{"gene":"MTMR6","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2003,"finding":"MTMR6 dephosphorylates both PtdIns3P and PtdIns(3,5)P2 in vitro, and PtdIns5P (the product of PtdIns(3,5)P2 hydrolysis) functions as a specific allosteric activator of MTMR6 phosphatase activity.","method":"In vitro phosphatase assay with defined lipid substrates; allosteric activation measured biochemically","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with defined substrates and allosteric activator, replicated across multiple family members in same study","pmids":["12646134"],"is_preprint":false},{"year":2001,"finding":"MTMR6 dephosphorylates phosphatidylinositol 3-phosphate (PI(3)P), establishing PI(3)P as a substrate common to active myotubularin family members.","method":"In vitro lipid phosphatase assay with recombinant MTMR6","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay, independently replicated in multiple subsequent studies","pmids":["11733541"],"is_preprint":false},{"year":2005,"finding":"MTMR6 specifically interacts with the Ca2+-activated K+ channel KCa3.1 via coiled-coil (CC) domains on both proteins, and overexpression of MTMR6 inhibits KCa3.1 channel activity by dephosphorylating PI(3)P; both CC and phosphatase domains are required for inhibition. A chimeric MTM1 with MTMR6's CC domain acquired the ability to inhibit KCa3.1, showing CC domains confer target specificity.","method":"Co-immunoprecipitation, domain swap chimera experiments, patch-clamp electrophysiology, PI(3)P rescue experiments","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain chimera mutagenesis, electrophysiology, and lipid rescue, multiple orthogonal methods in one study","pmids":["15831468"],"is_preprint":false},{"year":2005,"finding":"PI(3)P indirectly activates KCa3.1; a stretch of 14 amino acids in the carboxy-terminal calmodulin binding domain of KCa3.1 is sufficient to confer PI(3)P-dependent regulation, and MTMR6-mediated inhibition of KCa3.1 is rescued by exogenous PI(3)P.","method":"Chimeric KCa3.1/KCa2.3 channel constructs, patch-clamp electrophysiology, lipid rescue experiments","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — chimeric channel mutagenesis combined with electrophysiology and lipid rescue in same study","pmids":["16251351"],"is_preprint":false},{"year":2006,"finding":"MTMR6 negatively regulates Ca2+ influx and proliferation of reactivated human CD4 T cells by inhibiting KCa3.1 channel activity in a PI(3)P-dependent manner.","method":"MTMR6 overexpression and knockdown in primary human CD4 T cells, Ca2+ flux measurements, cell proliferation assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined loss- and gain-of-function experiments in primary T cells with specific mechanistic readouts (Ca2+ influx, proliferation), single lab but multiple orthogonal assays","pmids":["16847315"],"is_preprint":false},{"year":2006,"finding":"Both the coiled-coil (CC) and PH/GRAM domains of MTMR6 are required together for co-localization with KCa3.1 at the plasma membrane and for inhibition of KCa3.1 activity; neither domain alone is sufficient.","method":"Domain chimera construction between MTM family members, immunofluorescence microscopy, KCa3.1 activity assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain swap chimera mutagenesis combined with immunofluorescence localization and functional channel activity assays, single lab, multiple orthogonal methods","pmids":["16914545"],"is_preprint":false},{"year":2008,"finding":"MTMR6 forms a heteromeric complex with the catalytically inactive MTMR9 both in vitro and in cells; MTMR9 increases MTMR6 phospholipid binding and 3-phosphatase activity up to 6-fold, stabilizes both proteins by inhibiting their degradation, and co-expression of MTMR6/MTMR9 decreases etoposide-induced apoptosis.","method":"Co-immunoprecipitation, in vitro binding assays, in vitro phosphatase assays with phosphatidylserine liposomes, RNAi knockdown, etoposide apoptosis assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of complex with enzymatic assay, Co-IP in cells, RNAi functional assay; single lab with multiple orthogonal methods","pmids":["19038970"],"is_preprint":false},{"year":2012,"finding":"MTMR9 dimerization shifts the substrate preference of MTMR6: the MTMR6/MTMR9 complex prefers PtdIns(3,5)P2 over PtdIns3P as substrate, with MTMR9 increasing MTMR6 activity toward PtdIns(3,5)P2 by over 30-fold and toward PtdIns3P by only 2-fold. In cells, the MTMR6/MTMR9 complex significantly increases cellular PtdIns5P levels and serves to inhibit stress-induced apoptosis.","method":"In vitro phosphatase assays with defined lipid substrates, cellular phosphoinositide measurements, apoptosis assays","journal":"Proceedings of the National Academy of Sciences USA","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with substrate specificity measurements plus cellular lipid level quantification and functional apoptosis assay, single lab, multiple orthogonal methods","pmids":["22647598"],"is_preprint":false},{"year":2012,"finding":"Endogenous MTMR6 localizes to the cytoplasm with perinuclear condensation in a microtubule-dependent manner. MTMR6 preferentially interacts with GDP-bound Rab1B via its GRAM domain, co-localizing with Rab1B in pericentrosomal/peri-Golgi regions. Rab1B overexpression (GDP-bound) or Rab1B depletion disrupts MTMR6 localization. MTMR6 knockdown accelerates vesicular stomatitis virus glycoprotein transport and inhibits tubular omegasome formation in autophagy.","method":"Monoclonal antibody-based immunofluorescence, co-immunoprecipitation (GRAM domain–Rab1B), microtubule disruption, siRNA knockdown, VSV-G transport assay, DFCP1-overexpression omegasome assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain specificity, direct localization by immunofluorescence with functional disruption experiments, multiple orthogonal methods in one study","pmids":["23188820"],"is_preprint":false},{"year":2019,"finding":"MTMR9 recruits its active phosphatase partner MTMR6 to the intermediate compartment and Golgi apparatus, indicating MTMR9 determines the subcellular localization of MTMR6.","method":"Co-localization by immunofluorescence microscopy, co-expression experiments in cells","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization by fluorescence microscopy with co-expression, no in vitro reconstitution; finding consistent with prior GRAM-domain/Rab1B localization data","pmids":["31704058"],"is_preprint":false},{"year":2020,"finding":"The Drosophila ortholog of MTMR6 (dMtmr6/CG3530) is required for maintenance of autophagic flux in multiple cell types; loss of dMtmr6 leads to autophagic vesicle accumulation and disrupts endolysosomal homeostasis.","method":"Drosophila genetic screen for phosphoinositide phosphatases affecting autophagy; autophagic flux assays in multiple cell types","journal":"The Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in Drosophila with defined autophagic flux phenotype; ortholog study supporting mammalian function","pmids":["32915229"],"is_preprint":false},{"year":2021,"finding":"Drosophila Mtmr6 (ortholog of mammalian MTMR6–MTMR8) promotes autophagy under nutrient-rich conditions but blocks hyperactivation of autophagy under stress, demonstrating a dual, condition-dependent role in autophagy regulation.","method":"Drosophila genetic loss-of-function (RNAi/mutants), autophagic flux assays (LysoTracker, ref(2)P, TEM) under basal and stress conditions","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in Drosophila with multiple autophagic readouts under defined conditions; ortholog with consistent domain architecture","pmids":["33779490"],"is_preprint":false},{"year":2024,"finding":"Virulent L. donovani infection upregulates MTMR6 expression in macrophages via TLR2 signaling (Pam3CSK4 enhanced MTMR6 expression; TLR2 blockade reduced it). MTMR6 silencing reduced amastigote burden and IL-10, and increased IL-12 and IFN-γ in macrophage-T cell co-cultures.","method":"siRNA phosphatase library screen, TLR2 agonist/antagonist experiments, lentiviral shRNA knockdown, cytokine measurements, parasite load quantification","journal":"International Immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide siRNA screen identified MTMR6, confirmed by TLR2 manipulation and lentiviral knockdown with specific functional readouts; single lab","pmids":["38330797"],"is_preprint":false},{"year":2024,"finding":"MTMR6 silencing in BALB/c mice (via lentiviral MTMR6shRNA) reduced Leishmania donovani infection and restored IFN-γ expression, establishing an in vivo role for MTMR6 in suppressing anti-leishmanial immunity.","method":"Lentiviral shRNA knockdown in BALB/c mice, parasite burden quantification, IFN-γ measurement, challenge infection model","journal":"International Immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo lentiviral loss-of-function with defined immune and parasitological readouts; single lab","pmids":["38295542"],"is_preprint":false},{"year":2014,"finding":"miR-190b directly targets MTMR6 mRNA (confirmed by luciferase reporter assay); during SIV infection, miR-190b is upregulated in macrophages in response to viral replication, leading to decreased MTMR6 expression.","method":"Luciferase reporter assay, in vitro SIV infection of CD4+ T cells and primary intestinal macrophages, miRNA expression profiling","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — luciferase reporter confirms direct miR-190b targeting of MTMR6 3'UTR; in vitro infection establishes context; single lab","pmids":["24981450"],"is_preprint":false},{"year":2025,"finding":"MTMR6 knockdown alleviates MEHP-induced defects in endometrial stromal cell decidualization. Molecular docking suggests the active-site residue ALA-131 of Mtmr6 may be a direct binding site for MEHP.","method":"SiRNA knockdown of Mtmr6 in endometrial stromal cells, decidualization marker assays, proteomics, molecular docking","journal":"Reproductive Toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with phenotypic readout in one study; molecular docking is computational; no in vitro enzymatic or structural validation of the binding site","pmids":["40541746"],"is_preprint":false},{"year":2019,"finding":"miR-506-3p directly targets MTMR6 mRNA (confirmed by luciferase reporter assay); knockdown of MTMR6 in ovarian cancer cells inhibits proliferation and induces G0/G1 arrest and apoptosis, mimicking miR-506-3p overexpression.","method":"Luciferase reporter assay, siRNA knockdown, MTT and colony formation assays, flow cytometry cell cycle/apoptosis analysis","journal":"Journal of Biosciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — luciferase reporter confirms direct miRNA targeting, loss-of-function with multiple cellular phenotype readouts; single lab","pmids":["31894107"],"is_preprint":false},{"year":2025,"finding":"hsa-miR-544a directly targets MTMR6 (confirmed by luciferase assay) and suppresses its expression, thereby enhancing cisplatin resistance in oral squamous cell carcinoma cells. MTMR6 knockdown increases cisplatin resistance in vitro and in mouse xenografts.","method":"Luciferase reporter assay, antagomir and miRNA mimic assays, MTMR6 gain/loss-of-function experiments, mouse xenograft in vivo model","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter, gain/loss-of-function, and in vivo xenograft with cisplatin resistance as readout; single lab, multiple methods","pmids":["39891222"],"is_preprint":false}],"current_model":"MTMR6 