{"gene":"MTMR9","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2003,"finding":"MTMR9 was identified as a binding partner of MTMR7 by co-immunoprecipitation from neuroblastoma N1E-115 cells, with tandem mass spectrometry identification; the coiled-coil domain of MTMR9 was sufficient for binding to MTMR7, and the MTMR7/MTMR9 complex showed increased Ins(1,3)P2 phosphatase activity compared to MTMR7 alone.","method":"Co-immunoprecipitation, tandem mass spectrometry, domain mapping, in vitro phosphatase assay","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 with MS identification, domain-deletion mapping, and in vitro enzymatic assay in single study","pmids":["12890864"],"is_preprint":false},{"year":2006,"finding":"MTMR9 forms heteromeric complexes with MTMR8 (in addition to MTMR6 and MTMR7), as identified by directed two-hybrid screening and immunoprecipitation of epitope-tagged proteins; all previously described MTMR heteromers pair an active member with an inactive one.","method":"Yeast two-hybrid, co-immunoprecipitation of epitope-tagged proteins","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (Y2H + Co-IP), single lab, confirmed novel MTMR8–MTMR9 interaction","pmids":["16787938"],"is_preprint":false},{"year":2008,"finding":"MTMR9 forms a heteromer with catalytically active MTMR6 both in vitro and in cells; MTMR9 increases the 3-phosphatase activity of MTMR6 up to 6-fold, increases MTMR6 binding to phospholipids (without altering lipid-binding profile), stabilizes both proteins (likely by inhibiting degradation), and co-expression of MTMR6/MTMR9 decreases etoposide-induced apoptosis whereas RNAi knockdown of both increases cell death.","method":"Co-immunoprecipitation, in vitro binding, in vitro phosphatase assay with phospholipid liposomes, Western blot stability assay, RNAi knockdown, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (in vitro assay, Co-IP, RNAi + phenotype) in single study with rigorous controls","pmids":["19038970"],"is_preprint":false},{"year":2012,"finding":"MTMR9 dimerizes with MTMR6, MTMR7, and MTMR8, and complex formation determines enzymatic activity and substrate specificity: the MTMR6/MTMR9 complex prefers PtdIns(3,5)P2 (activity increased >30-fold) and increases cellular PtdIns(5)P levels, while the MTMR8/MTMR9 complex prefers PtdIns(3)P (activity increased ~4-fold) and reduces cellular PtdIns(3)P; the MTMR6/MTMR9 complex inhibits stress-induced apoptosis and the MTMR8/MTMR9 complex inhibits autophagy.","method":"In vitro phosphatase assays with defined lipid substrates, cellular phosphoinositide measurement, apoptosis assays, autophagy assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro enzymatic assays with substrate specificity measurements plus cellular functional readouts, replicated across multiple MTMR pairs","pmids":["22647598"],"is_preprint":false},{"year":2013,"finding":"Silencing MTMR9 by shRNA or siRNA in CD4 T cells results in enhanced Th1 differentiation and increased AKT phosphorylation in Th1 cells; reconstitution of irradiated mice with MTMR9 shRNA-transduced bone marrow elevated T-bet+ CD4 T cells in vivo, indicating MTMR9 suppresses Th1 differentiation possibly through regulation of PtdIns(3,4,5)P3 activity.","method":"shRNA/siRNA knockdown, flow cytometry for T-cell differentiation markers, intracellular AKT phosphorylation measurement, in vivo bone marrow reconstitution and adoptive transfer","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype (Th1 bias, AKT phosphorylation), validated in vitro and in vivo, single lab","pmids":["23630283"],"is_preprint":false},{"year":2019,"finding":"MTMR9 (catalytically inactive) localizes to the intermediate compartment and Golgi apparatus, recruits its active partners MTMR6 and MTMR8 to these locations, co-localizes with RAB1A and regulates RAB1A localization, and its loss compromises Golgi integrity, alters distribution of actin nucleation-promoting factor WHAMM, and decreases protein secretion rate; perturbation of MTMR9 levels reduces secretion of WNT3A.","method":"Immunofluorescence/subcellular localization, siRNA knockdown, overexpression, co-localization with RAB1A and WHAMM, secretion