Affinage

MTMR2

Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2 · UniProt Q13614

Length
643 aa
Mass
73.4 kDa
Annotated
2026-06-10
37 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MTMR2 is a phosphoinositide 3-phosphatase that controls endosomal membrane identity and membrane homeostasis, acting most prominently in myelinating Schwann cells and central neurons (PMID:11733541, PMID:15557122). It hydrolyzes PI(3)P with enzymatic properties indistinguishable from myotubularin (MTM1), and crystallographic and substrate-complex studies define a phosphatase domain structurally unique among protein tyrosine phosphatases, paired with a GRAM/PH-domain fold and an active-site pocket whose charge network and a flexible hydrophobic helix confer specificity for membrane-bound phosphoinositide headgroups (PMID:14690594, PMID:16410353). Catalytic activity and subcellular targeting are dictated by association through its coiled-coil domain with the catalytically inactive, membrane-bound family members MTMR5 and MTMR13/SBF2, which stimulate MTMR2 activity and direct its localization (PMID:12668758, PMID:15998640). In Schwann cells, MTMR2 acts cell-autonomously to restrain myelin membrane formation: its loss is sufficient and necessary to produce CMT4B1-like myelin outfoldings, and it functions through the paranodal scaffold Dlg1/SAP97, which couples a kif13B–Dlg1–Sec8 (exocyst) membrane-addition module to negative regulation by MTMR2 (PMID:15557122, PMID:16162938, PMID:19587293). Endosomal targeting is dynamically tuned by ERK1/2-mediated phosphorylation, with Ser58 governing general endosomal binding and Ser631 controlling shuttling between Rab5- and APPL1-positive early endosome subtypes, constituting a feedback loop on signal transduction (PMID:21372139, PMID:23378027). In central neurons MTMR2 binds PSD-95 to maintain excitatory synapse density and function by limiting endocytic and lysosomal degradation of GluR2 AMPA receptors, an activity requiring both PSD-95 binding and 3-phosphatase function (PMID:20410104). Distinct MTMR2 isoforms differ functionally: an N-terminal extension reduces the ability to substitute for MTM1, and a Schwann-cell-enriched short isoform driven by a SOX10-regulated alternative promoter behaves more like MTM1 (PMID:27466180, PMID:28934386). MTMR2 expression is mutated in CMT4B1 demyelinating neuropathy as established by the Schwann-cell-autonomous knockout phenotype (PMID:15557122, PMID:16162938).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 High

    Establishing MTMR2's biochemical activity answered whether this myotubularin-related protein is a functional lipid phosphatase and on which substrate it acts.

    Evidence In vitro lipid phosphatase assays with recombinant protein and GFP-fusion localization

    PMID:11733541

    Open questions at the time
    • Physiological substrate pool and in vivo endosomal targeting not yet defined
    • Did not address regulation of activity by partners
  2. 2003 High

    Crystal structure and substrate-complex work defined the structural basis of MTMR2's catalysis and phosphoinositide headgroup specificity, explaining how a PTP-fold enzyme selects a membrane lipid substrate.

    Evidence X-ray crystallography, substrate-complex crystallography, deuterium-exchange MS, and active-site mutagenesis

    PMID:14690594 PMID:16410353

    Open questions at the time
    • Structural basis of regulation by coiled-coil partners not resolved
    • Membrane-docking geometry inferred from charge/helix features rather than membrane-bound structure
  3. 2003 High

    Identification of coiled-coil-mediated binding to inactive family members MTMR5 and MTMR13 explained how a soluble phosphatase is activated and targeted to membranes.

    Evidence Co-IP, MS identification, coiled-coil mutagenesis, fractionation, and in vitro activity assays in HEK293 cells

    PMID:12668758 PMID:15998640

    Open questions at the time
    • Stoichiometry and assembly dynamics of the complex unresolved
    • Whether MTMR5 and MTMR13 act in distinct cell types not addressed
  4. 2005 High

    Cell-type-specific knockouts established that MTMR2 acts Schwann-cell-autonomously and is required to prevent CMT4B1 myelin outfoldings, localizing the disease mechanism.