is a PI(3)P and PtdIns(3,5)P2 3-phosphatase that is allosterically activated by PtdIns5P; it specifically inhibits the KCa3.1 K+ channel by depleting local PI(3)P pools, requiring both its coiled-coil and PH/GRAM domains for co-localization and inhibition; it forms a heteromeric complex with the catalytically inactive MTMR9, which dramatically increases its activity and shifts its substrate preference toward PtdIns(3,5)P2, stabilizes both proteins, and amplifies the complex's role in inhibiting stress-induced apoptosis; MTMR6 localizes to the perinuclear/peri-Golgi region in a microtubule-dependent manner, regulated by interaction with GDP-bound Rab1B via its GRAM domain, and participates in the early secretory pathway and autophagic flux; through KCa3.1 inhibition and PI(3)P depletion, MTMR6 acts as a negative regulator of Ca2+ influx and proliferation in CD4 T cells and suppresses anti-leishmanial immunity via TLR2-dependent upregulation in macrophages."},"narrative":{"mechanistic_narrative":"MTMR6 is a myotubularin-family phosphoinositide 3-phosphatase that dephosphorylates PtdIns3P and PtdIns(3,5)P2, with PtdIns5P serving as a specific allosteric activator of its catalytic activity [PMID:12646134, PMID:11733541]. A defining function is its specific inhibition of the Ca2+-activated K+ channel KCa3.1: MTMR6 binds KCa3.1 through reciprocal coiled-coil interactions and suppresses channel activity by depleting local PI(3)P, which the channel requires for activation; both the coiled-coil and PH/GRAM domains are needed for plasma-membrane co-localization and inhibition, and the coiled-coil confers target specificity [PMID:15831468, PMID:16251351, PMID:16914545]. Through this KCa3.1/PI(3)P axis MTMR6 acts as a negative regulator of Ca2+ influx and proliferation in reactivated CD4 T cells [PMID:16847315]. MTMR6 forms a heteromeric complex with the catalytically inactive MTMR9, which increases its lipid binding and 3-phosphatase activity, stabilizes both proteins, and shifts substrate preference strongly toward PtdIns(3,5)P2, raising cellular PtdIns5P and inhibiting stress-induced apoptosis [PMID:19038970, PMID:22647598]. Its subcellular distribution is governed by microtubule-dependent perinuclear/peri-Golgi targeting through GRAM-domain interaction with GDP-bound Rab1B and through recruitment by MTMR9, linking it to early secretory transport and autophagic flux [PMID:23188820, PMID:31704058]. Consistent ortholog studies show a conserved requirement in autophagy regulation [PMID:32915229, PMID:33779490]. In macrophages, TLR2-driven upregulation of MTMR6 during Leishmania donovani infection suppresses anti-leishmanial immunity, with silencing reducing parasite burden and restoring protective cytokines in vivo [PMID:38330797, PMID:38295542].","teleology":[{"year":2001,"claim":"Established the core enzymatic identity of MTMR6 by showing it dephosphorylates PI(3)P, placing it among catalytically active myotubularin-family lipid phosphatases.","evidence":"In vitro lipid phosphatase assay with recombinant MTMR6","pmids":["11733541"],"confidence":"High","gaps":["Did not define cellular substrate pools or in vivo targets","No structural basis for substrate recognition"]},{"year":2003,"claim":"Expanded the substrate range to PtdIns(3,5)P2 and identified PtdIns5P as a specific allosteric activator, revealing built-in regulatory feedback in MTMR6 catalysis.","evidence":"In vitro phosphatase assays with defined lipid substrates and allosteric activation measurement","pmids":["12646134"],"confidence":"High","gaps":["Allosteric activation not mapped to a structural site","Physiological relevance of PtdIns5P feedback in cells untested here"]},{"year":2005,"claim":"Connected MTMR6 lipid phosphatase activity to a discrete physiological target by showing it binds and inhibits KCa3.1 via coiled-coil interactions and PI(3)P depletion, with the coiled-coil conferring specificity.","evidence":"Co-IP, domain-swap chimeras, patch-clamp electrophysiology, PI(3)P rescue; plus chimeric channel mapping of PI(3)P regulation","pmids":["15831468","16251351"],"confidence":"High","gaps":["Did not establish endogenous physiological context for KCa3.1 regulation","Spatial coupling of phosphatase to channel not fully resolved"]},{"year":2006,"claim":"Defined the domain requirements (coiled-coil plus PH/GRAM together) for membrane targeting and showed the inhibitory axis controls Ca2+ influx and proliferation in primary CD4 T cells, giving the activity an immunological role.","evidence":"Domain chimeras with immunofluorescence and channel assays; gain/loss-of-function in primary human CD4 T cells with Ca2+ flux and proliferation readouts","pmids":["16914545","16847315"],"confidence":"High","gaps":["In vivo T-cell phenotype not tested","How the two domains cooperate mechanistically unresolved"]},{"year":2008,"claim":"Identified MTMR9 as a heteromeric partner that activates and stabilizes MTMR6 and links the complex to apoptosis suppression, showing MTMR6 functions within a regulated phosphatase complex.","evidence":"Co-IP, in vitro binding and phosphatase assays with liposomes, RNAi, etoposide apoptosis assay","pmids":["19038970"],"confidence":"High","gaps":["Structural basis of activation by inactive MTMR9 unknown","Direct lipid target of the apoptosis-relevant activity not pinpointed here"]},{"year":2012,"claim":"Resolved how MTMR9 reshapes MTMR6 output, showing the complex shifts strongly toward PtdIns(3,5)P2, raises cellular PtdIns5P, and inhibits stress-induced apoptosis.","evidence":"In vitro substrate-specificity phosphatase assays, cellular phosphoinositide quantification, apoptosis assays","pmids":["22647598"],"confidence":"High","gaps":["Subcellular