{"gene":"MTMR7","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2003,"finding":"MTMR7 is a phosphatase that dephosphorylates phosphatidylinositol 3-phosphate (PI3P) and inositol 1,3-bisphosphate [Ins(1,3)P2] at the D-3 position, with preference for the water-soluble substrate Ins(1,3)P2 over the lipid substrate, distinguishing its substrate specificity from other MTM family members.","method":"In vitro phosphatase assay with recombinant MTMR7","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay with recombinant protein, replicated and extended in subsequent publications","pmids":["12890864"],"is_preprint":false},{"year":2003,"finding":"MTMR7 is localized in Golgi-like granules and cytosol in neuronal N1E-115 cells, with both cytoplasmic and membrane fractions detected by subcellular fractionation.","method":"Immunofluorescence microscopy and subcellular fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal localization methods (immunofluorescence + fractionation) in a single study","pmids":["12890864"],"is_preprint":false},{"year":2003,"finding":"MTMR7 forms a complex with the catalytically inactive MTMR9; the coiled-coil domain of MTMR9 is sufficient for binding to MTMR7, and MTMR9 binding increases the Ins(1,3)P2 phosphatase activity of MTMR7.","method":"Anti-MTMR7 immunoprecipitation from N1E-115 cells followed by tandem mass spectrometry identification of MTMR9; domain mapping by co-immunoprecipitation; in vitro phosphatase activity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP with MS identification, domain mapping, and functional enzymatic assay; replicated and extended by subsequent PNAS 2012 paper","pmids":["12890864"],"is_preprint":false},{"year":2012,"finding":"The MTMR7/MTMR9 complex dephosphorylates both PI(3)P and PI(3,5)P2; MTMR9 binding modulates substrate specificity and increases catalytic activity of MTMR7. MTMR9 increased MTMR7 activity toward PI(3,5)P2 differently than toward PI(3)P, but the study focused more on the MTMR6/R9 and MTMR8/R9 complexes for quantitative fold-changes.","method":"In vitro phosphatase assay with recombinant complexes; cellular PIP level measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with quantitative enzymatic assays; independent lab replication of MTMR7/MTMR9 interaction","pmids":["22647598"],"is_preprint":false},{"year":2013,"finding":"Silencing MTMR7 by shRNA in CD4 T cells caused increased Th2 and Th17 differentiation and increased AKT phosphorylation in these cells, indicating MTMR7 negatively regulates PI(3,4,5)P3-dependent AKT signaling to control T-helper cell lineage decisions.","method":"Lentiviral shRNA knockdown screen followed by T-cell differentiation assay and AKT phosphorylation measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with defined cellular phenotype (lineage differentiation) and biochemical readout (AKT phosphorylation), single lab","pmids":["23630283"],"is_preprint":false},{"year":2016,"finding":"MTMR7 lowers cellular phosphoinositide levels and inhibits insulin-mediated AKT and ERK1/2 signaling as well as proliferation in human colorectal cancer cell lines, placing MTMR7 as a negative regulator of insulin receptor downstream signaling.","method":"MTMR7 overexpression/knockdown in CRC cell lines with PIP quantification, AKT/ERK1/2 phosphorylation immunoblotting, and proliferation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts (lipid levels, signaling, proliferation) in cell lines, single lab","pmids":["27409167"],"is_preprint":false},{"year":2017,"finding":"MTMR7 knockdown in C2C12 myoblasts enhanced proliferation through increased AKT phosphorylation and cyclinA2 expression, and also promoted early differentiation by altering Myf5 expression, demonstrating MTMR7 negatively regulates PI3K/AKT signaling in myoblasts.","method":"shRNA knockdown in C2C12 cells with proliferation assays, differentiation markers (Myf5), cyclinA2 and phospho-AKT immunoblotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and signaling readout, single lab","pmids":["28153733"],"is_preprint":false},{"year":2019,"finding":"MTMR7 is expressed exclusively in early germ cells in the testis, and morpholino-mediated knockdown of Mtmr7 in neonatal mouse testis caused excessive spermatogonial stem cell (SSC) proliferation due to aberrant activation of PI3K/AKT signaling, demonstrating MTMR7 maintains SSC homeostasis by inhibiting this pathway.","method":"Morpholino knockdown in neonatal mouse testis and SSC culture, proliferation assays, PI3K/AKT phosphorylation analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype and signaling readout, single lab","pmids":["31478454"],"is_preprint":false},{"year":2020,"finding":"MTMR7 is a cytosolic interaction partner of PPARγ; MTMR7 forms a complex with PPARγ and increases PPARγ transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARγ. The coiled-coil (CC) domain of MTMR7 containing LXXLL motifs is required for this activity, and CC peptides mimic PPARγ activation in vitro and in vivo.","method":"Co-immunoprecipitation, PPARγ transcriptional activity reporter assays in cancer cell lines, ERK1/2 phosphorylation immunoblotting, synthetic CC peptide treatment in C57BL/6J mice, molecular dynamics/docking simulations","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional transcriptional assay plus in vivo peptide validation, single lab, multiple