{"gene":"MTMR2","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2001,"finding":"MTMR2 is a lipid phosphatase highly specific for phosphatidylinositol 3-phosphate (PI(3)P) as its physiological substrate, with enzymatic properties indistinguishable from myotubularin (MTM1). MTMR2-GFP fusion proteins show overlapping but distinct subcellular localization compared to MTM1, and unlike MTM1, MTMR2 cannot modulate levels of endosomal PI(3)P.","method":"In vitro lipid phosphatase assays with recombinant protein; fluorescence microscopy of GFP fusion proteins; subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with recombinant protein and direct subcellular localization experiments, multiple orthogonal methods in a single study","pmids":["11733541"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of MTMR2 reveals a phosphatase domain structurally unique among PTPs. The GRAM domain is part of a larger motif with a pleckstrin homology (PH) domain fold. Active-site mutagenesis identified residues critical for enzymatic activity and phosphoinositide substrate specificity.","method":"X-ray crystallography; active-site mutagenesis with in vitro enzymatic activity assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determination combined with mutagenesis and enzymatic validation in a single rigorous study","pmids":["14690594"],"is_preprint":false},{"year":2003,"finding":"MTMR2 specifically interacts with the catalytically inactive family member MTMR5 via its coiled-coil domain; this interaction increases MTMR2 enzymatic activity and dictates its subcellular localization. Mutations in the coiled-coil domain of either protein abrogate the interaction.","method":"Co-immunoprecipitation; mass spectrometry identification of interacting partner; coiled-coil domain mutagenesis; in vitro phosphatase activity assays; subcellular localization studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, MS identification, mutagenesis, and enzymatic activity assay, multiple orthogonal methods in one study","pmids":["12668758"],"is_preprint":false},{"year":2004,"finding":"Disruption of Mtmr2 in Schwann cells (but not globally) is sufficient to reproduce CMT4B1-like myelin outfoldings in mice, establishing a Schwann cell-autonomous role for MTMR2 in myelin membrane homeostasis. In Schwann cells, MTMR2 physically interacts with Dlg1/SAP97, a scaffolding molecule enriched at the node/paranode region, and loss of this interaction dysregulates membrane homeostasis at the paranodal region.","method":"Conditional knockout mouse (Schwann cell-specific and neuron-specific Cre); Co-immunoprecipitation of endogenous proteins; nerve biopsy histology; electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific knockout with clear phenotypic readout plus reciprocal Co-IP identifying binding partner; replicated in follow-up study (PMID:16162938)","pmids":["15557122"],"is_preprint":false},{"year":2005,"finding":"Loss of Mtmr2 in Schwann cells, but not in motor neurons, is both sufficient and necessary to cause CMT4B1 neuropathy with myelin outfoldings, confirming the Schwann cell-autonomous mechanism.","method":"Cell-type-specific conditional knockout mice (Schwann cell-specific P0-Cre and motor neuron-specific Hb9-Cre); nerve histology and electron microscopy; nerve conduction velocity measurements","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean cell-type-specific KO with well-defined phenotypic readout, directly replicating and extending PMID:15557122","pmids":["16162938"],"is_preprint":false},{"year":2005,"finding":"Endogenous MTMR2 and MTMR13 proteins associate in HEK293 cells, mediated by coiled-coil sequences in each protein. MTMR13 is a predominantly membrane-associated protein, and its membrane association is mediated by the pseudophosphatase domain. MTMR2 and MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction.","method":"Co-immunoprecipitation of endogenous proteins; subcellular fractionation; fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — endogenous Co-IP plus subcellular fractionation and microscopy, multiple orthogonal methods in one study","pmids":["15998640"],"is_preprint":false},{"year":2006,"finding":"Crystallographic and deuterium-exchange mass spectrometry studies of MTMR2 in complex with phosphoinositides define the molecular basis for substrate specificity: phosphoinositide substrates bind in a positively charged pocket suggesting electrostatic membrane targeting; a flexible hydrophobic helix contacts diacylglycerol moieties conferring specificity for membrane-bound substrates; an H-bonding network and charge interactions in the active site determine headgroup specificity.","method":"X-ray crystallography of MTMR2-phosphoinositide complex; deuterium-exchange mass spectrometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of protein-substrate complex combined with orthogonal deuterium-exchange MS in one rigorous study","pmids":["16410353"],"is_preprint":false},{"year":2009,"finding":"In Schwann cells, Dlg1 interacts with kif13B and Sec8 (an exocyst component) in addition to Mtmr2. A proposed mechanism was established experimentally: kif13B transports Dlg1 to sites of membrane remodeling where Dlg1-Sec8 interaction promotes membrane addition while Dlg1-Mtmr2 interaction negatively regulates membrane formation. Myelin outfoldings in Mtmr2-null Schwann cells are rescued by Mtmr2 replacement in vitro.","method":"Co-immunoprecipitation; Schwann cell/DRG neuron cocultures from Mtmr2-null mice; Mtmr2 rescue experiments; electron microscopy of myelin","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction mapping plus functional rescue in null cell