site of the substrate switch not localized","Downstream apoptotic effectors of PtdIns5P unidentified"]},{"year":2012,"claim":"Located MTMR6 to perinuclear/peri-Golgi membranes via microtubule-dependent, GRAM-domain–mediated binding to GDP-bound Rab1B, and tied it to secretory transport and autophagic omegasome formation.","evidence":"Immunofluorescence, GRAM-domain Rab1B Co-IP, microtubule disruption, siRNA, VSV-G transport and omegasome assays","pmids":["23188820"],"confidence":"High","gaps":["Lipid substrate consumed at this location not directly measured","Mechanistic link between Rab1B targeting and autophagy unresolved"]},{"year":2019,"claim":"Showed MTMR9 directs MTMR6 to the intermediate compartment and Golgi, indicating partner-driven control of MTMR6 localization complements its Rab1B-dependent targeting.","evidence":"Co-localization immunofluorescence with co-expression in cells","pmids":["31704058"],"confidence":"Medium","gaps":["No in vitro reconstitution of the recruitment","Functional consequence of relocalization not assayed"]},{"year":2021,"claim":"Ortholog genetics established a conserved, condition-dependent role in autophagy, with MTMR6 promoting autophagy under nutrient-rich conditions and restraining hyperactivation under stress while maintaining endolysosomal homeostasis.","evidence":"Drosophila genetic loss-of-function with autophagic flux and endolysosomal readouts under basal and stress conditions","pmids":["32915229","33779490"],"confidence":"Medium","gaps":["Mammalian MTMR6 autophagy role not directly demonstrated in these studies","Substrate pool driving the dual phenotype not defined"]},{"year":2024,"claim":"Assigned an in vivo immunoregulatory function: TLR2-driven MTMR6 upregulation suppresses anti-leishmanial immunity, and silencing reduces parasite burden and restores protective cytokines.","evidence":"siRNA phosphatase screen, TLR2 agonist/antagonist, lentiviral shRNA in macrophages and BALB/c mice, cytokine and parasite-load readouts","pmids":["38330797","38295542"],"confidence":"Medium","gaps":["Whether the immunosuppressive effect requires KCa3.1/PI(3)P axis untested","Macrophage-intrinsic signaling downstream of MTMR6 not mapped"]},{"year":2025,"claim":"Multiple miRNA studies position MTMR6 as a regulated node whose loss alters proliferation, apoptosis, and drug response, but the mechanistic basis linking these phenotypes to its phosphatase activity is unresolved.","evidence":"Luciferase reporter validation of miR-190b, miR-506-3p, and miR-544a targeting; knockdown phenotypes in T cells/macrophages, ovarian cancer, and oral squamous carcinoma including xenografts","pmids":["24981450","31894107","39891222"],"confidence":"Medium","gaps":["Phenotypes not mechanistically connected to lipid-phosphatase function","Context-specific direct targets of MTMR6 in cancer cells unknown"]},{"year":null,"claim":"How MTMR6's biochemical activities (KCa3.1 inhibition, PtdIns(3,5)P2/PtdIns5P metabolism, secretory and autophagic regulation) are mechanistically unified to drive its disparate physiological roles in immunity, apoptosis, and proliferation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of MTMR6 or the MTMR6/MTMR9 complex","No demonstration that immune and cancer phenotypes depend on a specific lipid substrate at a defined membrane"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,6,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[8,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,10,11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,12,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7]}],"complexes":["MTMR6/MTMR9 heteromeric phosphatase complex"],"partners":["MTMR9","KCNN4","RAB1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y217","full_name":"Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR6","aliases":["Myotubularin-related protein 6","Phosphatidylinositol-3-phosphate phosphatase"],"length_aa":621,"mass_kda":72.0,"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:19038970, PubMed:22647598). Binds with high affinity to phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) but also to phosphatidylinositol 3-phosphate (PtdIns(3)P), phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 5-phosphate (PtdIns(5)P), phosphatidic acid and phosphatidylserine (PubMed:19038970). Negatively regulates ER-Golgi protein transport (By similarity). Probably in association with MTMR9, plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3-phosphate in membrane ruffles (PubMed:24591580). Acts as a negative regulator of KCNN4/KCa3.1 channel activity in CD4(+) T-cells possibly by decreasing intracellular levels of phosphatidylinositol 3-phosphate (PubMed:15831468). Negatively regulates proliferation of reactivated CD4(+) T-cells (PubMed:16847315). In complex with MTMR9, negatively regulates DNA damage-induced apoptosis (PubMed:19038970, PubMed:22647598). The formation of the MTMR6-MTMR9 complex stabilizes both MTMR6 and MTMR9 protein levels (PubMed:19038970)","subcellular_location":"Cytoplasm; Endoplasmic reticulum-Golgi intermediate compartment; Endoplasmic reticulum; Cell projection, ruffle membrane; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q9Y217/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTMR6","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":1208,"dependency_fraction":0.04718543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTMR6","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":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTMR6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y217","domains":[{"cath_id":"2.30.29.30","chopping":"7-100","consensus_level":"high","plddt":93.8041,"start":7,"end":100},{"cath_id":"-","chopping":"134-511","consensus_level":"medium","plddt":95.8501,"start":134,"end":511}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y217","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y217-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y217-F1-predicted_aligned_error_v6.png","plddt_mean":87.