methods","pmids":["32522977"],"is_preprint":false},{"year":2024,"finding":"MTMR7 directly binds and inhibits K-RAS (including the K-RASG12V mutant) at cellular membranes via its charged coiled-coil (CC) domain, reducing RAS GTPase activity, ERK1/2 phosphorylation, c-FOS transcription, and cancer cell proliferation; a cell-permeable MTMR7-CC peptide decreased tumor growth in mouse models of gastric and intestinal cancer.","method":"Co-immunoprecipitation, structural biology (cell biology + molecular modeling), RAS GTPase activity assays, ERK1/2 phosphorylation immunoblotting, proliferation assays in vitro, xenograft/mouse cancer models in vivo","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP and structural modeling, functional assays in vitro and in vivo, single lab","pmids":["38462034"],"is_preprint":false},{"year":2024,"finding":"MTMR7 inhibits VSMC phenotypic switching and vascular intimal hyperplasia after injury by suppressing p62/mTORC1-mediated glycolysis; mechanistically, MTMR7 causes dephosphorylation and dissociation of p62 from mTORC1, thereby reducing mTORC1 activity and glycolysis. Restoring mTORC1 or p62 abolished MTMR7's protective effects.","method":"Mtmr7-transgenic mice (in vivo carotid injury model), Lentiviral MTMR7 overexpression in VSMCs, mTORC1/p62 co-immunoprecipitation, glycolysis assays, Ki-67 proliferation, Calponin/SM-MHC expression, rescue experiments with mTORC1 activator and p62 overexpression","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model plus in vitro mechanistic dissection with genetic rescue experiments, single lab","pmids":["38342025"],"is_preprint":false},{"year":2024,"finding":"The coiled-coil (CC) domain of MTMR7 forms dimers, while the MTMR9-CC forms trimers; MTMR7-CC preferentially forms homodimers, and MTMR7/MTMR9 hetero-oligomerization involves these CC domains, providing structural insight into the MTMR7/MTMR9 complex.","method":"Biophysical characterization of recombinant CC domain proteins (oligomerization assays), bioinformatic analysis of IDRs and short linear motifs","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct biophysical measurement of oligomerization, single lab, limited to domain behavior in isolation","pmids":["39614773"],"is_preprint":false},{"year":2025,"finding":"MTMR7 interacts with STIM1 at the endoplasmic reticulum as identified by yeast two-hybrid analysis and confirmed by co-immunoprecipitation and fluorescence microscopy, identifying MTMR7 as a novel STIM1-binding protein that connects phosphoinositide signaling with store-operated Ca2+ entry (SOCE).","method":"Yeast two-hybrid, co-immunoprecipitation, fluorescence microscopy","journal":"Canadian journal of physiology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by three orthogonal methods (Y2H, Co-IP, imaging), single lab","pmids":["40327889"],"is_preprint":false},{"year":2026,"finding":"MTMR7 forms a complex with STIM1 and is positioned at ER-plasma membrane contact sites, where it alters local PI(3,5)P2 and PI(4,5)P2 levels to increase ORAI1 fast inactivation and decrease SOCE; loss of MTMR7 catalytic phosphatase activity weakens ORAI1 inactivation, while disruption of the MTMR7-STIM1 interaction retains ORAI1 inactivation independent of phosphatase activity.","method":"STIM1/MTMR7 complex analysis, phosphatase-dead MTMR7 mutant, MTMR7-STIM1 interaction disruption mutant, plasma membrane PIP level measurement (PI(3,5)P2 and PI(4,5)P2), electrophysiology/SOCE assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including active-site mutagenesis, protein interaction disruption mutant, lipid measurements, and SOCE functional assay in a single study","pmids":["42004029"],"is_preprint":false},{"year":2025,"finding":"MTMR7 regulates human spermatogonial stem cell (SSC) proliferation and migration; MTMR7 knockdown increased and overexpression inhibited these processes. Mass spectrometry and co-immunoprecipitation identified filamin B (FLNB) as an MTMR7-interacting protein. MTMR7 promotes FLNB ubiquitination and degradation, leading to reduced downstream β-catenin signaling.","method":"MTMR7 knockdown/overexpression in human SSCs, mass spectrometry, co-immunoprecipitation, ubiquitination assay, immunofluorescence, β-catenin signaling readouts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of interactor confirmed by Co-IP, functional ubiquitination assay and downstream signaling, single lab","pmids":["40638605"],"is_preprint":false},{"year":2025,"finding":"MTMR7 overexpression in pulmonary arterial smooth muscle cells (PASMCs) suppresses proliferation and migration by inhibiting ERK1/2 and STAT3 phosphorylation; epistasis experiments showed that restoring ERK1/2 also reversed MTMR7-mediated STAT3 dephosphorylation, placing ERK1/2 upstream of STAT3 in the MTMR7 pathway.","method":"Mtmr7-transgenic mice (MCT-induced PH model), adenoviral MTMR7 overexpression in PASMCs, ERK1/2 and STAT3 phosphorylation immunoblotting, genetic rescue with ERK1/2/STAT3 activators, proliferation and migration assays","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic plus in vitro mechanistic dissection with epistasis experiments, single lab","pmids":["39918745"],"is_preprint":false}],"current_model":"MTMR7 is a PI3P/PI(3,5)P2 lipid phosphatase that forms an activation complex with the catalytically inactive MTMR9 (via coiled-coil domain interaction), is recruited to ER-plasma membrane contact sites through direct STIM1 binding where it modulates local phosphoinositide levels to regulate ORAI1 inactivation and store-operated Ca2+ entry, and in the cytosol inhibits PI3K/AKT, ERK1/2, mTORC1, and STAT3 signaling to suppress cell proliferation, migration, and phenotypic switching across multiple cell types including neurons, T cells, smooth muscle cells, and spermatogonial stem cells; additionally, MTMR7 activates PPARγ and directly inhibits mutant K-RAS via its charged coiled-coil domain, and promotes FLNB ubiquitination/degradation to restrain β-catenin signaling."