Affinage

MTMR6

Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR6 · UniProt Q9Y217

Length
621 aa
Mass
72.0 kDa
Annotated
2026-06-10
25 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    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

    PMID:11733541

    Open questions at the time
    • Did not define cellular substrate pools or in vivo targets
    • No structural basis for substrate recognition
  2. 2003 High

    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

    PMID:12646134

    Open questions at the time
    • Allosteric activation not mapped to a structural site
    • Physiological relevance of PtdIns5P feedback in cells untested here
  3. 2005 High

    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

    PMID:15831468 PMID:16251351

    Open questions at the time
    • Did not establish endogenous physiological context for KCa3.1 regulation
    • Spatial coupling of phosphatase to channel not fully resolved
  4. 2006 High

    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

    PMID:16847315 PMID:16914545

    Open questions at the time
    • In vivo T-cell phenotype not tested
    • How the two domains cooperate mechanistically unresolved
  5. 2008 High

    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

    PMID:19038970

    Open questions at the time
    • Structural basis of activation by inactive MTMR9 unknown
    • Direct lipid target of the apoptosis-relevant activity not pinpointed here
  6. 2012 High

    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

    PMID:22647598

    Open questions at the time
    • Subcellular site of the substrate switch not localized
    • Downstream apoptotic effectors of PtdIns5P unidentified
  7. 2012 High

    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

    PMID:23188820

    Open questions at the time
    • Lipid substrate consumed at this location not directly measured
    • Mechanistic link between Rab1B targeting and autophagy unresolved
  8. 2019 Medium

    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

    PMID:31704058

    Open questions at the time
    • No in vitro reconstitution of the recruitment
    • Functional consequence of relocalization not assayed
  9. 2021 Medium

    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

    PMID:32915229 PMID:33779490

    Open questions at the time
    • Mammalian MTMR6 autophagy role not directly demonstrated in these studies
    • Substrate pool driving the dual phenotype not defined
  10. 2024 Medium

    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

    PMID:38295542 PMID:38330797

    Open questions at the time
    • Whether the immunosuppressive effect requires KCa3.1/PI(3)P axis untested
    • Macrophage-intrinsic signaling downstream of MTMR6 not mapped
  11. 2025 Medium

    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

    PMID:24981450 PMID:31894107 PMID:39891222

    Open questions at the time
    • Phenotypes not mechanistically connected to lipid-phosphatase function
    • Context-specific direct targets of MTMR6 in cancer cells unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0008289 lipid binding 2
Localization
GO:0005794 Golgi apparatus 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
KCNN4MTMR9RAB1B
Complex memberships
MTMR6/MTMR9 heteromeric phosphatase complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. In vitro phosphatase assay with defined lipid substrates; allosteric activation measured biochemically Current Biology High 12646134
2001 MTMR6 dephosphorylates phosphatidylinositol 3-phosphate (PI(3)P), establishing PI(3)P as a substrate common to active myotubularin family members. In vitro lipid phosphatase assay with recombinant MTMR6 The Journal of Biological Chemistry High 11733541
2005 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. Co-immunoprecipitation, domain swap chimera experiments, patch-clamp electrophysiology, PI(3)P rescue experiments Molecular and Cellular Biology High 15831468
2005 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. Chimeric KCa3.1/KCa2.3 channel constructs, patch-clamp electrophysiology, lipid rescue experiments Molecular Biology of the Cell High 16251351
2006 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. MTMR6 overexpression and knockdown in primary human CD4 T cells, Ca2+ flux measurements, cell proliferation assays Molecular and Cellular Biology High 16847315
2006 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. Domain chimera construction between MTM family members, immunofluorescence microscopy, KCa3.1 activity assays The Journal of Biological Chemistry High 16914545
2008 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. Co-immunoprecipitation, in vitro binding assays, in vitro phosphatase assays with phosphatidylserine liposomes, RNAi knockdown, etoposide apoptosis assay The Journal of Biological Chemistry High 19038970
2012 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. In vitro phosphatase assays with defined lipid substrates, cellular phosphoinositide measurements, apoptosis assays Proceedings of the National Academy of Sciences USA High 22647598
2012 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. Monoclonal antibody-based immunofluorescence, co-immunoprecipitation (GRAM domain–Rab1B), microtubule disruption, siRNA knockdown, VSV-G transport assay, DFCP1-overexpression omegasome assay The Journal of Biological Chemistry High 23188820
2019 MTMR9 recruits its active phosphatase partner MTMR6 to the intermediate compartment and Golgi apparatus, indicating MTMR9 determines the subcellular localization of MTMR6. Co-localization by immunofluorescence microscopy, co-expression experiments in cells Experimental Cell Research Medium 31704058
2020 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. Drosophila genetic screen for phosphoinositide phosphatases affecting autophagy; autophagic flux assays in multiple cell types The Journal of Cell Biology Medium 32915229
2021 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. Drosophila genetic loss-of-function (RNAi/mutants), autophagic flux assays (LysoTracker, ref(2)P, TEM) under basal and stress conditions Autophagy Medium 33779490
2024 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. siRNA phosphatase library screen, TLR2 agonist/antagonist experiments, lentiviral shRNA knockdown, cytokine measurements, parasite load quantification International Immunopharmacology Medium 38330797
2024 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. Lentiviral shRNA knockdown in BALB/c mice, parasite burden quantification, IFN-γ measurement, challenge infection model International Immunopharmacology Medium 38295542
2014 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. Luciferase reporter assay, in vitro SIV infection of CD4+ T cells and primary intestinal macrophages, miRNA expression profiling Journal of Immunology Medium 24981450
2025 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. SiRNA knockdown of Mtmr6 in endometrial stromal cells, decidualization marker assays, proteomics, molecular docking Reproductive Toxicology Low 40541746
2019 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. Luciferase reporter assay, siRNA knockdown, MTT and colony formation assays, flow cytometry cell cycle/apoptosis analysis Journal of Biosciences Medium 31894107
2025 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. Luciferase reporter assay, antagomir and miRNA mimic assays, MTMR6 gain/loss-of-function experiments, mouse xenograft in vivo model Cancer Cell International Medium 39891222