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTMR6","jax_strain_url":"https://www.jax.org/strain/search?query=MTMR6"},"sequence":{"accession":"Q9Y217","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y217.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y217/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y217"}},"corpus_meta":[{"pmid":"12646134","id":"PMC_12646134","title":"Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12646134","citation_count":150,"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":"15831468","id":"PMC_15831468","title":"The phosphatidylinositol 3-phosphate phosphatase myotubularin- related protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+ channel KCa3.1.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15831468","citation_count":87,"is_preprint":false},{"pmid":"12586635","id":"PMC_12586635","title":"The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12586635","citation_count":74,"is_preprint":false},{"pmid":"16251351","id":"PMC_16251351","title":"Phosphatidylinositol 3-phosphate indirectly activates KCa3.1 via 14 amino acids in the carboxy terminus of KCa3.1.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16251351","citation_count":62,"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":"16847315","id":"PMC_16847315","title":"Phosphatidylinositol-3 phosphatase myotubularin-related protein 6 negatively regulates CD4 T cells.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16847315","citation_count":47,"is_preprint":false},{"pmid":"19038970","id":"PMC_19038970","title":"MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19038970","citation_count":46,"is_preprint":false},{"pmid":"23188820","id":"PMC_23188820","title":"Phosphatidylinositol 3-phosphatase myotubularin-related protein 6 (MTMR6) is regulated by small GTPase Rab1B in the early secretory and autophagic pathways.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23188820","citation_count":42,"is_preprint":false},{"pmid":"32907841","id":"PMC_32907841","title":"A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Genes for Pancreatic Cancer Risk.","date":"2020","source":"Cancer 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A chimeric MTM1 with MTMR6's CC domain acquired the ability to inhibit KCa3.1, showing CC domains confer target specificity.\",\n      \"method\": \"Co-immunoprecipitation, domain swap chimera experiments, patch-clamp electrophysiology, PI(3)P rescue experiments\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain chimera mutagenesis, electrophysiology, and lipid rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15831468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PI(3)P indirectly activates KCa3.1; a stretch of 14 amino acids in the carboxy-terminal calmodulin binding domain of KCa3.1 is sufficient to confer PI(3)P-dependent regulation, and MTMR6-mediated inhibition of KCa3.1 is rescued by exogenous PI(3)P.\",\n      \"method\": \"Chimeric KCa3.1/KCa2.3 channel constructs, patch-clamp electrophysiology, lipid rescue experiments\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — chimeric channel mutagenesis combined with electrophysiology and lipid rescue in same study\",\n      \"pmids\": [\"16251351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MTMR6 negatively regulates Ca2+ influx and proliferation of reactivated human CD4 T cells by inhibiting KCa3.1 channel activity in a PI(3)P-dependent manner.\",\n      \"method\": \"MTMR6 overexpression and knockdown in primary human CD4 T cells, Ca2+ flux measurements, cell proliferation assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss- and gain-of-function experiments in primary T cells with specific mechanistic readouts (Ca2+ influx, proliferation), single lab but multiple orthogonal assays\",\n      \"pmids\": [\"16847315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Both the coiled-coil (CC) and PH/GRAM domains of MTMR6 are required together for co-localization with KCa3.1 at the plasma membrane and for inhibition of KCa3.1 activity; neither domain alone is sufficient.\",\n      \"method\": \"Domain chimera construction between MTM family members, immunofluorescence microscopy, KCa3.1 activity assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain swap chimera mutagenesis combined with immunofluorescence localization and functional channel activity assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16914545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MTMR6 forms a heteromeric complex with the catalytically inactive MTMR9 both in vitro and in cells; MTMR9 increases MTMR6 phospholipid binding and 3-phosphatase activity up to 6-fold, stabilizes both proteins by inhibiting their degradation, and co-expression of MTMR6/MTMR9 decreases etoposide-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, in vitro phosphatase assays with phosphatidylserine liposomes, RNAi knockdown, etoposide apoptosis assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of complex with enzymatic assay, Co-IP in cells, RNAi functional assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19038970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MTMR9 dimerization shifts the substrate preference of MTMR6: the MTMR6/MTMR9 complex prefers PtdIns(3,5)P2 over PtdIns3P as substrate, with MTMR9 increasing MTMR6 activity toward PtdIns(3,5)P2 by over 30-fold and toward PtdIns3P by only 2-fold. In cells, the MTMR6/MTMR9 complex significantly increases cellular PtdIns5P levels and serves to inhibit stress-induced apoptosis.