},"narrative":{"mechanistic_narrative":"MTMR7 is a myotubularin-family 3-phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and the soluble inositol substrate Ins(1,3)P2, with a distinctive preference for the water-soluble substrate, and that broadly restrains proliferative and survival signaling by lowering cellular phosphoinositide levels [PMID:12890864, PMID:27409167]. Catalytic output is set by complex formation with the inactive paralog MTMR9: MTMR9 binds MTMR7 through coiled-coil/CC-domain interactions and enhances its phosphatase activity, and the reconstituted complex acts on both PI(3)P and PI(3,5)P2 [PMID:12890864, PMID:22647598, PMID:39614773]. Through this lipid-phosphatase activity MTMR7 functions as a negative regulator of PI3K/AKT signaling in diverse cell types, suppressing AKT phosphorylation and proliferation in T cells, myoblasts, spermatogonial stem cells, and colorectal cancer cells, where it also dampens insulin-driven ERK1/2 signaling [PMID:23630283, PMID:27409167, PMID:28153733, PMID:31478454]. MTMR7 is recruited via direct STIM1 binding to ER–plasma membrane contact sites, where its catalytic activity alters local PI(3,5)P2 and PI(4,5)P2 to promote ORAI1 fast inactivation and limit store-operated Ca2+ entry [PMID:40327889, PMID:42004029]. Beyond its phosphatase function, MTMR7 acts through its charged coiled-coil domain to directly bind and inhibit K-RAS (including the G12V mutant), reducing RAS GTPase activity and downstream ERK1/2 signaling [PMID:38462034], complexes with PPARγ to enhance its transcriptional activity by blocking ERK1/2-dependent PPARγ phosphorylation [PMID:32522977], suppresses VSMC phenotypic switching via dephosphorylation and dissociation of p62 from mTORC1 [PMID:38342025], inhibits PASMC proliferation through an ERK1/2→STAT3 axis [PMID:39918745], and promotes FLNB ubiquitination and degradation to restrain β-catenin signaling in spermatogonial stem cells [PMID:40638605].","teleology":[{"year":2003,"claim":"Establishing MTMR7's enzymatic identity answered what biochemical reaction it catalyzes, defining it as a 3-phosphatase with an unusual preference for a soluble inositol substrate distinct from other MTM members.","evidence":"In vitro phosphatase assay with recombinant MTMR7 on PI3P and Ins(1,3)P2","pmids":["12890864"],"confidence":"High","gaps":["Physiological relevance of soluble Ins(1,3)P2 dephosphorylation versus lipid dephosphorylation in cells not resolved","No structural basis for substrate preference"]},{"year":2003,"claim":"Identifying MTMR9 as a binding partner answered how MTMR7 catalytic activity is regulated, showing the inactive paralog acts as an activating subunit via its coiled-coil domain.","evidence":"Anti-MTMR7 Co-IP with mass-spec identification, domain mapping, and in vitro activity assay in N1E-115 cells","pmids":["12890864"],"confidence":"High","gaps":["Stoichiometry of the complex not defined here","How MTMR9 binding alters active-site chemistry unknown"]},{"year":2012,"claim":"Reconstituting the complex answered which lipid substrates MTMR7/MTMR9 acts on, extending activity to PI(3,5)P2 and confirming MTMR9 modulates both specificity and rate.","evidence":"In vitro phosphatase assays with recombinant complexes and cellular PIP measurement","pmids":["22647598"],"confidence":"High","gaps":["Quantitative fold-changes focused on other MTMR/R9 pairs","In vivo substrate prioritization unresolved"]},{"year":2013,"claim":"Loss-of-function in T cells answered whether MTMR7 has a cellular signaling role, establishing it as a negative regulator of AKT controlling T-helper lineage decisions.","evidence":"shRNA knockdown with T-cell differentiation assay and phospho-AKT readout","pmids":["23630283"],"confidence":"Medium","gaps":["Direct link between phosphatase activity and AKT suppression not isolated","Single lab, no catalytic-dead rescue"]},{"year":2017,"claim":"Knockdown across colorectal cancer cells, myoblasts, and stem cells answered whether AKT suppression is a general MTMR7 function, showing it restrains proliferation by lowering phosphoinositides in multiple lineages.","evidence":"Overexpression/knockdown in CRC and C2C12 cells with PIP quantification, AKT/ERK1/2 immunoblotting, and proliferation assays","pmids":["27409167","28153733"],"confidence":"Medium","gaps":["Causality between specific lipid pools and each signaling output not dissected","Differentiation effects mechanistically separate from proliferation effects unclear"]},{"year":2019,"claim":"In vivo testis knockdown answered whether MTMR7 governs stem-cell homeostasis, showing it maintains spermatogonial stem cells by inhibiting PI3K/AKT.","evidence":"Morpholino knockdown in neonatal mouse testis and SSC culture with proliferation and PI3K/AKT analysis","pmids":["31478454"],"confidence":"Medium","gaps":["Phosphatase-dependence