culture, multiple orthogonal methods","pmids":["19587293"],"is_preprint":false},{"year":2010,"finding":"MTMR2 localizes to excitatory synapses of central neurons via direct interaction with PSD-95. Knockdown of MTMR2 reduces excitatory synapse density and function; this effect is rescued by wild-type MTMR2 but not by a mutant lacking PSD-95 binding or 3-phosphatase activity. MTMR2 knockdown alters early endosome distribution in dendrites and promotes endocytosis and lysosomal degradation of GluR2 AMPA receptor subunits.","method":"Co-immunoprecipitation; shRNA knockdown in cultured neurons; rescue with domain mutants; immunofluorescence; endocytosis assays with internalized GluR2","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain-mutant rescue, endocytosis assays, multiple orthogonal methods in one study","pmids":["20410104"],"is_preprint":false},{"year":2011,"finding":"Phosphorylation of MTMR2 at serine 58 markedly decreases its localization to endocytic vesicular structures; a phosphorylation-deficient S58A mutant constitutively localizes to early endocytic structures accompanied by displacement of a PI(3)P sensor and increased signal transduction. ERK1/2 is the kinase responsible for phosphorylating MTMR2 at Ser58, constituting a negative feedback mechanism regulating endosomal targeting.","method":"Mass spectrometry identification of phosphorylation site; site-directed mutagenesis (S58E phosphomimetic and S58A phosphorylation-deficient); subcellular localization by fluorescence microscopy; in vitro kinase assays; cellular MAPK inhibitors; siRNA knockdown; phospho-specific antibody","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-identified phosphosite, mutagenesis, in vitro kinase assay, and localization studies; multiple orthogonal methods in one study","pmids":["21372139"],"is_preprint":false},{"year":2011,"finding":"Overexpression of Mtmr2 prevents EGFR degradation and leads to sustained AKT activation (but not ERK activation). Mtmr13/Sbf2 counteracts the blockage of EGFR degradation without affecting prolonged AKT activation, indicating that Mtmr2 and Mtmr13/Sbf2 regulate EGFR sorting and downstream signaling.","method":"Overexpression in cell lines; Western blotting for pAKT and pERK; EGFR degradation assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with signaling readouts; mechanistic follow-up limited to single lab","pmids":["19912440"],"is_preprint":false},{"year":2013,"finding":"ERK1/2-mediated differential phosphorylation of MTMR2 at Ser58 and Ser631 regulates its compartmentalization on endosomal subtypes: Ser58 phosphorylation status controls general endosomal binding, while Ser631 phosphorylation status mediates shuttling between Rab5-positive and APPL1-positive early endosome subtypes. A double phosphorylation-deficient S58A/S631A MTMR2 variant localizes to APPL1 endosomes and produces more sustained ERK1/2 activation than S58A alone.","method":"In vitro kinase assays; MAPK inhibitors; siRNA knockdown; phospho-specific antibody; site-directed mutagenesis of Ser58 and Ser631; fluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, mutagenesis of two phosphosites, and localization studies with multiple orthogonal methods in one study","pmids":["23378027"],"is_preprint":false},{"year":2016,"finding":"SOX10 regulates an alternative promoter at MTMR2 that directs transcription of a Schwann cell-enriched MTMR2 transcript predicted to encode an N-terminally truncated isoform. The shorter isoform displays higher nuclear localization compared to the longer isoform when overexpressed in HeLa cells.","method":"Computational promoter analysis; luciferase reporter assays in S16 Schwann cells; RT-PCR for transcript enrichment; SOX10 ectopic expression and knockdown; GFP-tagged isoform localization by fluorescence microscopy","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional reporter assays and localization experiments, but full mechanistic significance of the isoform not yet established","pmids":["27466180"],"is_preprint":false},{"year":2017,"finding":"The N-terminal domain is responsible for functional differences between MTM1 and MTMR2. An N-terminal extension present in MTMR2 but absent in MTM1 reduces its ability to substitute for MTM1; the short MTMR2 isoform lacking this extension behaves similarly to MTM1 in yeast complementation and in Mtm1 knockout mice. AAV-mediated expression of MTMR2 isoforms in Mtm1-KO mice ameliorates myopathic phenotype, with the short isoform providing better rescue.","method":"Heterologous expression in yeast (complementation); AAV-mediated gene delivery in Mtm1-KO mice; muscle force measurements; histology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast complementation (functional epistasis), in vivo mouse rescue with isoform comparison, multiple orthogonal methods","pmids":["28934386"],"is_preprint":false},{"year":2019,"finding":"MTMR2 mediates epithelial-mesenchymal transition (EMT) in gastric cancer cells through inactivation of the IFNγ/STAT1/IRF1 signaling pathway, leading to ZEB1 upregulation. MTMR2 knockdown increases phosphorylation of STAT1 and IRF1, whereas overexpression decreases it; silencing IRF1 upregulates ZEB1 and enhances invasion.","method":"Gain- and loss-of-function assays (siRNA knockdown and overexpression); mRNA expression profiling; in vitro invasion/migration assays; in vivo metastasis assays; Western blotting for pSTAT1, IRF1, ZEB1","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD/OE with pathway readouts and epistasis by IRF1 silencing, but single lab and limited mechanistic depth on phosphatase mechanism","pmids":["31113461"],"is_preprint":false}],"current_model":"MTMR2 is a PI(3)P and PI(3,5)P2 3-phosphatase whose crystal structure defines a PH-GRAM domain and unique phosphatase domain; it functions in Schwann cells to negatively regulate myelin membrane formation by interacting via its coiled-coil domain with the pseudophosphatase MTMR13/SBF2 (which stabilizes and membrane-targets MTMR2) and the scaffold Dlg1/SAP97 (which links MTMR2 to the exocyst-mediated membrane addition machinery at paranodal regions), while its endosomal targeting is dynamically controlled by ERK1/2-mediated phosphorylation at Ser58 (regulating general endosomal binding) and Ser631 (regulating shuttling between Rab5- and APPL1-positive endosome subtypes); in neurons, MTMR2 additionally maintains excitatory synapses by interacting with PSD-95 and suppressing excessive endosomal degradation of AMPA receptors."