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1-hexanoyl-2-lysophosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-hexanoyl-2-lysophosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
hexanoylglyceryl 1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
hexanoylglyceryl 1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
inositol 1,3-bisphosphate + H2O
inositol 1-phosphate + phosphate
phosphatidylinositol 3,4-bisphosphate + H2O
phosphatidylinositol 4-phosphate + phosphate
-
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
additional information
?
-
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
enzyme shows specific enzymatic activity against PI(3)P but no detectable activity against PI(3,5)P2
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
enzyme shows specific enzymatic activity against PI(3)P but no detectable activity against PI(3,5)P2
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
inositol 1,3-bisphosphate + H2O
inositol 1-phosphate + phosphate
-
two enzyme forms, type I and type II 3-phosphatase, with differing relative specificities for phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate, the catalytic efficiency of type I enzyme is 19fold higher than that of type II enzyme
-
?
inositol 1,3-bisphosphate + H2O
inositol 1-phosphate + phosphate
-
type I enzyme may regulate inositol 1,3-bisphosphate levels in cells and is designated inositol-polyphosphate 3-phosphatase
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
-
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
-
-
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
-
-
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
-
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
MTM1 and MTMR6, in vitro
product causes MTM1 to form a heptameric ring and is a specific allosteric activator of MTM1, MTMR3 and MTMR6
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
physiologically relevant substrate
product could activate enzyme by a positive feedback mechanism
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
-
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
MTM1 and MTMR6
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
phosphoinositide metabolism
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
two enzyme forms, type I and type II 3-phosphatase, with differing relative specificities for phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate, hydrolysis by type II enzyme at 3times the rate of type I enzyme
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
specifically removes phosphate from the D-3-ring position of the substrate
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
type II enzyme functions primarily to metabolize phosphatidylinositol 3-phosphate and is designated phosphatidylinositol-3-phosphatase
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
enzyme may terminate a metabolic signal or regulate precursor levels for other phosphatidylinositols that are phosphorylated in the D-3 position
-
?
additional information
?
-
not: phosphatidylinositol 3,4,5-trisphosphate
-
-
?
additional information
?
-
-
not: phosphatidylinositol 3,4,5-trisphosphate
-
-
?
additional information
?
-
-
myotubularins, e.g. MTM1 and MTMR6, are a family of phosphatidylinositol 3-phosphate phosphatases
-
-
?
additional information
?
-
the adapter subunit 3-PAP of phosphatidylinositol 3-phosphate phosphatase alone is catalytically inactive
-
-
?
additional information
?
-
-
the adapter subunit 3-PAP of phosphatidylinositol 3-phosphate phosphatase alone is catalytically inactive
-
-
?
additional information
?
-
enzyme deficiency is involved in XLMTM myopathies
-
-
?
additional information
?
-
-
enzyme deficiency is involved in XLMTM myopathies
-
-
?
additional information
?
-
MTMR2, a phosphoinositide-3-phosphatase, associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-tooth disease
-
-
?
additional information
?
-
-
MTMR2, a phosphoinositide-3-phosphatase, associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-tooth disease
-
-
?
additional information
?
-
-
MTMR6 is a negative regulator of the Ca2+-activated K+ channel KCa3.1 requiring MTMR6 enzyme activity with 1-phosphatidyl-1D-myo-inositol 3-phosphate, and the CC domain
-
-
?
additional information
?
-
analysis of binding between recombinant MTMR2 and MTMR13, overview
-
-
?
additional information
?
-
-
analysis of binding between recombinant MTMR2 and MTMR13, overview
-
-
?
additional information
?
-
the enzyme shows specificity for 1-phosphatidyl-1D-myo-inositol 3-phosphate and 1-phosphatidyl-1D-myo-inositol 3,3-bisphosphate independent of the side acyl chain length
-
-
?
additional information
?
-
-
the enzyme shows specificity for 1-phosphatidyl-1D-myo-inositol 3-phosphate and 1-phosphatidyl-1D-myo-inositol 3,3-bisphosphate independent of the side acyl chain length
-
-
?
additional information
?
-
-
MTMR1, MTMR2, MTMR3, MTMR4, MTMR6, MTMR7, MTMR8 and Jumpy (also known as MTMR14), possess an active phosphatase domain, that specifically dephosphorylates 1-phosphatidyl-1D-myo-inositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate at position 3 on inositol ring
-
-
?
additional information
?
-
-
PSD-95 interacts with MTMR2. MTMR2 is a 3-phosphatase specific for the phosphoinositides PI(3)P and PI(3,5)P2
-
-
?
additional information
?
-
-
PtdIns3P phosphatase binds protein DFCP1, which is associated with autophagosome formation, and DFCP1 localizes to the endoplasmic reticulum and omegasomes
-
-
?
additional information
?