assay for WNT3A","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequences (Golgi integrity, RAB1A mislocalization, altered secretion), loss-of-function and gain-of-function, single lab","pmids":["31704058"],"is_preprint":false},{"year":2022,"finding":"Knockdown of MTMR9 did not significantly enhance neuronal degradation of TDP-43 (an autophagy substrate), in contrast to knockdown of MTMR5 or MTMR2, establishing MTMR9 as NOT a critical determinant of neuronal autophagy in this context.","method":"shRNA knockdown, optical pulse labeling to measure TDP-43 turnover in iPSC-derived neurons","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with live-cell pulse-labeling readout; negative finding for MTMR9 specifically, single lab","pmids":["35580604"],"is_preprint":false},{"year":2024,"finding":"The coiled-coil (CC) domain of MTMR9 forms trimers, while MTMR7-CC preferentially forms dimers; biophysical characterization demonstrates homo- and hetero-oligomerization capacity of the CC domains, with MTMR9-CC showing a preference for trimer formation.","method":"Biophysical methods (CC domain characterization), oligomerization assays","journal":"Proteins","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, biophysical characterization without full functional validation in cellular context; abstract does not detail specific biophysical method used","pmids":["39614773"],"is_preprint":false}],"current_model":"MTMR9 is a catalytically inactive myotubularin family member that functions as a regulatory subunit: it heterodimerizes with active phosphatases MTMR6, MTMR7, and MTMR8 via its coiled-coil domain, dramatically increasing their 3-phosphatase activity (up to >30-fold for MTMR6 toward PtdIns(3,5)P2) and shifting substrate specificity, while also stabilizing partner proteins; MTMR9 localizes to the intermediate compartment and Golgi apparatus where it recruits MTMR6/MTMR8, regulates RAB1A localization, maintains Golgi integrity, and controls protein secretion (including WNT3A); in immune cells, MTMR9 suppresses Th1 differentiation and AKT signaling, likely through modulation of phosphoinositide levels."},"narrative":{"mechanistic_narrative":"MTMR9 is a catalytically inactive member of the myotubularin family that functions as a regulatory subunit, partnering with active 3-phosphatases to control phosphoinositide metabolism and downstream cellular processes [PMID:22647598]. Through its coiled-coil domain it heterodimerizes with the active phosphatases MTMR6, MTMR7, and MTMR8, and these complexes dictate both catalytic output and substrate preference: the MTMR6/MTMR9 complex strongly prefers PtdIns(3,5)P2 with activity increased over 30-fold and raises cellular PtdIns(5)P, whereas the MTMR8/MTMR9 complex prefers PtdIns(3)P [PMID:12890864, PMID:22647598]. Beyond activating its partners, MTMR9 stabilizes them against degradation and enhances their association with phospholipid membranes [PMID:19038970]. Functionally, the MTMR6/MTMR9 complex inhibits stress-induced apoptosis while the MTMR8/MTMR9 complex inhibits autophagy [PMID:22647598]. MTMR9 localizes to the intermediate compartment and Golgi apparatus, where it recruits MTMR6 and MTMR8, regulates RAB1A localization, maintains Golgi integrity, and supports protein secretion including that of WNT3A [PMID:31704058]. In CD4 T cells MTMR9 suppresses Th1 differentiation and limits AKT phosphorylation, consistent with regulation of phosphoinositide signaling [PMID:23630283].","teleology":[{"year":2003,"claim":"Established that MTMR9 is a binding partner of an active myotubularin and that this physical association modulates enzymatic output, defining MTMR9 as a regulatory rather than catalytic protein.","evidence":"Co-immunoprecipitation with MS identification, domain mapping, and in vitro phosphatase assay in neuroblastoma cells","pmids":["12890864"],"confidence":"High","gaps":["Did not test other active MTMR partners","Cellular consequences of the activity increase not addressed","Structural basis of CC-mediated binding not resolved"]},{"year":2006,"claim":"Extended the partnership repertoire by showing MTMR9 pairs with MTMR8, supporting a general model in which