not tested by catalytic mutant","Long-term spermatogenesis consequences not assessed"]},{"year":2020,"claim":"Discovery of the PPARγ interaction answered whether MTMR7 has phosphatase-independent functions, revealing a CC-domain-dependent role enhancing PPARγ transcription by blocking ERK1/2-mediated phosphorylation.","evidence":"Co-IP, PPARγ reporter assays, CC peptide treatment in mice, and docking simulations","pmids":["32522977"],"confidence":"Medium","gaps":["Direct versus indirect effect on ERK1/2 not separated from lipid activity","Single lab"]},{"year":2024,"claim":"Direct K-RAS inhibition answered how MTMR7 suppresses oncogenic RAS signaling, defining the charged CC domain as a binding module that reduces RAS GTPase activity even for the G12V mutant.","evidence":"Co-IP, molecular modeling, RAS GTPase assays, ERK1/2 immunoblotting, and CC-peptide tumor models in mice","pmids":["38462034"],"confidence":"Medium","gaps":["High-resolution structure of the MTMR7-CC/K-RAS interface lacking","Relationship between CC binding and lipid-phosphatase function unresolved"]},{"year":2024,"claim":"VSMC and CC-domain studies answered how MTMR7 controls cell phenotype beyond AKT, linking it to mTORC1 inhibition via p62 dephosphorylation and providing structural detail on CC oligomerization.","evidence":"Mtmr7-transgenic carotid injury model, mTORC1/p62 Co-IP and glycolysis assays with rescue; biophysical CC-domain oligomerization analysis","pmids":["38342025","39614773"],"confidence":"Medium","gaps":["Whether p62 dephosphorylation is direct MTMR7 catalysis not shown","CC oligomerization measured in isolation, not in full-length complex"]},{"year":2025,"claim":"STIM1 interaction and FLNB/STAT3 studies answered how MTMR7 is spatially targeted and what additional effectors it controls, placing it at the ER as a STIM1 partner and linking it to FLNB degradation/β-catenin and an ERK1/2→STAT3 axis.","evidence":"Yeast two-hybrid, Co-IP and imaging for STIM1; MS/Co-IP/ubiquitination for FLNB in human SSCs; transgenic PH model with epistasis for ERK1/2/STAT3 in PASMCs","pmids":["40327889","40638605","39918745"],"confidence":"Medium","gaps":["Mechanism of FLNB ubiquitination (E3 partner) unidentified","How STIM1 recruitment integrates with cytosolic signaling roles unclear"]},{"year":2026,"claim":"Functional dissection at ER-PM contact sites answered how MTMR7 connects phosphoinositide turnover to calcium signaling, showing STIM1-anchored MTMR7 tunes local PI(3,5)P2/PI(4,5)P2 to promote ORAI1 inactivation and limit SOCE.","evidence":"Phosphatase-dead and STIM1-interaction-disruption mutants, PM lipid measurement, and electrophysiology/SOCE assays","pmids":["42004029"],"confidence":"High","gaps":["Quantitative contribution of MTMR7 to physiological Ca2+ responses in tissue not established","Interplay between STIM1-anchored and cytosolic MTMR7 pools unresolved"]},{"year":null,"claim":"Whether MTMR7's lipid-phosphatase activity and its phosphatase-independent CC-domain protein interactions (K-RAS, PPARγ, STIM1) operate as a single integrated mechanism or as separable functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of full-length MTMR7","No genetic separation-of-function across all reported effectors in one system","No Mendelian disease association established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[12,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,9,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,15]}],"complexes":["MTMR7/MTMR9 phosphatase complex","MTMR7-STIM1 complex"],"partners":["MTMR9","STIM1","PPARG","KRAS","FLNB","ORAI1","SQSTM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y216","full_name":"Phosphatidylinositol-3-phosphate phosphatase MTMR7","aliases":["Inositol 1,3-bisphosphate phosphatase","Myotubularin-related protein 7"],"length_aa":660,"mass_kda":75.8,"function":"Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate (PtdIns(3)P) and inositol 1,3-bisphosphate (Ins(1,3)P2)","subcellular_location":"Cytoplasm; Endomembrane system","url":"https://www.uniprot.org/uniprotkb/Q9Y216/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTMR7","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTMR7","total_profiled":1310},"omim":[{"mim_id":"606260","title":"MYOTUBULARIN-RELATED PROTEIN 9; MTMR9","url":"https://www.omim.org/entry/606260"},{"mim_id":"603562","title":"MYOTUBULARIN-RELATED PROTEIN 7; MTMR7","url":"https://www.omim.org/entry/603562"},{"mim_id":"603561","title":"MYOTUBULARIN-RELATED PROTEIN 6; MTMR6","url":"https://www.omim.org/entry/603561"},{"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":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":11.6},{"tissue":"retina","ntpm":26.3}],"url":"https://www.proteinatlas.org/search/MTMR7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y216","domains":[{"cath_id":"2.30.29.30","chopping":"9-103","consensus_level":"high","plddt":91.9313,"start":9,"end":103},{"cath_id":"-","chopping":"121-488_498-521","consensus_level":"medium","plddt":94.8234,"start":121,"end":521}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y216","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y216-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y216-F1-predicted_aligned_error_v6.png","plddt_mean":83.