    Evidence Schwann-cell- and neuron-specific conditional Cre knockout mice with histology, EM, and nerve conduction measurements

    PMID:15557122 PMID:16162938

    Open questions at the time
    • Molecular link between phosphatase activity and outfolding suppression not fully detailed
    • Lipid substrate dysregulated in vivo not measured directly
  5. 2009 High

    Mapping the Dlg1–kif13B–Sec8 module showed how MTMR2 integrates into a membrane-addition machinery, providing a mechanism for negative regulation of myelin membrane formation.

    Evidence Co-IP interaction mapping and Mtmr2 rescue in Schwann cell/DRG cocultures with EM

    PMID:19587293

    Open questions at the time
    • Direct lipid signal coordinating exocyst activity not identified
    • Quantitative balance between membrane addition and MTMR2 restraint unresolved
  6. 2010 High

    Discovery of PSD-95 binding extended MTMR2 function to neurons, showing it limits AMPA-receptor degradation to maintain excitatory synapses.

    Evidence Co-IP, shRNA knockdown with domain-mutant rescue, and GluR2 endocytosis assays in cultured neurons

    PMID:20410104

    Open questions at the time
    • In vivo synaptic and behavioral consequences not established
    • Endosomal lipid changes driving GluR2 sorting not directly measured
  7. 2013 High

    Identifying ERK1/2 phosphorylation at Ser58 and Ser631 revealed how MTMR2 endosomal compartmentalization is dynamically regulated, linking it to signal-transduction feedback.

    Evidence In vitro kinase assays, phospho-site mutagenesis, MAPK inhibition, siRNA, and localization microscopy

    PMID:21372139 PMID:23378027

    Open questions at the time
    • Physiological cues triggering site-specific phosphorylation unclear
    • Whether this regulation operates in Schwann cells or neurons in vivo unknown
  8. 2017 Medium

    Comparing MTMR2 isoforms with MTM1 showed that the N-terminal extension and a SOX10-driven short isoform tune functional equivalence and tissue-specific output.

    Evidence Yeast complementation, AAV-mediated isoform rescue in Mtm1-KO mice, alternative-promoter reporter assays, and isoform localization

    PMID:27466180 PMID:28934386

    Open questions at the time
    • Endogenous abundance and role of the short nuclear isoform not established
    • Mechanistic basis for differential rescue not fully resolved
  9. 2019 Medium

    Linking MTMR2 to IFNγ/STAT1/IRF1 signaling and EMT extended its activity to gastric cancer invasion through ZEB1 upregulation.

    Evidence Knockdown/overexpression with invasion and metastasis assays, IRF1-silencing epistasis, and Western blots in gastric cancer cells

    PMID:31113461

    Open questions at the time
    • Single lab and limited mechanistic depth on the phosphatase contribution
    • Whether the effect requires catalytic activity not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MTMR2's lipid-phosphatase activity, partner-directed targeting, and ERK-controlled endosomal localization are quantitatively coordinated in vivo across Schwann cells, neurons, and disease contexts remains open.
  • No unified in vivo measurement of substrate flux linked to phenotype
  • Tissue-specific isoform contributions to disease unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2
Localization
GO:0005768 endosome 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Partners
DLG1KIF13BMTMR13MTMR5PSD-95SEC8