inactive MTMRs heteromerize with active members.","evidence":"Directed yeast two-hybrid and co-immunoprecipitation of epitope-tagged proteins","pmids":["16787938"],"confidence":"Medium","gaps":["Functional output of the MTMR8-MTMR9 pair not measured here","No endogenous complex confirmation","Stoichiometry undefined"]},{"year":2008,"claim":"Demonstrated that MTMR9 both activates MTMR6's 3-phosphatase activity and stabilizes the partner proteins, linking the complex to cell survival.","evidence":"In vitro phosphatase assays with liposomes, Co-IP, protein stability Western blots, RNAi knockdown with apoptosis readout","pmids":["19038970"],"confidence":"High","gaps":["Mechanism of protein stabilization (degradation pathway) not identified","Substrate specificity not yet dissected"]},{"year":2012,"claim":"Resolved how complex composition determines substrate specificity and cellular function, showing distinct phosphoinositide preferences and divergent control of apoptosis versus autophagy.","evidence":"Reconstituted in vitro phosphatase assays with defined lipid substrates, cellular phosphoinositide measurement, apoptosis and autophagy assays","pmids":["22647598"],"confidence":"High","gaps":["In vivo relevance of each pair not established","Subcellular site of catalysis not defined here","Regulation of which partner MTMR9 selects unknown"]},{"year":2013,"claim":"Placed MTMR9 in an immune-regulatory context, showing it suppresses Th1 differentiation and AKT activation, implicating phosphoinositide control in T-cell fate.","evidence":"shRNA/siRNA knockdown in CD4 T cells, flow cytometry, AKT phosphorylation, in vivo bone marrow reconstitution","pmids":["23630283"],"confidence":"Medium","gaps":["Which MTMR partner mediates the T-cell effect not identified","Direct link to a specific phosphoinositide species not shown","Mechanism connecting MTMR9 to AKT not resolved"]},{"year":2019,"claim":"Defined a specific subcellular site and secretory function for MTMR9, showing it recruits active partners to the Golgi/intermediate compartment and regulates RAB1A and protein secretion.","evidence":"Immunofluorescence localization, siRNA knockdown and overexpression, co-localization with RAB1A and WHAMM, WNT3A secretion assay","pmids":["31704058"],"confidence":"Medium","gaps":["Phosphoinositide species driving Golgi/secretory effects not pinpointed","Mechanism of RAB1A regulation unresolved","Direct interaction with RAB1A versus indirect effect not distinguished"]},{"year":2022,"claim":"Distinguished MTMR9 from other MTMRs by showing it is not a critical determinant of neuronal autophagic clearance of TDP-43, refining the boundaries of its functional roles.","evidence":"shRNA knockdown with optical pulse labeling of TDP-43 turnover in iPSC-derived neurons","pmids":["35580604"],"confidence":"Medium","gaps":["Negative result limited to TDP-43 and this neuronal context","Does not exclude autophagy roles in other cell types"]},{"year":2024,"claim":"Began to define the structural basis of MTMR9 oligomerization, showing its coiled-coil domain favors trimer formation, hinting at a higher-order assembly capacity distinct from partner MTMRs.","evidence":"Biophysical characterization of isolated coiled-coil domains and oligomerization assays","pmids":["39614773"],"confidence":"Low","gaps":["Single-lab biophysical study without cellular validation","Functional consequence of trimerization for phosphatase complexes unknown","Full-length protein assembly not characterized"]},{"year":null,"claim":"How MTMR9's choice of partner, its trimerization tendency, and its Golgi localization are coordinated to direct specific phosphoinositide outputs in distinct tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a full MTMR9-partner complex","Determinants of partner selection in vivo unknown","Direct mechanistic link between phosphoinositide changes and Th1/AKT and secretion phenotypes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":["MTMR6/MTMR9 complex","MTMR7/MTMR9 complex","MTMR8/MTMR9 complex"],"partners":["MTMR6","MTMR7","MTMR8","RAB1A","WHAMM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QG7","full_name":"Myotubularin-related protein 