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTMR7","jax_strain_url":"https://www.jax.org/strain/search?query=MTMR7"},"sequence":{"accession":"Q9Y216","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y216.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y216/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y216"}},"corpus_meta":[{"pmid":"12890864","id":"PMC_12890864","title":"Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12890864","citation_count":90,"is_preprint":false},{"pmid":"22647598","id":"PMC_22647598","title":"Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22647598","citation_count":55,"is_preprint":false},{"pmid":"23518043","id":"PMC_23518043","title":"Genetics of prion diseases.","date":"2013","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/23518043","citation_count":48,"is_preprint":false},{"pmid":"22137330","id":"PMC_22137330","title":"Genome-wide study links MTMR7 gene to variant 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[Ins(1,3)P2] at the D-3 position, with preference for the water-soluble substrate Ins(1,3)P2 over the lipid substrate, distinguishing its substrate specificity from other MTM family members.\",\n      \"method\": \"In vitro phosphatase assay with recombinant MTMR7\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay with recombinant protein, replicated and extended in subsequent publications\",\n      \"pmids\": [\"12890864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MTMR7 is localized in Golgi-like granules and cytosol in neuronal N1E-115 cells, with both cytoplasmic and membrane fractions detected by subcellular fractionation.\",\n      \"method\": \"Immunofluorescence microscopy and subcellular fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal localization methods (immunofluorescence + fractionation) in a single study\",\n      \"pmids\": [\"12890864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MTMR7 forms a complex with the catalytically inactive MTMR9; the coiled-coil domain of MTMR9 is sufficient for binding to MTMR7, and MTMR9 binding increases the Ins(1,3)P2 phosphatase activity of MTMR7.\",\n      \"method\": \"Anti-MTMR7 immunoprecipitation from N1E-115 cells followed by tandem mass spectrometry identification of MTMR9; domain mapping by co-immunoprecipitation; in vitro phosphatase activity assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP with MS identification, domain mapping, and functional enzymatic assay; replicated and extended by subsequent PNAS 2012 paper\",\n      \"pmids\": [\"12890864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The MTMR7/MTMR9 complex dephosphorylates both PI(3)P and PI(3,5)P2; MTMR9 binding modulates substrate specificity and increases catalytic activity of MTMR7. MTMR9 increased MTMR7 activity toward PI(3,5)P2 differently than toward PI(3)P, but the study focused more on the MTMR6/R9 and MTMR8/R9 complexes for quantitative fold-changes.\",\n      \"method\": \"In vitro phosphatase assay with recombinant complexes; cellular PIP level measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with quantitative enzymatic assays; independent lab replication of MTMR7/MTMR9 interaction\",\n      \"pmids\": [\"22647598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Silencing MTMR7 by shRNA in CD4 T cells caused increased Th2 and Th17 differentiation and increased AKT phosphorylation in these cells, indicating MTMR7 negatively regulates PI(3,4,5)P3-dependent AKT signaling to control T-helper cell lineage decisions.\",\n      \"method\": \"Lentiviral shRNA knockdown screen followed by T-cell differentiation assay and AKT phosphorylation measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with defined cellular phenotype (lineage differentiation) and biochemical readout (AKT phosphorylation), single lab\",\n      \"pmids\": [\"23630283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MTMR7 lowers cellular phosphoinositide levels and inhibits insulin-mediated AKT and ERK1/2 signaling as well as proliferation in human colorectal cancer cell lines, placing MTMR7 as a negative regulator of insulin receptor downstream signaling.\",\n      \"method\": \"MTMR7 overexpression/knockdown in CRC cell lines with PIP quantification, AKT/ERK1/2 phosphorylation immunoblotting, and proliferation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts (lipid levels, signaling, proliferation) in cell lines, single lab\",\n      \"pmids\": [\"27409167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MTMR7 knockdown in C2C12 myoblasts enhanced proliferation through increased AKT phosphorylation and cyclinA2 expression, and also promoted early differentiation by altering Myf5 expression, demonstrating MTMR7 negatively regulates PI3K/AKT signaling in myoblasts.\",\n      \"method\": \"shRNA knockdown in C2C12 cells with proliferation assays, differentiation markers (Myf5), cyclinA2 and phospho-AKT immunoblotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and signaling readout, single lab\",\n      \"pmids\": [\"28153733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTMR7 is expressed exclusively in early germ cells in the testis, and morpholino-mediated knockdown of Mtmr7 in neonatal mouse testis caused excessive spermatogonial stem cell (SSC) proliferation due to aberrant activation of PI3K/AKT signaling, demonstrating MTMR7 maintains SSC homeostasis by inhibiting this pathway.