},"narrative":{"mechanistic_narrative":"MTMR2 is a phosphoinositide 3-phosphatase that controls endosomal membrane identity and membrane homeostasis, acting most prominently in myelinating Schwann cells and central neurons [PMID:11733541, PMID:15557122]. It hydrolyzes PI(3)P with enzymatic properties indistinguishable from myotubularin (MTM1), and crystallographic and substrate-complex studies define a phosphatase domain structurally unique among protein tyrosine phosphatases, paired with a GRAM/PH-domain fold and an active-site pocket whose charge network and a flexible hydrophobic helix confer specificity for membrane-bound phosphoinositide headgroups [PMID:14690594, PMID:16410353]. Catalytic activity and subcellular targeting are dictated by association through its coiled-coil domain with the catalytically inactive, membrane-bound family members MTMR5 and MTMR13/SBF2, which stimulate MTMR2 activity and direct its localization [PMID:12668758, PMID:15998640]. In Schwann cells, MTMR2 acts cell-autonomously to restrain myelin membrane formation: its loss is sufficient and necessary to produce CMT4B1-like myelin outfoldings, and it functions through the paranodal scaffold Dlg1/SAP97, which couples a kif13B–Dlg1–Sec8 (exocyst) membrane-addition module to negative regulation by MTMR2 [PMID:15557122, PMID:16162938, PMID:19587293]. Endosomal targeting is dynamically tuned by ERK1/2-mediated phosphorylation, with Ser58 governing general endosomal binding and Ser631 controlling shuttling between Rab5- and APPL1-positive early endosome subtypes, constituting a feedback loop on signal transduction [PMID:21372139, PMID:23378027]. In central neurons MTMR2 binds PSD-95 to maintain excitatory synapse density and function by limiting endocytic and lysosomal degradation of GluR2 AMPA receptors, an activity requiring both PSD-95 binding and 3-phosphatase function [PMID:20410104]. Distinct MTMR2 isoforms differ functionally: an N-terminal extension reduces the ability to substitute for MTM1, and a Schwann-cell-enriched short isoform driven by a SOX10-regulated alternative promoter behaves more like MTM1 [PMID:27466180, PMID:28934386]. MTMR2 expression is mutated in CMT4B1 demyelinating neuropathy as established by the Schwann-cell-autonomous knockout phenotype [PMID:15557122, PMID:16162938].","teleology":[{"year":2001,"claim":"Establishing MTMR2's biochemical activity answered whether this myotubularin-related protein is a functional lipid phosphatase and on which substrate it acts.","evidence":"In vitro lipid phosphatase assays with recombinant protein and GFP-fusion localization","pmids":["11733541"],"confidence":"High","gaps":["Physiological substrate pool and in vivo endosomal targeting not yet defined","Did not address regulation of activity by partners"]},{"year":2003,"claim":"Crystal structure and substrate-complex work defined the structural basis of MTMR2's catalysis and phosphoinositide headgroup specificity, explaining how a PTP-fold enzyme selects a membrane lipid substrate.","evidence":"X-ray crystallography, substrate-complex crystallography, deuterium-exchange MS, and active-site mutagenesis","pmids":["14690594","16410353"],"confidence":"High","gaps":["Structural basis of regulation by coiled-coil partners not resolved","Membrane-docking geometry inferred from charge/helix features rather than membrane-bound structure"]},{"year":2003,"claim":"Identification of coiled-coil-mediated binding to inactive family members MTMR5 and MTMR13 explained how a soluble phosphatase is activated and targeted to membranes.","evidence":"Co-IP, MS identification, coiled-coil mutagenesis, fractionation, and in vitro activity assays in HEK293 cells","pmids":["12668758","15998640"],"confidence":"High","gaps":["Stoichiometry and assembly dynamics of the complex unresolved","Whether MTMR5 and MTMR13 act in distinct cell types not addressed"]},{"year":2005,"claim":"Cell-type-specific knockouts established that MTMR2 acts Schwann-cell-autonomously and is required to prevent CMT4B1 myelin outfoldings, localizing the disease mechanism.","evidence":"Schwann-cell- and neuron-specific conditional Cre knockout mice with histology, EM, and nerve conduction measurements","pmids":["15557122","16162938"],"confidence":"High","gaps":["Molecular link between phosphatase activity and outfolding suppression not fully detailed","Lipid substrate dysregulated in vivo not measured directly"]},{"year":2009,"claim":"Mapping the Dlg1–kif13B–Sec8 module showed how MTMR2 integrates into a membrane-addition machinery, providing a mechanism for negative regulation of myelin membrane formation.","evidence":"Co-IP interaction mapping and Mtmr2 rescue in Schwann cell/DRG cocultures with EM","pmids":["19587293"],"confidence":"High","gaps":["Direct lipid signal coordinating exocyst activity not