\",\n      \"method\": \"In vitro phosphatase assays with defined lipid substrates, cellular phosphoinositide measurements, apoptosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences USA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with substrate specificity measurements plus cellular lipid level quantification and functional apoptosis assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22647598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Endogenous MTMR6 localizes to the cytoplasm with perinuclear condensation in a microtubule-dependent manner. MTMR6 preferentially interacts with GDP-bound Rab1B via its GRAM domain, co-localizing with Rab1B in pericentrosomal/peri-Golgi regions. Rab1B overexpression (GDP-bound) or Rab1B depletion disrupts MTMR6 localization. MTMR6 knockdown accelerates vesicular stomatitis virus glycoprotein transport and inhibits tubular omegasome formation in autophagy.\",\n      \"method\": \"Monoclonal antibody-based immunofluorescence, co-immunoprecipitation (GRAM domain–Rab1B), microtubule disruption, siRNA knockdown, VSV-G transport assay, DFCP1-overexpression omegasome assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain specificity, direct localization by immunofluorescence with functional disruption experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23188820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTMR9 recruits its active phosphatase partner MTMR6 to the intermediate compartment and Golgi apparatus, indicating MTMR9 determines the subcellular localization of MTMR6.\",\n      \"method\": \"Co-localization by immunofluorescence microscopy, co-expression experiments in cells\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization by fluorescence microscopy with co-expression, no in vitro reconstitution; finding consistent with prior GRAM-domain/Rab1B localization data\",\n      \"pmids\": [\"31704058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The Drosophila ortholog of MTMR6 (dMtmr6/CG3530) is required for maintenance of autophagic flux in multiple cell types; loss of dMtmr6 leads to autophagic vesicle accumulation and disrupts endolysosomal homeostasis.\",\n      \"method\": \"Drosophila genetic screen for phosphoinositide phosphatases affecting autophagy; autophagic flux assays in multiple cell types\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in Drosophila with defined autophagic flux phenotype; ortholog study supporting mammalian function\",\n      \"pmids\": [\"32915229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Drosophila Mtmr6 (ortholog of mammalian MTMR6–MTMR8) promotes autophagy under nutrient-rich conditions but blocks hyperactivation of autophagy under stress, demonstrating a dual, condition-dependent role in autophagy regulation.\",\n      \"method\": \"Drosophila genetic loss-of-function (RNAi/mutants), autophagic flux assays (LysoTracker, ref(2)P, TEM) under basal and stress conditions\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in Drosophila with multiple autophagic readouts under defined conditions; ortholog with consistent domain architecture\",\n      \"pmids\": [\"33779490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Virulent L. donovani infection upregulates MTMR6 expression in macrophages via TLR2 signaling (Pam3CSK4 enhanced MTMR6 expression; TLR2 blockade reduced it). MTMR6 silencing reduced amastigote burden and IL-10, and increased IL-12 and IFN-γ in macrophage-T cell co-cultures.\",\n      \"method\": \"siRNA phosphatase library screen, TLR2 agonist/antagonist experiments, lentiviral shRNA knockdown, cytokine measurements, parasite load quantification\",\n      \"journal\": \"International Immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide siRNA screen identified MTMR6, confirmed by TLR2 manipulation and lentiviral knockdown with specific functional readouts; single lab\",\n      \"pmids\": [\"38330797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MTMR6 silencing in BALB/c mice (via lentiviral MTMR6shRNA) reduced Leishmania donovani infection and restored IFN-γ expression, establishing an in vivo role for MTMR6 in suppressing anti-leishmanial immunity.\",\n      \"method\": \"Lentiviral shRNA knockdown in BALB/c mice, parasite burden quantification, IFN-γ measurement, challenge infection model\",\n      \"journal\": \"International Immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo lentiviral loss-of-function with defined immune and parasitological readouts; single lab\",\n      \"pmids\": [\"38295542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-190b directly targets MTMR6 mRNA (confirmed by luciferase reporter assay); during SIV infection, miR-190b is upregulated in macrophages in response to viral replication, leading to decreased MTMR6 expression.\",\n      \"method\": \"Luciferase reporter assay, in vitro SIV infection of CD4+ T cells and primary intestinal macrophages, miRNA expression profiling\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — luciferase reporter confirms direct miR-190b targeting of MTMR6 3'UTR; in vitro infection establishes context; single lab\",\n      \"pmids\": [\"24981450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTMR6 knockdown alleviates MEHP-induced defects in endometrial stromal cell decidualization. Molecular docking suggests the active-site residue ALA-131 of Mtmr6 may be a direct binding site for MEHP.