\",\n      \"method\": \"Morpholino knockdown in neonatal mouse testis and SSC culture, proliferation assays, PI3K/AKT phosphorylation analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype and signaling readout, single lab\",\n      \"pmids\": [\"31478454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MTMR7 is a cytosolic interaction partner of PPARγ; MTMR7 forms a complex with PPARγ and increases PPARγ transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARγ. The coiled-coil (CC) domain of MTMR7 containing LXXLL motifs is required for this activity, and CC peptides mimic PPARγ activation in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, PPARγ transcriptional activity reporter assays in cancer cell lines, ERK1/2 phosphorylation immunoblotting, synthetic CC peptide treatment in C57BL/6J mice, molecular dynamics/docking simulations\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional transcriptional assay plus in vivo peptide validation, single lab, multiple methods\",\n      \"pmids\": [\"32522977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MTMR7 directly binds and inhibits K-RAS (including the K-RASG12V mutant) at cellular membranes via its charged coiled-coil (CC) domain, reducing RAS GTPase activity, ERK1/2 phosphorylation, c-FOS transcription, and cancer cell proliferation; a cell-permeable MTMR7-CC peptide decreased tumor growth in mouse models of gastric and intestinal cancer.\",\n      \"method\": \"Co-immunoprecipitation, structural biology (cell biology + molecular modeling), RAS GTPase activity assays, ERK1/2 phosphorylation immunoblotting, proliferation assays in vitro, xenograft/mouse cancer models in vivo\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP and structural modeling, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"38462034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MTMR7 inhibits VSMC phenotypic switching and vascular intimal hyperplasia after injury by suppressing p62/mTORC1-mediated glycolysis; mechanistically, MTMR7 causes dephosphorylation and dissociation of p62 from mTORC1, thereby reducing mTORC1 activity and glycolysis. Restoring mTORC1 or p62 abolished MTMR7's protective effects.\",\n      \"method\": \"Mtmr7-transgenic mice (in vivo carotid injury model), Lentiviral MTMR7 overexpression in VSMCs, mTORC1/p62 co-immunoprecipitation, glycolysis assays, Ki-67 proliferation, Calponin/SM-MHC expression, rescue experiments with mTORC1 activator and p62 overexpression\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model plus in vitro mechanistic dissection with genetic rescue experiments, single lab\",\n      \"pmids\": [\"38342025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The coiled-coil (CC) domain of MTMR7 forms dimers, while the MTMR9-CC forms trimers; MTMR7-CC preferentially forms homodimers, and MTMR7/MTMR9 hetero-oligomerization involves these CC domains, providing structural insight into the MTMR7/MTMR9 complex.\",\n      \"method\": \"Biophysical characterization of recombinant CC domain proteins (oligomerization assays), bioinformatic analysis of IDRs and short linear motifs\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct biophysical measurement of oligomerization, single lab, limited to domain behavior in isolation\",\n      \"pmids\": [\"39614773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTMR7 interacts with STIM1 at the endoplasmic reticulum as identified by yeast two-hybrid analysis and confirmed by co-immunoprecipitation and fluorescence microscopy, identifying MTMR7 as a novel STIM1-binding protein that connects phosphoinositide signaling with store-operated Ca2+ entry (SOCE).\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, fluorescence microscopy\",\n      \"journal\": \"Canadian journal of physiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by three orthogonal methods (Y2H, Co-IP, imaging), single lab\",\n      \"pmids\": [\"40327889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MTMR7 forms a complex with STIM1 and is positioned at ER-plasma membrane contact sites, where it alters local PI(3,5)P2 and PI(4,5)P2 levels to increase ORAI1 fast inactivation and decrease SOCE; loss of MTMR7 catalytic phosphatase activity weakens ORAI1 inactivation, while disruption of the MTMR7-STIM1 interaction retains ORAI1 inactivation independent of phosphatase activity.\",\n      \"method\": \"STIM1/MTMR7 complex analysis, phosphatase-dead MTMR7 mutant, MTMR7-STIM1 interaction disruption mutant, plasma membrane PIP level measurement (PI(3,5)P2 and PI(4,5)P2), electrophysiology/SOCE assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including active-site mutagenesis, protein interaction disruption mutant, lipid measurements, and SOCE functional assay in a single study\",\n      \"pmids\": [\"42004029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTMR7 regulates human spermatogonial stem cell (SSC) proliferation and migration; MTMR7 knockdown increased and overexpression inhibited these processes. Mass spectrometry and co-immunoprecipitation identified filamin B (FLNB) as an MTMR7-interacting protein. MTMR7 promotes FLNB ubiquitination and degradation, leading to reduced downstream β-catenin signaling.