identified","Quantitative balance between membrane addition and MTMR2 restraint unresolved"]},{"year":2010,"claim":"Discovery of PSD-95 binding extended MTMR2 function to neurons, showing it limits AMPA-receptor degradation to maintain excitatory synapses.","evidence":"Co-IP, shRNA knockdown with domain-mutant rescue, and GluR2 endocytosis assays in cultured neurons","pmids":["20410104"],"confidence":"High","gaps":["In vivo synaptic and behavioral consequences not established","Endosomal lipid changes driving GluR2 sorting not directly measured"]},{"year":2013,"claim":"Identifying ERK1/2 phosphorylation at Ser58 and Ser631 revealed how MTMR2 endosomal compartmentalization is dynamically regulated, linking it to signal-transduction feedback.","evidence":"In vitro kinase assays, phospho-site mutagenesis, MAPK inhibition, siRNA, and localization microscopy","pmids":["21372139","23378027"],"confidence":"High","gaps":["Physiological cues triggering site-specific phosphorylation unclear","Whether this regulation operates in Schwann cells or neurons in vivo unknown"]},{"year":2017,"claim":"Comparing MTMR2 isoforms with MTM1 showed that the N-terminal extension and a SOX10-driven short isoform tune functional equivalence and tissue-specific output.","evidence":"Yeast complementation, AAV-mediated isoform rescue in Mtm1-KO mice, alternative-promoter reporter assays, and isoform localization","pmids":["27466180","28934386"],"confidence":"Medium","gaps":["Endogenous abundance and role of the short nuclear isoform not established","Mechanistic basis for differential rescue not fully resolved"]},{"year":2019,"claim":"Linking MTMR2 to IFNγ/STAT1/IRF1 signaling and EMT extended its activity to gastric cancer invasion through ZEB1 upregulation.","evidence":"Knockdown/overexpression with invasion and metastasis assays, IRF1-silencing epistasis, and Western blots in gastric cancer cells","pmids":["31113461"],"confidence":"Medium","gaps":["Single lab and limited mechanistic depth on the phosphatase contribution","Whether the effect requires catalytic activity not tested"]},{"year":null,"claim":"How MTMR2's lipid-phosphatase activity, partner-directed targeting, and ERK-controlled endosomal localization are quantitatively coordinated in vivo across Schwann cells, neurons, and disease contexts remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified in vivo measurement of substrate flux linked to phenotype","Tissue-specific isoform contributions to disease unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,7,8]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[9,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,8]}],"pathway":[],"complexes":[],"partners":["MTMR13","MTMR5","DLG1","PSD-95","SEC8","KIF13B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13614","full_name":"Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2","aliases":["Myotubularin-related protein 2","Phosphatidylinositol-3-phosphate phosphatase"],"length_aa":643,"mass_kda":73.4,"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:11733541, PubMed:12668758, PubMed:14690594, PubMed:21372139). Regulates the level of these phosphoinositides critical for various biological processes including autophagy initiation and autophagosome maturation (PubMed:35580604)","subcellular_location":"Cytoplasm; Early endosome membrane; Cytoplasm, perinuclear region; Cell projection, axon; Endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q13614/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTMR2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000087053","cell_line_id":"CID000147","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"LUC7L3","stoichiometry":4.0},{"gene":"MTMR12","stoichiometry":4.0},{"gene":"MTMR10","stoichiometry":4.0},{"gene":"MTMR1","stoichiometry":0.2},{"gene":"SBF1","stoichiometry":0.2},{"gene":"G6PD","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"COX7A2","stoichiometry":0.2},{"gene":"C20ORF24","stoichiometry":0.2},{"gene":"DR1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000147","total_profiled":1310},"omim":[{"mim_id":"620553","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 93; CCDC93","url":"https://www.omim.org/entry/620553"},{"mim_id":"618981","title":"VPS35 ENDOSOMAL PROTEIN-SORTING FACTOR-LIKE; VPS35L","url":"https://www.omim.org/entry/618981"},{"mim_id":"607697","title":"SET-BINDING FACTOR 2; SBF2","url":"https://www.omim.org/entry/607697"},{"mim_id":"607238","title":"COMM DOMAIN-CONTAINING PROTEIN 1; COMMD1","url":"https://www.omim.org/entry/607238"},{"mim_id":"604563","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4B2; CMT4B2","url":"https://www.omim.org/entry/604563"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTMR2"},"hgnc":{"alias_symbol":["KIAA1073"],"prev_symbol":["CMT4B"]},"alphafold":{"accession":"Q13614","domains":[{"cath_id":"2.30.29.30","chopping":"76-183","consensus_level":"high","plddt":95.7675,"start":76,"end":183},{"cath_id":"-","chopping":"213-586","consensus_level":"medium","plddt":97.5068,"start":213,"end":586}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13614","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13614-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13614-F1-predicted_aligned_error_v6.png","plddt_mean":88.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTMR2","jax_strain_url":"https://www.jax.org/strain/search?query=MTMR2"},"sequence":{"accession":"Q13614","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13614.