9","aliases":["Inactive phosphatidylinositol 3-phosphatase 9"],"length_aa":549,"mass_kda":63.5,"function":"Acts as an adapter for myotubularin-related phosphatases (PubMed:19038970, PubMed:22647598). Increases lipid phosphatase MTMR6 catalytic activity, specifically towards phosphatidylinositol 3,5-bisphosphate and MTMR6 binding affinity for phosphorylated phosphatidylinositols (PubMed:19038970, PubMed:22647598). Positively regulates lipid phosphatase MTMR7 catalytic activity (By similarity). Increases MTMR8 catalytic activity towards phosphatidylinositol 3-phosphate (PubMed:22647598). The formation of the MTMR6-MTMR9 complex, stabilizes both MTMR6 and MTMR9 protein levels (PubMed:19038970). Stabilizes MTMR8 protein levels (PubMed:22647598). Plays a role in the late stages of macropinocytosis possibly by regulating MTMR6-mediated dephosphorylation of phosphatidylinositol 3-phosphate in membrane ruffles (PubMed:24591580). Negatively regulates autophagy, in part via its association with MTMR8 (PubMed:22647598). Negatively regulates DNA damage-induced apoptosis, in part via its association with MTMR6 (PubMed:19038970, PubMed:22647598). Does not bind mono-, di- and tri-phosphorylated phosphatidylinositols, phosphatidic acid and phosphatidylserine (PubMed:19038970)","subcellular_location":"Cytoplasm; Cell projection, ruffle membrane; Cytoplasm, perinuclear region; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q96QG7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTMR9","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTMR9","total_profiled":1310},"omim":[{"mim_id":"606641","title":"BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 1; BMIQ1","url":"https://www.omim.org/entry/606641"},{"mim_id":"606260","title":"MYOTUBULARIN-RELATED PROTEIN 9; MTMR9","url":"https://www.omim.org/entry/606260"},{"mim_id":"301061","title":"MYOTUBULARIN-RELATED PROTEIN 8; MTMR8","url":"https://www.omim.org/entry/301061"},{"mim_id":"300415","title":"MYOTUBULARIN; MTM1","url":"https://www.omim.org/entry/300415"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTMR9"},"hgnc":{"alias_symbol":["DKFZp434K171","LIP-STYX"],"prev_symbol":["C8orf9","MTMR8"]},"alphafold":{"accession":"Q96QG7","domains":[{"cath_id":"2.30.29.30","chopping":"3-102","consensus_level":"high","plddt":92.825,"start":3,"end":102},{"cath_id":"-","chopping":"187-502","consensus_level":"high","plddt":96.7399,"start":187,"end":502},{"cath_id":"1.20.5","chopping":"505-533","consensus_level":"medium","plddt":93.68,"start":505,"end":533}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QG7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QG7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QG7-F1-predicted_aligned_error_v6.png","plddt_mean":95.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTMR9","jax_strain_url":"https://www.jax.org/strain/search?query=MTMR9"},"sequence":{"accession":"Q96QG7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QG7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QG7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QG7"}},"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":"16787938","id":"PMC_16787938","title":"Systematic analysis of myotubularins: heteromeric interactions, subcellular localisation and endosome related functions.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16787938","citation_count":76,"is_preprint":false},{"pmid":"21796137","id":"PMC_21796137","title":"Association of variations in the FTO, SCG3 and MTMR9 genes with metabolic syndrome in a Japanese population.","date":"2011","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21796137","citation_count":62,"is_preprint":false},{"pmid":"22647598","id":"PMC_22647598","title":"Myotubularin-related protein (MTMR) 9 determines the 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the coiled-coil domain of MTMR9 was sufficient for binding to MTMR7, and the MTMR7/MTMR9 complex showed increased Ins(1,3)P2 phosphatase activity compared to MTMR7 alone.