\",\n      \"method\": \"MTMR7 knockdown/overexpression in human SSCs, mass spectrometry, co-immunoprecipitation, ubiquitination assay, immunofluorescence, β-catenin signaling readouts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of interactor confirmed by Co-IP, functional ubiquitination assay and downstream signaling, single lab\",\n      \"pmids\": [\"40638605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTMR7 overexpression in pulmonary arterial smooth muscle cells (PASMCs) suppresses proliferation and migration by inhibiting ERK1/2 and STAT3 phosphorylation; epistasis experiments showed that restoring ERK1/2 also reversed MTMR7-mediated STAT3 dephosphorylation, placing ERK1/2 upstream of STAT3 in the MTMR7 pathway.\",\n      \"method\": \"Mtmr7-transgenic mice (MCT-induced PH model), adenoviral MTMR7 overexpression in PASMCs, ERK1/2 and STAT3 phosphorylation immunoblotting, genetic rescue with ERK1/2/STAT3 activators, proliferation and migration assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic plus in vitro mechanistic dissection with epistasis experiments, single lab\",\n      \"pmids\": [\"39918745\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTMR7 is a PI3P/PI(3,5)P2 lipid phosphatase that forms an activation complex with the catalytically inactive MTMR9 (via coiled-coil domain interaction), is recruited to ER-plasma membrane contact sites through direct STIM1 binding where it modulates local phosphoinositide levels to regulate ORAI1 inactivation and store-operated Ca2+ entry, and in the cytosol inhibits PI3K/AKT, ERK1/2, mTORC1, and STAT3 signaling to suppress cell proliferation, migration, and phenotypic switching across multiple cell types including neurons, T cells, smooth muscle cells, and spermatogonial stem cells; additionally, MTMR7 activates PPARγ and directly inhibits mutant K-RAS via its charged coiled-coil domain, and promotes FLNB ubiquitination/degradation to restrain β-catenin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTMR7 is a myotubularin-family 3-phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and the soluble inositol substrate Ins(1,3)P2, with a distinctive preference for the water-soluble substrate, and that broadly restrains proliferative and survival signaling by lowering cellular phosphoinositide levels [#0, #5]. Catalytic output is set by complex formation with the inactive paralog MTMR9: MTMR9 binds MTMR7 through coiled-coil/CC-domain interactions and enhances its phosphatase activity, and the reconstituted complex acts on both PI(3)P and PI(3,5)P2 [#2, #3, #11]. Through this lipid-phosphatase activity MTMR7 functions as a negative regulator of PI3K/AKT signaling in diverse cell types, suppressing AKT phosphorylation and proliferation in T cells, myoblasts, spermatogonial stem cells, and colorectal cancer cells, where it also dampens insulin-driven ERK1/2 signaling [#4, #5, #6, #7]. MTMR7 is recruited via direct STIM1 binding to ER–plasma membrane contact sites, where its catalytic activity alters local PI(3,5)P2 and PI(4,5)P2 to promote ORAI1 fast inactivation and limit store-operated Ca2+ entry [#12, #13]. Beyond its phosphatase function, MTMR7 acts through its charged coiled-coil domain to directly bind and inhibit K-RAS (including the G12V mutant), reducing RAS GTPase activity and downstream ERK1/2 signaling [#9], complexes with PPARγ to enhance its transcriptional activity by blocking ERK1/2-dependent PPARγ phosphorylation [#8], suppresses VSMC phenotypic switching via dephosphorylation and dissociation of p62 from mTORC1 [#10], inhibits PASMC proliferation through an ERK1/2→STAT3 axis [#15], and promotes FLNB ubiquitination and degradation to restrain β-catenin signaling in spermatogonial stem cells [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing MTMR7's enzymatic identity answered what biochemical reaction it catalyzes, defining it as a 3-phosphatase with an unusual preference for a soluble inositol substrate distinct from other MTM members.\",\n      \"evidence\": \"In vitro phosphatase assay with recombinant MTMR7 on PI3P and Ins(1,3)P2\",\n      \"pmids\": [\"12890864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of soluble Ins(1,3)P2 dephosphorylation versus lipid dephosphorylation in cells not resolved\", \"No structural basis for substrate preference\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying MTMR9 as a binding partner answered how MTMR7 catalytic activity is regulated, showing the inactive paralog acts as an activating subunit via its coiled-coil domain.\",\n      \"evidence\": \"Anti-MTMR7 Co-IP with mass-spec identification, domain mapping, and in vitro activity assay in N1E-115 cells\",\n      \"pmids\": [\"12890864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the complex not defined here\", \"How MTMR9 binding alters active-site chemistry unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconstituting the complex answered which lipid substrates MTMR7/MTMR9 acts on, extending activity to PI(3,5)P2 and confirming MTMR9 modulates both specificity and rate.\",\n      \"evidence\": \"In vitro phosphatase assays with recombinant complexes and cellular PIP measurement\",\n      \"pmids\": [\"22647598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative fold-changes focused on other MTMR/R9 pairs\", \"In vivo substrate prioritization unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss-of-function in T cells answered whether MTMR7 has a cellular signaling role, establishing it as a negative regulator of AKT controlling T-helper lineage decisions.