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 MTMR2 is a lipid phosphatase highly specific for phosphatidylinositol 3-phosphate (PI(3)P) as its physiological substrate, with enzymatic properties indistinguishable from myotubularin (MTM1). MTMR2-GFP fusion proteins show overlapping but distinct subcellular localization compared to MTM1, and unlike MTM1, MTMR2 cannot modulate levels of endosomal PI(3)P. In vitro lipid phosphatase assays with recombinant protein; fluorescence microscopy of GFP fusion proteins; subcellular fractionation The Journal of biological chemistry High 11733541
2003 Crystal structure of MTMR2 reveals a phosphatase domain structurally unique among PTPs. The GRAM domain is part of a larger motif with a pleckstrin homology (PH) domain fold. Active-site mutagenesis identified residues critical for enzymatic activity and phosphoinositide substrate specificity. X-ray crystallography; active-site mutagenesis with in vitro enzymatic activity assays Molecular cell High 14690594
2003 MTMR2 specifically interacts with the catalytically inactive family member MTMR5 via its coiled-coil domain; this interaction increases MTMR2 enzymatic activity and dictates its subcellular localization. Mutations in the coiled-coil domain of either protein abrogate the interaction. Co-immunoprecipitation; mass spectrometry identification of interacting partner; coiled-coil domain mutagenesis; in vitro phosphatase activity assays; subcellular localization studies Proceedings of the National Academy of Sciences of the United States of America High 12668758
2004 Disruption of Mtmr2 in Schwann cells (but not globally) is sufficient to reproduce CMT4B1-like myelin outfoldings in mice, establishing a Schwann cell-autonomous role for MTMR2 in myelin membrane homeostasis. In Schwann cells, MTMR2 physically interacts with Dlg1/SAP97, a scaffolding molecule enriched at the node/paranode region, and loss of this interaction dysregulates membrane homeostasis at the paranodal region. Conditional knockout mouse (Schwann cell-specific and neuron-specific Cre); Co-immunoprecipitation of endogenous proteins; nerve biopsy histology; electron microscopy The Journal of cell biology High 15557122
2005 Loss of Mtmr2 in Schwann cells, but not in motor neurons, is both sufficient and necessary to cause CMT4B1 neuropathy with myelin outfoldings, confirming the Schwann cell-autonomous mechanism. Cell-type-specific conditional knockout mice (Schwann cell-specific P0-Cre and motor neuron-specific Hb9-Cre); nerve histology and electron microscopy; nerve conduction velocity measurements The Journal of neuroscience : the official journal of the Society for Neuroscience High 16162938
2005 Endogenous MTMR2 and MTMR13 proteins associate in HEK293 cells, mediated by coiled-coil sequences in each protein. MTMR13 is a predominantly membrane-associated protein, and its membrane association is mediated by the pseudophosphatase domain. MTMR2 and MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction. Co-immunoprecipitation of endogenous proteins; subcellular fractionation; fluorescence microscopy The Journal of biological chemistry High 15998640
2006 Crystallographic and deuterium-exchange mass spectrometry studies of MTMR2 in complex with phosphoinositides define the molecular basis for substrate specificity: phosphoinositide substrates bind in a positively charged pocket suggesting electrostatic membrane targeting; a flexible hydrophobic helix contacts diacylglycerol moieties conferring specificity for membrane-bound substrates; an H-bonding network and charge interactions in the active site determine headgroup specificity. X-ray crystallography of MTMR2-phosphoinositide complex; deuterium-exchange mass spectrometry Proceedings of the National Academy of Sciences of the United States of America High 16410353
2009 In Schwann cells, Dlg1 interacts with kif13B and Sec8 (an exocyst component) in addition to Mtmr2. A proposed mechanism was established experimentally: kif13B transports Dlg1 to sites of membrane remodeling where Dlg1-Sec8 interaction promotes membrane addition while Dlg1-Mtmr2 interaction negatively regulates membrane formation. Myelin outfoldings in Mtmr2-null Schwann cells are rescued by Mtmr2 replacement in vitro. Co-immunoprecipitation; Schwann cell/DRG neuron cocultures from Mtmr2-null mice; Mtmr2 rescue experiments; electron microscopy of myelin The Journal of neuroscience : the official journal of the Society for Neuroscience High 19587293