\",\n      \"method\": \"Co-immunoprecipitation, tandem mass spectrometry, domain mapping, in vitro phosphatase 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 / Moderate — reciprocal Co-IP with MS identification, domain-deletion mapping, and in vitro enzymatic assay in single study\",\n      \"pmids\": [\"12890864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MTMR9 forms heteromeric complexes with MTMR8 (in addition to MTMR6 and MTMR7), as identified by directed two-hybrid screening and immunoprecipitation of epitope-tagged proteins; all previously described MTMR heteromers pair an active member with an inactive one.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of epitope-tagged proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (Y2H + Co-IP), single lab, confirmed novel MTMR8–MTMR9 interaction\",\n      \"pmids\": [\"16787938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MTMR9 forms a heteromer with catalytically active MTMR6 both in vitro and in cells; MTMR9 increases the 3-phosphatase activity of MTMR6 up to 6-fold, increases MTMR6 binding to phospholipids (without altering lipid-binding profile), stabilizes both proteins (likely by inhibiting degradation), and co-expression of MTMR6/MTMR9 decreases etoposide-induced apoptosis whereas RNAi knockdown of both increases cell death.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding, in vitro phosphatase assay with phospholipid liposomes, Western blot stability assay, RNAi knockdown, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (in vitro assay, Co-IP, RNAi + phenotype) in single study with rigorous controls\",\n      \"pmids\": [\"19038970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MTMR9 dimerizes with MTMR6, MTMR7, and MTMR8, and complex formation determines enzymatic activity and substrate specificity: the MTMR6/MTMR9 complex prefers PtdIns(3,5)P2 (activity increased >30-fold) and increases cellular PtdIns(5)P levels, while the MTMR8/MTMR9 complex prefers PtdIns(3)P (activity increased ~4-fold) and reduces cellular PtdIns(3)P; the MTMR6/MTMR9 complex inhibits stress-induced apoptosis and the MTMR8/MTMR9 complex inhibits autophagy.\",\n      \"method\": \"In vitro phosphatase assays with defined lipid substrates, cellular phosphoinositide measurement, apoptosis assays, autophagy assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro enzymatic assays with substrate specificity measurements plus cellular functional readouts, replicated across multiple MTMR pairs\",\n      \"pmids\": [\"22647598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Silencing MTMR9 by shRNA or siRNA in CD4 T cells results in enhanced Th1 differentiation and increased AKT phosphorylation in Th1 cells; reconstitution of irradiated mice with MTMR9 shRNA-transduced bone marrow elevated T-bet+ CD4 T cells in vivo, indicating MTMR9 suppresses Th1 differentiation possibly through regulation of PtdIns(3,4,5)P3 activity.\",\n      \"method\": \"shRNA/siRNA knockdown, flow cytometry for T-cell differentiation markers, intracellular AKT phosphorylation measurement, in vivo bone marrow reconstitution and adoptive transfer\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype (Th1 bias, AKT phosphorylation), validated in vitro and in vivo, single lab\",\n      \"pmids\": [\"23630283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTMR9 (catalytically inactive) localizes to the intermediate compartment and Golgi apparatus, recruits its active partners MTMR6 and MTMR8 to these locations, co-localizes with RAB1A and regulates RAB1A localization, and its loss compromises Golgi integrity, alters distribution of actin nucleation-promoting factor WHAMM, and decreases protein secretion rate; perturbation of MTMR9 levels reduces secretion of WNT3A.\",\n      \"method\": \"Immunofluorescence/subcellular localization, siRNA knockdown, overexpression, co-localization with RAB1A and WHAMM, secretion assay for WNT3A\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequences (Golgi integrity, RAB1A mislocalization, altered secretion), loss-of-function and gain-of-function, single lab\",\n      \"pmids\": [\"31704058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of MTMR9 did not significantly enhance neuronal degradation of TDP-43 (an autophagy substrate), in contrast to knockdown of MTMR5 or MTMR2, establishing MTMR9 as NOT a critical determinant of neuronal autophagy in this context.