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13614/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13614"}},"corpus_meta":[{"pmid":"12687498","id":"PMC_12687498","title":"Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12687498","citation_count":232,"is_preprint":false},{"pmid":"15557122","id":"PMC_15557122","title":"Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15557122","citation_count":153,"is_preprint":false},{"pmid":"14690594","id":"PMC_14690594","title":"Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/14690594","citation_count":127,"is_preprint":false},{"pmid":"12668758","id":"PMC_12668758","title":"Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12668758","citation_count":121,"is_preprint":false},{"pmid":"11733541","id":"PMC_11733541","title":"Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11733541","citation_count":101,"is_preprint":false},{"pmid":"15998640","id":"PMC_15998640","title":"The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15998640","citation_count":95,"is_preprint":false},{"pmid":"19587293","id":"PMC_19587293","title":"Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19587293","citation_count":90,"is_preprint":false},{"pmid":"16162938","id":"PMC_16162938","title":"Loss of Mtmr2 phosphatase in Schwann cells but not in motor neurons causes Charcot-Marie-Tooth type 4B1 neuropathy with myelin outfoldings.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16162938","citation_count":81,"is_preprint":false},{"pmid":"16410353","id":"PMC_16410353","title":"Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16410353","citation_count":79,"is_preprint":false},{"pmid":"11335693","id":"PMC_11335693","title":"Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin.","date":"2001","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11335693","citation_count":73,"is_preprint":false},{"pmid":"31113461","id":"PMC_31113461","title":"MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31113461","citation_count":39,"is_preprint":false},{"pmid":"9521281","id":"PMC_9521281","title":"Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B).","date":"1998","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/9521281","citation_count":37,"is_preprint":false},{"pmid":"15304601","id":"PMC_15304601","title":"SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma.","date":"2004","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15304601","citation_count":34,"is_preprint":false},{"pmid":"31070812","id":"PMC_31070812","title":"A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs).","date":"2019","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31070812","citation_count":32,"is_preprint":false},{"pmid":"11354824","id":"PMC_11354824","title":"Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-Marie-Tooth disease suggests a low frequency of 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MTMR2-GFP fusion proteins show overlapping but distinct subcellular localization compared to MTM1, and unlike MTM1, MTMR2 cannot modulate levels of endosomal PI(3)P.\",\n      \"method\": \"In vitro lipid phosphatase assays with recombinant protein; fluorescence microscopy of GFP fusion proteins; subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with recombinant protein and direct subcellular localization experiments, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"11733541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of MTMR2 reveals a phosphatase domain structurally unique among PTPs. The GRAM domain is part of a larger motif with a pleckstrin homology (PH) domain fold. Active-site mutagenesis identified residues critical for enzymatic activity and phosphoinositide substrate specificity.\",\n      \"method\": \"X-ray crystallography; active-site mutagenesis with in vitro enzymatic activity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determination combined with mutagenesis and enzymatic validation in a single rigorous study\",\n      \"pmids\": [\"14690594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MTMR2 specifically interacts with the catalytically inactive family member MTMR5 via its coiled-coil domain; this interaction increases MTMR2 enzymatic activity and dictates its subcellular localization. Mutations in the coiled-coil domain of either protein abrogate the interaction.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry identification of interacting partner; coiled-coil domain mutagenesis; in vitro phosphatase activity assays; subcellular localization studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, MS identification, mutagenesis, and enzymatic activity assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12668758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Disruption of Mtmr2 in Schwann cells (but not globally) is sufficient to reproduce CMT4B1-like myelin outfoldings in mice, establishing a Schwann cell-autonomous role for MTMR2 in myelin membrane homeostasis. In Schwann cells, MTMR2 physically interacts with Dlg1/SAP97, a scaffolding molecule enriched at the node/paranode region, and loss of this interaction dysregulates membrane homeostasis at the paranodal region.\",\n      \"method\": \"Conditional knockout mouse (Schwann cell-specific and neuron-specific Cre); Co-immunoprecipitation of endogenous proteins; nerve biopsy histology; electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific knockout with clear phenotypic readout plus reciprocal Co-IP identifying binding partner; replicated in follow-up study (PMID:16162938)\",\n      \"pmids\": [\"15557122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Loss of Mtmr2 in Schwann cells, but not in motor neurons, is both sufficient and necessary to cause CMT4B1 neuropathy with myelin outfoldings, confirming the Schwann cell-autonomous mechanism.