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases. Current biology : CB 150 12646134
2001 Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease. The Journal of biological chemistry 101 11733541
2005 The phosphatidylinositol 3-phosphate phosphatase myotubularin- related protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+ channel KCa3.1. Molecular and cellular biology 87 15831468
2003 The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays. Blood 74 12586635
2005 Phosphatidylinositol 3-phosphate indirectly activates KCa3.1 via 14 amino acids in the carboxy terminus of KCa3.1. Molecular biology of the cell 62 16251351
2012 Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8. Proceedings of the National Academy of Sciences of the United States of America 55 22647598
2006 Phosphatidylinositol-3 phosphatase myotubularin-related protein 6 negatively regulates CD4 T cells. Molecular and cellular biology 47 16847315
2008 MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis. The Journal of biological chemistry 46 19038970
2012 Phosphatidylinositol 3-phosphatase myotubularin-related protein 6 (MTMR6) is regulated by small GTPase Rab1B in the early secretory and autophagic pathways. The Journal of biological chemistry 42 23188820
2020 A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Genes for Pancreatic Cancer Risk. Cancer research 36 32907841
2006 Specificity of the myotubularin family of phosphatidylinositol-3-phosphatase is determined by the PH/GRAM domain. The Journal of biological chemistry 29 16914545
2020 Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 23 32731254
2020 A conserved myotubularin-related phosphatase regulates autophagy by maintaining autophagic flux. The Journal of cell biology 22 32915229
2019 MiR-506-3p suppresses the proliferation of ovarian cancer cells by negatively regulating the expression of MTMR6. Journal of biosciences 22 31894107
2014 miR-190b is markedly upregulated in the intestine in response to simian immunodeficiency virus replication and partly regulates myotubularin-related protein-6 expression. Journal of immunology (Baltimore, Md. : 1950) 15 24981450
2024 Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism. EBioMedicine 12 39002386
2021 Condition-dependent functional shift of two Drosophila Mtmr lipid phosphatases in autophagy control. Autophagy 10 33779490
2013 Use of proteomic analysis tools to identify HCV-proteins down-regulated by acetylsalicylic acid. Annals of hepatology 9 24018490
2025 MTMR6 downregulation contributes to cisplatin resistance in oral squamous cell carcinoma. Cancer cell international 6 39891222
2024 Interplay between myotubularins and Ca2+ homeostasis. Biochimica et biophysica acta. Molecular cell research 4 38710289
2019 Human myotubularin-related protein 9 regulates ER-to-Golgi trafficking and modulates WNT3A secretion. Experimental cell research 4 31704058
2024 Admixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos. Alzheimer's & dementia : the journal of the Alzheimer's Association 2 38946675
2024 Myotubularin-related protein-6 silencing protects mice from Leishmania donovani infection. International immunopharmacology 1 38295542
2024 Myotubularin-related protein 6 is an ion channel-associated pro-leishmanial phosphatase. International immunopharmacology 1 38330797
2025 DEHP and its metabolite MEHP exposure impairs endometrial decidualization during early pregnancy via up-regulation of Mtmr6. Reproductive toxicology (Elmsford, N.Y.) 0 40541746

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