\",\n      \"method\": \"shRNA knockdown, optical pulse labeling to measure TDP-43 turnover in iPSC-derived neurons\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with live-cell pulse-labeling readout; negative finding for MTMR9 specifically, single lab\",\n      \"pmids\": [\"35580604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The coiled-coil (CC) domain of MTMR9 forms trimers, while MTMR7-CC preferentially forms dimers; biophysical characterization demonstrates homo- and hetero-oligomerization capacity of the CC domains, with MTMR9-CC showing a preference for trimer formation.\",\n      \"method\": \"Biophysical methods (CC domain characterization), oligomerization assays\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, biophysical characterization without full functional validation in cellular context; abstract does not detail specific biophysical method used\",\n      \"pmids\": [\"39614773\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTMR9 is a catalytically inactive myotubularin family member that functions as a regulatory subunit: it heterodimerizes with active phosphatases MTMR6, MTMR7, and MTMR8 via its coiled-coil domain, dramatically increasing their 3-phosphatase activity (up to >30-fold for MTMR6 toward PtdIns(3,5)P2) and shifting substrate specificity, while also stabilizing partner proteins; MTMR9 localizes to the intermediate compartment and Golgi apparatus where it recruits MTMR6/MTMR8, regulates RAB1A localization, maintains Golgi integrity, and controls protein secretion (including WNT3A); in immune cells, MTMR9 suppresses Th1 differentiation and AKT signaling, likely through modulation of phosphoinositide levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTMR9 is a catalytically inactive member of the myotubularin family that functions as a regulatory subunit, partnering with active 3-phosphatases to control phosphoinositide metabolism and downstream cellular processes [#3]. Through its coiled-coil domain it heterodimerizes with the active phosphatases MTMR6, MTMR7, and MTMR8, and these complexes dictate both catalytic output and substrate preference: the MTMR6/MTMR9 complex strongly prefers PtdIns(3,5)P2 with activity increased over 30-fold and raises cellular PtdIns(5)P, whereas the MTMR8/MTMR9 complex prefers PtdIns(3)P [#0, #3]. Beyond activating its partners, MTMR9 stabilizes them against degradation and enhances their association with phospholipid membranes [#2]. Functionally, the MTMR6/MTMR9 complex inhibits stress-induced apoptosis while the MTMR8/MTMR9 complex inhibits autophagy [#3]. MTMR9 localizes to the intermediate compartment and Golgi apparatus, where it recruits MTMR6 and MTMR8, regulates RAB1A localization, maintains Golgi integrity, and supports protein secretion including that of WNT3A [#5]. In CD4 T cells MTMR9 suppresses Th1 differentiation and limits AKT phosphorylation, consistent with regulation of phosphoinositide signaling [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that MTMR9 is a binding partner of an active myotubularin and that this physical association modulates enzymatic output, defining MTMR9 as a regulatory rather than catalytic protein.\",\n      \"evidence\": \"Co-immunoprecipitation with MS identification, domain mapping, and in vitro phosphatase assay in neuroblastoma cells\",\n      \"pmids\": [\"12890864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test other active MTMR partners\", \"Cellular consequences of the activity increase not addressed\", \"Structural basis of CC-mediated binding not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended the partnership repertoire by showing MTMR9 pairs with MTMR8, supporting a general model in which inactive MTMRs heteromerize with active members.\",\n      \"evidence\": \"Directed yeast two-hybrid and co-immunoprecipitation of epitope-tagged proteins\",\n      \"pmids\": [\"16787938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of the MTMR8-MTMR9 pair not measured here\", \"No endogenous complex confirmation\", \"Stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that MTMR9 both activates MTMR6's 3-phosphatase activity and stabilizes the partner proteins, linking the complex to cell survival.