\",\n      \"method\": \"Cell-type-specific conditional knockout mice (Schwann cell-specific P0-Cre and motor neuron-specific Hb9-Cre); nerve histology and electron microscopy; nerve conduction velocity measurements\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean cell-type-specific KO with well-defined phenotypic readout, directly replicating and extending PMID:15557122\",\n      \"pmids\": [\"16162938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Endogenous MTMR2 and MTMR13 proteins associate in HEK293 cells, mediated by coiled-coil sequences in each protein. MTMR13 is a predominantly membrane-associated protein, and its membrane association is mediated by the pseudophosphatase domain. MTMR2 and MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins; subcellular fractionation; fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous Co-IP plus subcellular fractionation and microscopy, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15998640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystallographic and deuterium-exchange mass spectrometry studies of MTMR2 in complex with phosphoinositides define the molecular basis for substrate specificity: phosphoinositide substrates bind in a positively charged pocket suggesting electrostatic membrane targeting; a flexible hydrophobic helix contacts diacylglycerol moieties conferring specificity for membrane-bound substrates; an H-bonding network and charge interactions in the active site determine headgroup specificity.\",\n      \"method\": \"X-ray crystallography of MTMR2-phosphoinositide complex; deuterium-exchange mass spectrometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of protein-substrate complex combined with orthogonal deuterium-exchange MS in one rigorous study\",\n      \"pmids\": [\"16410353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Schwann cells, Dlg1 interacts with kif13B and Sec8 (an exocyst component) in addition to Mtmr2. A proposed mechanism was established experimentally: kif13B transports Dlg1 to sites of membrane remodeling where Dlg1-Sec8 interaction promotes membrane addition while Dlg1-Mtmr2 interaction negatively regulates membrane formation. Myelin outfoldings in Mtmr2-null Schwann cells are rescued by Mtmr2 replacement in vitro.\",\n      \"method\": \"Co-immunoprecipitation; Schwann cell/DRG neuron cocultures from Mtmr2-null mice; Mtmr2 rescue experiments; electron microscopy of myelin\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction mapping plus functional rescue in null cell culture, multiple orthogonal methods\",\n      \"pmids\": [\"19587293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MTMR2 localizes to excitatory synapses of central neurons via direct interaction with PSD-95. Knockdown of MTMR2 reduces excitatory synapse density and function; this effect is rescued by wild-type MTMR2 but not by a mutant lacking PSD-95 binding or 3-phosphatase activity. MTMR2 knockdown alters early endosome distribution in dendrites and promotes endocytosis and lysosomal degradation of GluR2 AMPA receptor subunits.\",\n      \"method\": \"Co-immunoprecipitation; shRNA knockdown in cultured neurons; rescue with domain mutants; immunofluorescence; endocytosis assays with internalized GluR2\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain-mutant rescue, endocytosis assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20410104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Phosphorylation of MTMR2 at serine 58 markedly decreases its localization to endocytic vesicular structures; a phosphorylation-deficient S58A mutant constitutively localizes to early endocytic structures accompanied by displacement of a PI(3)P sensor and increased signal transduction. ERK1/2 is the kinase responsible for phosphorylating MTMR2 at Ser58, constituting a negative feedback mechanism regulating endosomal targeting.\",\n      \"method\": \"Mass spectrometry identification of phosphorylation site; site-directed mutagenesis (S58E phosphomimetic and S58A phosphorylation-deficient); subcellular localization by fluorescence microscopy; in vitro kinase assays; cellular MAPK inhibitors; siRNA knockdown; phospho-specific antibody\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified phosphosite, mutagenesis, in vitro kinase assay, and localization studies; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21372139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of Mtmr2 prevents EGFR degradation and leads to sustained AKT activation (but not ERK activation). Mtmr13/Sbf2 counteracts the blockage of EGFR degradation without affecting prolonged AKT activation, indicating that Mtmr2 and Mtmr13/Sbf2 regulate EGFR sorting and downstream signaling.\",\n      \"method\": \"Overexpression in cell lines; Western blotting for pAKT and pERK; EGFR degradation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with signaling readouts; mechanistic follow-up limited to single lab\",\n      \"pmids\": [\"19912440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERK1/2-mediated differential phosphorylation of MTMR2 at Ser58 and Ser631 regulates its compartmentalization on endosomal subtypes: Ser58 phosphorylation status controls general endosomal binding, while Ser631 phosphorylation status mediates shuttling between Rab5-positive and APPL1-positive early endosome subtypes. A double phosphorylation-deficient S58A/S631A MTMR2 variant localizes to APPL1 endosomes and produces more sustained ERK1/2 activation than S58A alone.