance of Golgi pool not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed MTMR3 as a negative regulator of autophagosome formation and size by locally depleting PtdIns3P at formation sites.\",\n      \"evidence\": \"Reciprocal overexpression/knockdown with GFP-DFCP1 and GFP-WIPI-1\\u03b1 PtdIns3P reporters and autophagosome quantification\",\n      \"pmids\": [\"20059746\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Recruitment mechanism to formation sites unknown\", \"Relationship to other myotubularins at autophagosomes unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a PIKfyve\\u2013MTMR3 loop that converts PtdIns(3,5)P2 to PtdIns5P downstream of class III PI3K to drive cell migration.\",\n      \"evidence\": \"siRNA migration screen, exogenous PtdIns5P and bacterial enzyme supplementation, Drosophila in vivo migration model\",\n      \"pmids\": [\"23154468\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct PtdIns5P effector in migration not identified at this stage\", \"Spatial organization of the loop unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected the PIKfyve\\u2013MTMR3 loop to Rac1 activation as the effector arm driving cancer cell migration and invasion.\",\n      \"evidence\": \"siRNA knockdown, PIKfyve inhibitor (YM201636), cell tracking, Rac1 activation and invasion assays in cancer lines\",\n      \"pmids\": [\"24840251\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking PtdIns5P to Rac1 GEF/GAP activity not defined\", \"Single-lab finding with two perturbation modalities\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed MTMR3 restrains PRR-induced autophagy and PtdIns3P in macrophages, thereby promoting caspase-1/IL-1\\u03b2 and NF-\\u03baB output, dependent on PH-GRAM and Cys413.\",\n      \"evidence\": \"siRNA knockdown, PH-GRAM/Cys413 mutants, PtdIns3P and autophagy assays, caspase-1, NF-\\u03baB, cytokine readouts, chemical epistasis\",\n      \"pmids\": [\"26240347\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo immune phenotype not tested here\", \"PRR receptor specificity not fully mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a physical interaction with mTORC1 and suppression of its kinase activity by the N-terminal half of MTMR3.\",\n      \"evidence\": \"Co-immunoprecipitation, domain-deletion constructs, wild-type vs phosphatase-dead MTMR3, S6K phosphorylation readout, microscopy\",\n      \"pmids\": [\"26787466\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Reciprocal/endogenous interaction not shown\", \"Mechanism of mTORC1 suppression (lipid-dependent vs scaffolding) unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that MTMR3 and MTMR4 jointly control STING trafficking and dampen cytosolic-DNA-induced type I interferon by regulating PtdIns3P-positive compartments.\",\n      \"evidence\": \"CRISPR/Cas9 MTMR3/4 double knockout macrophages, ISD/HSV-1 stimulation, IFN/IRF3 readouts, STING/PtdIns3P colocalization microscopy\",\n      \"pmids\": [\"30944173\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Individual contribution of MTMR3 vs MTMR4 not separated\", \"Direct dephosphorylation event inferred, not biochemically isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established an in vivo role for MTMR3 in TLR9-induced IgA production dependent on its PtdIns3P-binding domain, with relevance to glomerular IgA deposition.\",\n      \"evidence\": \"Mtmr3-knockout mice, TLR9 stimulation, serum/glomerular IgA assays, domain-binding mutant in vitro, RNA-seq\",\n      \"pmids\": [\"37414396\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cell-type responsible for the IgA phenotype not pinpointed\", \"Direct lipid substrate event in this pathway not demonstrated\", \"Human disease causality not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTMR3's distinct molecular roles\\u2014PtdIns3P depletion, PtdIns5P generation, and mTORC1 binding\\u2014are spatially and temporally partitioned among autophagy, migration, and immune compartments remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of substrate selection vs allosteric PtdIns5P sensing\", \"Mechanism coupling PtdIns5P to Rac1 unresolved\", \"Determinants of compartment-specific recruitment unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PIKfyve\", \"MTMR4\", \"MTOR\", \"STING1\", \"RAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}