\",\n      \"evidence\": \"In vitro phosphatase assays with liposomes, Co-IP, protein stability Western blots, RNAi knockdown with apoptosis readout\",\n      \"pmids\": [\"19038970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of protein stabilization (degradation pathway) not identified\", \"Substrate specificity not yet dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how complex composition determines substrate specificity and cellular function, showing distinct phosphoinositide preferences and divergent control of apoptosis versus autophagy.\",\n      \"evidence\": \"Reconstituted in vitro phosphatase assays with defined lipid substrates, cellular phosphoinositide measurement, apoptosis and autophagy assays\",\n      \"pmids\": [\"22647598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of each pair not established\", \"Subcellular site of catalysis not defined here\", \"Regulation of which partner MTMR9 selects unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed MTMR9 in an immune-regulatory context, showing it suppresses Th1 differentiation and AKT activation, implicating phosphoinositide control in T-cell fate.\",\n      \"evidence\": \"shRNA/siRNA knockdown in CD4 T cells, flow cytometry, AKT phosphorylation, in vivo bone marrow reconstitution\",\n      \"pmids\": [\"23630283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which MTMR partner mediates the T-cell effect not identified\", \"Direct link to a specific phosphoinositide species not shown\", \"Mechanism connecting MTMR9 to AKT not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a specific subcellular site and secretory function for MTMR9, showing it recruits active partners to the Golgi/intermediate compartment and regulates RAB1A and protein secretion.\",\n      \"evidence\": \"Immunofluorescence localization, siRNA knockdown and overexpression, co-localization with RAB1A and WHAMM, WNT3A secretion assay\",\n      \"pmids\": [\"31704058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphoinositide species driving Golgi/secretory effects not pinpointed\", \"Mechanism of RAB1A regulation unresolved\", \"Direct interaction with RAB1A versus indirect effect not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished MTMR9 from other MTMRs by showing it is not a critical determinant of neuronal autophagic clearance of TDP-43, refining the boundaries of its functional roles.\",\n      \"evidence\": \"shRNA knockdown with optical pulse labeling of TDP-43 turnover in iPSC-derived neurons\",\n      \"pmids\": [\"35580604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result limited to TDP-43 and this neuronal context\", \"Does not exclude autophagy roles in other cell types\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Began to define the structural basis of MTMR9 oligomerization, showing its coiled-coil domain favors trimer formation, hinting at a higher-order assembly capacity distinct from partner MTMRs.\",\n      \"evidence\": \"Biophysical characterization of isolated coiled-coil domains and oligomerization assays\",\n      \"pmids\": [\"39614773\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab biophysical study without cellular validation\", \"Functional consequence of trimerization for phosphatase complexes unknown\", \"Full-length protein assembly not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTMR9's choice of partner, its trimerization tendency, and its Golgi localization are coordinated to direct specific phosphoinositide outputs in distinct tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a full MTMR9-partner complex\", \"Determinants of partner selection in vivo unknown\", \"Direct mechanistic link between phosphoinositide changes and Th1/AKT and secretion phenotypes not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"MTMR6/MTMR9 complex\",\n      \"MTMR7/MTMR9 complex\",\n      \"MTMR8/MTMR9 complex\"\n    ],\n    \"partners\": [\n      \"MTMR6\",\n      \"MTMR7\",\n      \"MTMR8\",\n      \"RAB1A\",\n      \"WHAMM\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}