\",\n      \"method\": \"In vitro kinase assays; MAPK inhibitors; siRNA knockdown; phospho-specific antibody; site-directed mutagenesis of Ser58 and Ser631; fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, mutagenesis of two phosphosites, and localization studies with multiple orthogonal methods in one study\",\n      \"pmids\": [\"23378027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SOX10 regulates an alternative promoter at MTMR2 that directs transcription of a Schwann cell-enriched MTMR2 transcript predicted to encode an N-terminally truncated isoform. The shorter isoform displays higher nuclear localization compared to the longer isoform when overexpressed in HeLa cells.\",\n      \"method\": \"Computational promoter analysis; luciferase reporter assays in S16 Schwann cells; RT-PCR for transcript enrichment; SOX10 ectopic expression and knockdown; GFP-tagged isoform localization by fluorescence microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional reporter assays and localization experiments, but full mechanistic significance of the isoform not yet established\",\n      \"pmids\": [\"27466180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The N-terminal domain is responsible for functional differences between MTM1 and MTMR2. An N-terminal extension present in MTMR2 but absent in MTM1 reduces its ability to substitute for MTM1; the short MTMR2 isoform lacking this extension behaves similarly to MTM1 in yeast complementation and in Mtm1 knockout mice. AAV-mediated expression of MTMR2 isoforms in Mtm1-KO mice ameliorates myopathic phenotype, with the short isoform providing better rescue.\",\n      \"method\": \"Heterologous expression in yeast (complementation); AAV-mediated gene delivery in Mtm1-KO mice; muscle force measurements; histology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast complementation (functional epistasis), in vivo mouse rescue with isoform comparison, multiple orthogonal methods\",\n      \"pmids\": [\"28934386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTMR2 mediates epithelial-mesenchymal transition (EMT) in gastric cancer cells through inactivation of the IFNγ/STAT1/IRF1 signaling pathway, leading to ZEB1 upregulation. MTMR2 knockdown increases phosphorylation of STAT1 and IRF1, whereas overexpression decreases it; silencing IRF1 upregulates ZEB1 and enhances invasion.\",\n      \"method\": \"Gain- and loss-of-function assays (siRNA knockdown and overexpression); mRNA expression profiling; in vitro invasion/migration assays; in vivo metastasis assays; Western blotting for pSTAT1, IRF1, ZEB1\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD/OE with pathway readouts and epistasis by IRF1 silencing, but single lab and limited mechanistic depth on phosphatase mechanism\",\n      \"pmids\": [\"31113461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTMR2 is a PI(3)P and PI(3,5)P2 3-phosphatase whose crystal structure defines a PH-GRAM domain and unique phosphatase domain; it functions in Schwann cells to negatively regulate myelin membrane formation by interacting via its coiled-coil domain with the pseudophosphatase MTMR13/SBF2 (which stabilizes and membrane-targets MTMR2) and the scaffold Dlg1/SAP97 (which links MTMR2 to the exocyst-mediated membrane addition machinery at paranodal regions), while its endosomal targeting is dynamically controlled by ERK1/2-mediated phosphorylation at Ser58 (regulating general endosomal binding) and Ser631 (regulating shuttling between Rab5- and APPL1-positive endosome subtypes); in neurons, MTMR2 additionally maintains excitatory synapses by interacting with PSD-95 and suppressing excessive endosomal degradation of AMPA receptors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTMR2 is a phosphoinositide 3-phosphatase that controls endosomal membrane identity and membrane homeostasis, acting most prominently in myelinating Schwann cells and central neurons [#0, #3]. It hydrolyzes PI(3)P with enzymatic properties indistinguishable from myotubularin (MTM1), and crystallographic and substrate-complex studies define a phosphatase domain structurally unique among protein tyrosine phosphatases, paired with a GRAM/PH-domain fold and an active-site pocket whose charge network and a flexible hydrophobic helix confer specificity for membrane-bound phosphoinositide headgroups [#1, #6]. Catalytic activity and subcellular targeting are dictated by association through its coiled-coil domain with the catalytically inactive, membrane-bound family members MTMR5 and MTMR13/SBF2, which stimulate MTMR2 activity and direct its localization [#2, #5]. In Schwann cells, MTMR2 acts cell-autonomously to restrain myelin membrane formation: its loss is sufficient and necessary to produce CMT4B1-like myelin outfoldings, and it functions through the paranodal scaffold Dlg1/SAP97, which couples a kif13B–Dlg1–Sec8 (exocyst) membrane-addition module to negative regulation by MTMR2 [#3, #4, #7]. Endosomal targeting is dynamically tuned by ERK1/2-mediated phosphorylation, with Ser58 governing general endosomal binding and Ser631 controlling shuttling between Rab5- and APPL1-positive early endosome subtypes, constituting a feedback loop on signal transduction [#9, #11]. In central neurons MTMR2 binds PSD-95 to maintain excitatory synapse density and function by limiting endocytic and lysosomal degradation of GluR2 AMPA receptors, an activity requiring both PSD-95 binding and 3-phosphatase function [#8]. Distinct MTMR2 isoforms differ functionally: an N-terminal extension reduces the ability to substitute for MTM1, and a Schwann-cell-enriched short isoform driven by a SOX10-regulated alternative promoter behaves more like MTM1 [#12, #13]. MTMR2 expression is mutated in CMT4B1 demyelinating neuropathy as established by the Schwann-cell-autonomous knockout phenotype [#3, #4].