2010 MTMR2 localizes to excitatory synapses of central neurons via direct interaction with PSD-95. Knockdown of MTMR2 reduces excitatory synapse density and function; this effect is rescued by wild-type MTMR2 but not by a mutant lacking PSD-95 binding or 3-phosphatase activity. MTMR2 knockdown alters early endosome distribution in dendrites and promotes endocytosis and lysosomal degradation of GluR2 AMPA receptor subunits. Co-immunoprecipitation; shRNA knockdown in cultured neurons; rescue with domain mutants; immunofluorescence; endocytosis assays with internalized GluR2 The Journal of neuroscience : the official journal of the Society for Neuroscience High 20410104
2011 Phosphorylation of MTMR2 at serine 58 markedly decreases its localization to endocytic vesicular structures; a phosphorylation-deficient S58A mutant constitutively localizes to early endocytic structures accompanied by displacement of a PI(3)P sensor and increased signal transduction. ERK1/2 is the kinase responsible for phosphorylating MTMR2 at Ser58, constituting a negative feedback mechanism regulating endosomal targeting. Mass spectrometry identification of phosphorylation site; site-directed mutagenesis (S58E phosphomimetic and S58A phosphorylation-deficient); subcellular localization by fluorescence microscopy; in vitro kinase assays; cellular MAPK inhibitors; siRNA knockdown; phospho-specific antibody The Journal of biological chemistry High 21372139
2011 Overexpression of Mtmr2 prevents EGFR degradation and leads to sustained AKT activation (but not ERK activation). Mtmr13/Sbf2 counteracts the blockage of EGFR degradation without affecting prolonged AKT activation, indicating that Mtmr2 and Mtmr13/Sbf2 regulate EGFR sorting and downstream signaling. Overexpression in cell lines; Western blotting for pAKT and pERK; EGFR degradation assays Journal of cellular and molecular medicine Medium 19912440
2013 ERK1/2-mediated differential phosphorylation of MTMR2 at Ser58 and Ser631 regulates its compartmentalization on endosomal subtypes: Ser58 phosphorylation status controls general endosomal binding, while Ser631 phosphorylation status mediates shuttling between Rab5-positive and APPL1-positive early endosome subtypes. A double phosphorylation-deficient S58A/S631A MTMR2 variant localizes to APPL1 endosomes and produces more sustained ERK1/2 activation than S58A alone. In vitro kinase assays; MAPK inhibitors; siRNA knockdown; phospho-specific antibody; site-directed mutagenesis of Ser58 and Ser631; fluorescence microscopy Journal of cell science High 23378027
2016 SOX10 regulates an alternative promoter at MTMR2 that directs transcription of a Schwann cell-enriched MTMR2 transcript predicted to encode an N-terminally truncated isoform. The shorter isoform displays higher nuclear localization compared to the longer isoform when overexpressed in HeLa cells. Computational promoter analysis; luciferase reporter assays in S16 Schwann cells; RT-PCR for transcript enrichment; SOX10 ectopic expression and knockdown; GFP-tagged isoform localization by fluorescence microscopy Human molecular genetics Medium 27466180
2017 The N-terminal domain is responsible for functional differences between MTM1 and MTMR2. An N-terminal extension present in MTMR2 but absent in MTM1 reduces its ability to substitute for MTM1; the short MTMR2 isoform lacking this extension behaves similarly to MTM1 in yeast complementation and in Mtm1 knockout mice. AAV-mediated expression of MTMR2 isoforms in Mtm1-KO mice ameliorates myopathic phenotype, with the short isoform providing better rescue. Heterologous expression in yeast (complementation); AAV-mediated gene delivery in Mtm1-KO mice; muscle force measurements; histology Human molecular genetics High 28934386
2019 MTMR2 mediates epithelial-mesenchymal transition (EMT) in gastric cancer cells through inactivation of the IFNγ/STAT1/IRF1 signaling pathway, leading to ZEB1 upregulation. MTMR2 knockdown increases phosphorylation of STAT1 and IRF1, whereas overexpression decreases it; silencing IRF1 upregulates ZEB1 and enhances invasion. Gain- and loss-of-function assays (siRNA knockdown and overexpression); mRNA expression profiling; in vitro invasion/migration assays; in vivo metastasis assays; Western blotting for pSTAT1, IRF1, ZEB1 Journal of experimental & clinical cancer research : CR Medium 31113461