\",\n      \"method\": \"SiRNA knockdown of Mtmr6 in endometrial stromal cells, decidualization marker assays, proteomics, molecular docking\",\n      \"journal\": \"Reproductive Toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with phenotypic readout in one study; molecular docking is computational; no in vitro enzymatic or structural validation of the binding site\",\n      \"pmids\": [\"40541746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-506-3p directly targets MTMR6 mRNA (confirmed by luciferase reporter assay); knockdown of MTMR6 in ovarian cancer cells inhibits proliferation and induces G0/G1 arrest and apoptosis, mimicking miR-506-3p overexpression.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown, MTT and colony formation assays, flow cytometry cell cycle/apoptosis analysis\",\n      \"journal\": \"Journal of Biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — luciferase reporter confirms direct miRNA targeting, loss-of-function with multiple cellular phenotype readouts; single lab\",\n      \"pmids\": [\"31894107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hsa-miR-544a directly targets MTMR6 (confirmed by luciferase assay) and suppresses its expression, thereby enhancing cisplatin resistance in oral squamous cell carcinoma cells. MTMR6 knockdown increases cisplatin resistance in vitro and in mouse xenografts.\",\n      \"method\": \"Luciferase reporter assay, antagomir and miRNA mimic assays, MTMR6 gain/loss-of-function experiments, mouse xenograft in vivo model\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter, gain/loss-of-function, and in vivo xenograft with cisplatin resistance as readout; single lab, multiple methods\",\n      \"pmids\": [\"39891222\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTMR6 is a PI(3)P and PtdIns(3,5)P2 3-phosphatase that is allosterically activated by PtdIns5P; it specifically inhibits the KCa3.1 K+ channel by depleting local PI(3)P pools, requiring both its coiled-coil and PH/GRAM domains for co-localization and inhibition; it forms a heteromeric complex with the catalytically inactive MTMR9, which dramatically increases its activity and shifts its substrate preference toward PtdIns(3,5)P2, stabilizes both proteins, and amplifies the complex's role in inhibiting stress-induced apoptosis; MTMR6 localizes to the perinuclear/peri-Golgi region in a microtubule-dependent manner, regulated by interaction with GDP-bound Rab1B via its GRAM domain, and participates in the early secretory pathway and autophagic flux; through KCa3.1 inhibition and PI(3)P depletion, MTMR6 acts as a negative regulator of Ca2+ influx and proliferation in CD4 T cells and suppresses anti-leishmanial immunity via TLR2-dependent upregulation in macrophages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTMR6 is a myotubularin-family phosphoinositide 3-phosphatase that dephosphorylates PtdIns3P and PtdIns(3,5)P2, with PtdIns5P serving as a specific allosteric activator of its catalytic activity [#0, #1]. A defining function is its specific inhibition of the Ca2+-activated K+ channel KCa3.1: MTMR6 binds KCa3.1 through reciprocal coiled-coil interactions and suppresses channel activity by depleting local PI(3)P, which the channel requires for activation; both the coiled-coil and PH/GRAM domains are needed for plasma-membrane co-localization and inhibition, and the coiled-coil confers target specificity [#2, #3, #5]. Through this KCa3.1/PI(3)P axis MTMR6 acts as a negative regulator of Ca2+ influx and proliferation in reactivated CD4 T cells [#4]. MTMR6 forms a heteromeric complex with the catalytically inactive MTMR9, which increases its lipid binding and 3-phosphatase activity, stabilizes both proteins, and shifts substrate preference strongly toward PtdIns(3,5)P2, raising cellular PtdIns5P and inhibiting stress-induced apoptosis [#6, #7]. Its subcellular distribution is governed by microtubule-dependent perinuclear/peri-Golgi targeting through GRAM-domain interaction with GDP-bound Rab1B and through recruitment by MTMR9, linking it to early secretory transport and autophagic flux [#8, #9]. Consistent ortholog studies show a conserved requirement in autophagy regulation [#10, #11]. In macrophages, TLR2-driven upregulation of MTMR6 during Leishmania donovani infection suppresses anti-leishmanial immunity, with silencing reducing parasite burden and restoring protective cytokines in vivo [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the core enzymatic identity of MTMR6 by showing it dephosphorylates PI(3)P, placing it among catalytically active myotubularin-family lipid phosphatases.\",\n      \"evidence\": \"In vitro lipid phosphatase assay with recombinant MTMR6\",\n      \"pmids\": [\"11733541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define cellular substrate pools or in vivo targets\", \"No structural basis for substrate recognition\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Expanded the substrate range to PtdIns(3,5)P2 and identified PtdIns5P as a specific allosteric activator, revealing built-in regulatory feedback in MTMR6 catalysis.\",\n      \"evidence\": \"In vitro phosphatase assays with defined lipid substrates and allosteric activation measurement\",\n      \"pmids\": [\"12646134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allosteric activation not mapped to a structural site\", \"Physiological relevance of PtdIns5P feedback in cells untested here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected MTMR6 lipid phosphatase activity to a discrete physiological target by showing it binds and inhibits KCa3.1 via coiled-coil interactions and PI(3)P depletion, with the coiled-coil conferring specificity.