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing MTMR2's biochemical activity answered whether this myotubularin-related protein is a functional lipid phosphatase and on which substrate it acts.\",\n      \"evidence\": \"In vitro lipid phosphatase assays with recombinant protein and GFP-fusion localization\",\n      \"pmids\": [\"11733541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate pool and in vivo endosomal targeting not yet defined\", \"Did not address regulation of activity by partners\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Crystal structure and substrate-complex work defined the structural basis of MTMR2's catalysis and phosphoinositide headgroup specificity, explaining how a PTP-fold enzyme selects a membrane lipid substrate.\",\n      \"evidence\": \"X-ray crystallography, substrate-complex crystallography, deuterium-exchange MS, and active-site mutagenesis\",\n      \"pmids\": [\"14690594\", \"16410353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of regulation by coiled-coil partners not resolved\", \"Membrane-docking geometry inferred from charge/helix features rather than membrane-bound structure\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of coiled-coil-mediated binding to inactive family members MTMR5 and MTMR13 explained how a soluble phosphatase is activated and targeted to membranes.\",\n      \"evidence\": \"Co-IP, MS identification, coiled-coil mutagenesis, fractionation, and in vitro activity assays in HEK293 cells\",\n      \"pmids\": [\"12668758\", \"15998640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly dynamics of the complex unresolved\", \"Whether MTMR5 and MTMR13 act in distinct cell types not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Cell-type-specific knockouts established that MTMR2 acts Schwann-cell-autonomously and is required to prevent CMT4B1 myelin outfoldings, localizing the disease mechanism.\",\n      \"evidence\": \"Schwann-cell- and neuron-specific conditional Cre knockout mice with histology, EM, and nerve conduction measurements\",\n      \"pmids\": [\"15557122\", \"16162938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between phosphatase activity and outfolding suppression not fully detailed\", \"Lipid substrate dysregulated in vivo not measured directly\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping the Dlg1–kif13B–Sec8 module showed how MTMR2 integrates into a membrane-addition machinery, providing a mechanism for negative regulation of myelin membrane formation.\",\n      \"evidence\": \"Co-IP interaction mapping and Mtmr2 rescue in Schwann cell/DRG cocultures with EM\",\n      \"pmids\": [\"19587293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid signal coordinating exocyst activity not identified\", \"Quantitative balance between membrane addition and MTMR2 restraint unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery of PSD-95 binding extended MTMR2 function to neurons, showing it limits AMPA-receptor degradation to maintain excitatory synapses.\",\n      \"evidence\": \"Co-IP, shRNA knockdown with domain-mutant rescue, and GluR2 endocytosis assays in cultured neurons\",\n      \"pmids\": [\"20410104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo synaptic and behavioral consequences not established\", \"Endosomal lipid changes driving GluR2 sorting not directly measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying ERK1/2 phosphorylation at Ser58 and Ser631 revealed how MTMR2 endosomal compartmentalization is dynamically regulated, linking it to signal-transduction feedback.\",\n      \"evidence\": \"In vitro kinase assays, phospho-site mutagenesis, MAPK inhibition, siRNA, and localization microscopy\",\n      \"pmids\": [\"21372139\", \"23378027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological cues triggering site-specific phosphorylation unclear\", \"Whether this regulation operates in Schwann cells or neurons in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Comparing MTMR2 isoforms with MTM1 showed that the N-terminal extension and a SOX10-driven short isoform tune functional equivalence and tissue-specific output.\",\n      \"evidence\": \"Yeast complementation, AAV-mediated isoform rescue in Mtm1-KO mice, alternative-promoter reporter assays, and isoform localization\",\n      \"pmids\": [\"27466180\", \"28934386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous abundance and role of the short nuclear isoform not established\", \"Mechanistic basis for differential rescue not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking MTMR2 to IFNγ/STAT1/IRF1 signaling and EMT extended its activity to gastric cancer invasion through ZEB1 upregulation.\",\n      \"evidence\": \"Knockdown/overexpression with invasion and metastasis assays, IRF1-silencing epistasis, and Western blots in gastric cancer cells\",\n      \"pmids\": [\"31113461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and limited mechanistic depth on the phosphatase contribution\", \"Whether the effect requires catalytic activity not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTMR2's lipid-phosphatase activity, partner-directed targeting, and ERK-controlled endosomal localization are quantitatively coordinated in vivo across Schwann cells, neurons, and disease contexts remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified in vivo measurement of substrate flux linked to phenotype\", \"Tissue-specific isoform contributions to disease unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTMR13\", \"MTMR5\", \"DLG1\", \"PSD-95\", \"SEC8\", \"KIF13B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}