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. American journal of human genetics 232 12687498
2004 Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis. The Journal of cell biology 153 15557122
2003 Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Molecular cell 127 14690594
2003 Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proceedings of the National Academy of Sciences of the United States of America 121 12668758
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 phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease. The Journal of biological chemistry 95 15998640
2009 Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 90 19587293
2005 Loss of Mtmr2 phosphatase in Schwann cells but not in motor neurons causes Charcot-Marie-Tooth type 4B1 neuropathy with myelin outfoldings. The Journal of neuroscience : the official journal of the Society for Neuroscience 81 16162938
2006 Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proceedings of the National Academy of Sciences of the United States of America 79 16410353
2001 Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin. Brain : a journal of neurology 73 11335693
2019 MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling. Journal of experimental & clinical cancer research : CR 39 31113461
1998 Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B). Neurology 37 9521281
2004 SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma. Neurology 34 15304601
2019 A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs). Annals of neurology 32 31070812
2001 Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-Marie-Tooth disease suggests a low frequency of mutation in inherited neuropathy. Neurogenetics 31 11354824
2010 The phosphoinositide 3-phosphatase MTMR2 interacts with PSD-95 and maintains excitatory synapses by modulating endosomal traffic. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 20410104
2011 The CMT4B disease-causing proteins MTMR2 and MTMR13/SBF2 regulate AKT signalling. Journal of cellular and molecular medicine 28 19912440
2002 Molecular characterization and expression analysis of Mtmr2, mouse homologue of MTMR2, the Myotubularin-related 2 gene, mutated in CMT4B. Gene 28 11867209
2011 Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes. Neuromuscular disorders : NMD 23 21741241
2017 Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy. Human molecular genetics 21 28934386
2011 Endosomal targeting of the phosphoinositide 3-phosphatase MTMR2 is regulated by an N-terminal phosphorylation site. The Journal of biological chemistry 21 21372139
1999 Autosomal Recessive Hereditary Motor and Sensory Neuropathy with Focally Folded Myelin Sheaths (CMT4B). Annals of the New York Academy of Sciences 19 29086986
2018 Intravenous Administration of a MTMR2-Encoding AAV Vector Ameliorates the Phenotype of Myotubular Myopathy in Mice. Journal of neuropathology and experimental neurology 15 29408998
2000 Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22. Genomics 13 10673338
2019 Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking. Frontiers in neuroscience 12 31680794
2013 Differential phosphorylation of the phosphoinositide 3-phosphatase MTMR2 regulates its association with early endosomal subtypes. Journal of cell science 11 23378027
2020 MTMR2 promotes the progression of NK/T cell lymphoma by targeting JAK1. European review for medical and pharmacological sciences 9 32767332
2007 Silencing of the Charcot-Marie-Tooth associated MTMR2 gene decreases proliferation and enhances cell death in primary cultures of Schwann cells. Neurobiology of disease 9 17336078
2023 Canine models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 variants in golden retrievers with congenital hypomyelinating polyneuropathy. Neuromuscular disorders : NMD 7 37400349
2018 An In Vitro Model of Charcot-Marie-Tooth Disease Type 4B2 Provides Insight Into the Roles of MTMR13 and MTMR2 in Schwann Cell Myelination. ASN neuro 6 30419760
2017 Whole-Exome Sequencing Identifies a Novel Homozygous Frameshift Mutation in the MTMR2 Gene as a Causative Mutation in a Patient with Charcot-Marie-Tooth Disease Type 4B1. Molecular neurobiology 4 28509084
1999 Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B). Annals of the New York Academy of Sciences 3 10586229
1998 Exclusion of the SCN2B gene as candidate for CMT4B. European journal of human genetics : EJHG 3 9887383
2020 Novel MTMR2 mutation causing severe Charcot-Marie-Tooth type 4B1 disease: a case report. Neurogenetics 2 32488727
2016 SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2. Human molecular genetics 2 27466180
2024 Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot-Marie-Tooth Disease Type 4B1. The application of clinical genetics 1 38835974
2010 [Mutation analysis of LITAF, RAB7, LMNA and MTMR2 genes in Chinese Charcot-Marie-Tooth disease.]. Yi chuan = Hereditas 1 20709679

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