\",\n      \"evidence\": \"shRNA knockdown with T-cell differentiation assay and phospho-AKT readout\",\n      \"pmids\": [\"23630283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between phosphatase activity and AKT suppression not isolated\", \"Single lab, no catalytic-dead rescue\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Knockdown across colorectal cancer cells, myoblasts, and stem cells answered whether AKT suppression is a general MTMR7 function, showing it restrains proliferation by lowering phosphoinositides in multiple lineages.\",\n      \"evidence\": \"Overexpression/knockdown in CRC and C2C12 cells with PIP quantification, AKT/ERK1/2 immunoblotting, and proliferation assays\",\n      \"pmids\": [\"27409167\", \"28153733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between specific lipid pools and each signaling output not dissected\", \"Differentiation effects mechanistically separate from proliferation effects unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo testis knockdown answered whether MTMR7 governs stem-cell homeostasis, showing it maintains spermatogonial stem cells by inhibiting PI3K/AKT.\",\n      \"evidence\": \"Morpholino knockdown in neonatal mouse testis and SSC culture with proliferation and PI3K/AKT analysis\",\n      \"pmids\": [\"31478454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphatase-dependence not tested by catalytic mutant\", \"Long-term spermatogenesis consequences not assessed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery of the PPARγ interaction answered whether MTMR7 has phosphatase-independent functions, revealing a CC-domain-dependent role enhancing PPARγ transcription by blocking ERK1/2-mediated phosphorylation.\",\n      \"evidence\": \"Co-IP, PPARγ reporter assays, CC peptide treatment in mice, and docking simulations\",\n      \"pmids\": [\"32522977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect effect on ERK1/2 not separated from lipid activity\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Direct K-RAS inhibition answered how MTMR7 suppresses oncogenic RAS signaling, defining the charged CC domain as a binding module that reduces RAS GTPase activity even for the G12V mutant.\",\n      \"evidence\": \"Co-IP, molecular modeling, RAS GTPase assays, ERK1/2 immunoblotting, and CC-peptide tumor models in mice\",\n      \"pmids\": [\"38462034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-resolution structure of the MTMR7-CC/K-RAS interface lacking\", \"Relationship between CC binding and lipid-phosphatase function unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"VSMC and CC-domain studies answered how MTMR7 controls cell phenotype beyond AKT, linking it to mTORC1 inhibition via p62 dephosphorylation and providing structural detail on CC oligomerization.\",\n      \"evidence\": \"Mtmr7-transgenic carotid injury model, mTORC1/p62 Co-IP and glycolysis assays with rescue; biophysical CC-domain oligomerization analysis\",\n      \"pmids\": [\"38342025\", \"39614773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p62 dephosphorylation is direct MTMR7 catalysis not shown\", \"CC oligomerization measured in isolation, not in full-length complex\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"STIM1 interaction and FLNB/STAT3 studies answered how MTMR7 is spatially targeted and what additional effectors it controls, placing it at the ER as a STIM1 partner and linking it to FLNB degradation/β-catenin and an ERK1/2→STAT3 axis.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP and imaging for STIM1; MS/Co-IP/ubiquitination for FLNB in human SSCs; transgenic PH model with epistasis for ERK1/2/STAT3 in PASMCs\",\n      \"pmids\": [\"40327889\", \"40638605\", \"39918745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of FLNB ubiquitination (E3 partner) unidentified\", \"How STIM1 recruitment integrates with cytosolic signaling roles unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Functional dissection at ER-PM contact sites answered how MTMR7 connects phosphoinositide turnover to calcium signaling, showing STIM1-anchored MTMR7 tunes local PI(3,5)P2/PI(4,5)P2 to promote ORAI1 inactivation and limit SOCE.\",\n      \"evidence\": \"Phosphatase-dead and STIM1-interaction-disruption mutants, PM lipid measurement, and electrophysiology/SOCE assays\",\n      \"pmids\": [\"42004029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of MTMR7 to physiological Ca2+ responses in tissue not established\", \"Interplay between STIM1-anchored and cytosolic MTMR7 pools unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether MTMR7's lipid-phosphatase activity and its phosphatase-independent CC-domain protein interactions (K-RAS, PPARγ, STIM1) operate as a single integrated mechanism or as separable functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of full-length MTMR7\", \"No genetic separation-of-function across all reported effectors in one system\", \"No Mendelian disease association established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 9, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 15]}\n    ],\n    \"complexes\": [\n      \"MTMR7/MTMR9 phosphatase complex\",\n      \"MTMR7-STIM1 complex\"\n    ],\n    \"partners\": [\n      \"MTMR9\",\n      \"STIM1\",\n      \"PPARG\",\n      \"KRAS\",\n      \"FLNB\",\n      \"ORAI1\",\n      \"SQSTM1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}