\",\n      \"evidence\": \"Co-IP, domain-swap chimeras, patch-clamp electrophysiology, PI(3)P rescue; plus chimeric channel mapping of PI(3)P regulation\",\n      \"pmids\": [\"15831468\", \"16251351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish endogenous physiological context for KCa3.1 regulation\", \"Spatial coupling of phosphatase to channel not fully resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the domain requirements (coiled-coil plus PH/GRAM together) for membrane targeting and showed the inhibitory axis controls Ca2+ influx and proliferation in primary CD4 T cells, giving the activity an immunological role.\",\n      \"evidence\": \"Domain chimeras with immunofluorescence and channel assays; gain/loss-of-function in primary human CD4 T cells with Ca2+ flux and proliferation readouts\",\n      \"pmids\": [\"16914545\", \"16847315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo T-cell phenotype not tested\", \"How the two domains cooperate mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified MTMR9 as a heteromeric partner that activates and stabilizes MTMR6 and links the complex to apoptosis suppression, showing MTMR6 functions within a regulated phosphatase complex.\",\n      \"evidence\": \"Co-IP, in vitro binding and phosphatase assays with liposomes, RNAi, etoposide apoptosis assay\",\n      \"pmids\": [\"19038970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of activation by inactive MTMR9 unknown\", \"Direct lipid target of the apoptosis-relevant activity not pinpointed here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how MTMR9 reshapes MTMR6 output, showing the complex shifts strongly toward PtdIns(3,5)P2, raises cellular PtdIns5P, and inhibits stress-induced apoptosis.\",\n      \"evidence\": \"In vitro substrate-specificity phosphatase assays, cellular phosphoinositide quantification, apoptosis assays\",\n      \"pmids\": [\"22647598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular site of the substrate switch not localized\", \"Downstream apoptotic effectors of PtdIns5P unidentified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Located MTMR6 to perinuclear/peri-Golgi membranes via microtubule-dependent, GRAM-domain–mediated binding to GDP-bound Rab1B, and tied it to secretory transport and autophagic omegasome formation.\",\n      \"evidence\": \"Immunofluorescence, GRAM-domain Rab1B Co-IP, microtubule disruption, siRNA, VSV-G transport and omegasome assays\",\n      \"pmids\": [\"23188820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid substrate consumed at this location not directly measured\", \"Mechanistic link between Rab1B targeting and autophagy unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed MTMR9 directs MTMR6 to the intermediate compartment and Golgi, indicating partner-driven control of MTMR6 localization complements its Rab1B-dependent targeting.\",\n      \"evidence\": \"Co-localization immunofluorescence with co-expression in cells\",\n      \"pmids\": [\"31704058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the recruitment\", \"Functional consequence of relocalization not assayed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Ortholog genetics established a conserved, condition-dependent role in autophagy, with MTMR6 promoting autophagy under nutrient-rich conditions and restraining hyperactivation under stress while maintaining endolysosomal homeostasis.\",\n      \"evidence\": \"Drosophila genetic loss-of-function with autophagic flux and endolysosomal readouts under basal and stress conditions\",\n      \"pmids\": [\"32915229\", \"33779490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian MTMR6 autophagy role not directly demonstrated in these studies\", \"Substrate pool driving the dual phenotype not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Assigned an in vivo immunoregulatory function: TLR2-driven MTMR6 upregulation suppresses anti-leishmanial immunity, and silencing reduces parasite burden and restores protective cytokines.\",\n      \"evidence\": \"siRNA phosphatase screen, TLR2 agonist/antagonist, lentiviral shRNA in macrophages and BALB/c mice, cytokine and parasite-load readouts\",\n      \"pmids\": [\"38330797\", \"38295542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the immunosuppressive effect requires KCa3.1/PI(3)P axis untested\", \"Macrophage-intrinsic signaling downstream of MTMR6 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple miRNA studies position MTMR6 as a regulated node whose loss alters proliferation, apoptosis, and drug response, but the mechanistic basis linking these phenotypes to its phosphatase activity is unresolved.\",\n      \"evidence\": \"Luciferase reporter validation of miR-190b, miR-506-3p, and miR-544a targeting; knockdown phenotypes in T cells/macrophages, ovarian cancer, and oral squamous carcinoma including xenografts\",\n      \"pmids\": [\"24981450\", \"31894107\", \"39891222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phenotypes not mechanistically connected to lipid-phosphatase function\", \"Context-specific direct targets of MTMR6 in cancer cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTMR6's biochemical activities (KCa3.1 inhibition, PtdIns(3,5)P2/PtdIns5P metabolism, secretory and autophagic regulation) are mechanistically unified to drive its disparate physiological roles in immunity, apoptosis, and proliferation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of MTMR6 or the MTMR6/MTMR9 complex\", \"No demonstration that immune and cancer phenotypes depend on a specific lipid substrate at a defined membrane\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 10, 11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 12, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"MTMR6/MTMR9 heteromeric phosphatase complex\"],\n    \"partners\": [\"MTMR9\", \"KCNN4\", \"RAB1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}