-
-
MTMR1, MTMR2, MTMR3, MTMR4, MTMR6, MTMR7, MTMR8 and Jumpy (also known as MTMR14), possess an active phosphatase domain, that specifically dephosphorylates 1-phosphatidyl-1D-myo-inositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate at position 3 on inositol ring
-
-
?
additional information
?
-
-
MTMR6 interacts with GDP-bound Rab1B via the GRAM domain
-
-
?
additional information
?
-
-
not: phosphatidylinositol 4-phosphate, phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 1,3-bisphosphate
-
-
?
additional information
?
-
-
not: inositol 1,3,4,5-tetrakisphosphate, inositol 1,3,4-trisphosphate or inositol 3,4-bisphosphate
-
-
?
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1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
inositol 1,3-bisphosphate + H2O
inositol 1-phosphate + phosphate
-
type I enzyme may regulate inositol 1,3-bisphosphate levels in cells and is designated inositol-polyphosphate 3-phosphatase
-
?
phosphatidylinositol 3,5-bisphosphate + H2O
phosphatidylinositol 5-phosphate + phosphate
-
physiologically relevant substrate
product could activate enzyme by a positive feedback mechanism
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
additional information
?
-
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
-
-
-
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
phosphoinositide metabolism
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
type II enzyme functions primarily to metabolize phosphatidylinositol 3-phosphate and is designated phosphatidylinositol-3-phosphatase
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
-
enzyme may terminate a metabolic signal or regulate precursor levels for other phosphatidylinositols that are phosphorylated in the D-3 position
-
?
additional information
?
-
enzyme deficiency is involved in XLMTM myopathies
-
-
?
additional information
?
-
-
enzyme deficiency is involved in XLMTM myopathies
-
-
?
additional information
?
-
MTMR2, a phosphoinositide-3-phosphatase, associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-tooth disease
-
-
?
additional information
?
-
-
MTMR2, a phosphoinositide-3-phosphatase, associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-tooth disease
-
-
?
additional information
?
-
-
MTMR6 is a negative regulator of the Ca2+-activated K+ channel KCa3.1 requiring MTMR6 enzyme activity with 1-phosphatidyl-1D-myo-inositol 3-phosphate, and the CC domain
-
-
?
additional information
?
-
-
MTMR1, MTMR2, MTMR3, MTMR4, MTMR6, MTMR7, MTMR8 and Jumpy (also known as MTMR14), possess an active phosphatase domain, that specifically dephosphorylates 1-phosphatidyl-1D-myo-inositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate at position 3 on inositol ring
-
-
?
additional information
?
-
-
PSD-95 interacts with MTMR2. MTMR2 is a 3-phosphatase specific for the phosphoinositides PI(3)P and PI(3,5)P2
-
-
?
additional information
?
-
-
PtdIns3P phosphatase binds protein DFCP1, which is associated with autophagosome formation, and DFCP1 localizes to the endoplasmic reticulum and omegasomes
-
-
?
additional information
?
-
-
MTMR1, MTMR2, MTMR3, MTMR4, MTMR6, MTMR7, MTMR8 and Jumpy (also known as MTMR14), possess an active phosphatase domain, that specifically dephosphorylates 1-phosphatidyl-1D-myo-inositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate at position 3 on inositol ring
-
-
?
additional information
?
-
-
MTMR6 interacts with GDP-bound Rab1B via the GRAM domain
-
-
?
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malfunction
-
four of the fifteen PI3P phosphatases present in mammals have been linked to serious human diseases. MTM1 defects cause X-linked myotubular myopathy also known as centronuclear myopathy, a severe congenital disorder affecting the physiology of skeletal muscle fibers and characterized by centrally localized nuclei and hypotonia. More than two hundred different mutations, truncations and missenses, in MTM1 are reported in XLMTM patients that result in loss or decrease of MTM1 level. MTMR2 and MTMR13 are mutated in two forms of Charcot-Marie-Tooth type 4B, CMT type 4, disease, an autosomal recessive disorder of the peripheral nervous system characterized by nerve demyelination and myelin outfoldings. CMT type 4B1 is caused by missense or deletion mutations in MTMR2 gene that result in MTMR2 loss of function. In addition to CMT4B1, one patient manifests azoospermia suggesting that MTMR2 also plays a role in testis
malfunction
-
inactivation or knockdown of MTMR3 initiates autophagosome formation, and overexpression of wild-type MTMR3 led to significantly smaller nascent autophagosomes and a net reduction in autophagic activity
malfunction
-
knockdown of MTMR2 reduces excitatory synapse number and suppresses synaptic transmission. Mutations in the MTMR2 gene in Schwann cells lead to a severe demyelinating peripheral neuropathy known as Charcot-Marie-Tooth disease type 4B1. Knockdown of MTMR2 in cultured neurons markedly reduces excitatory synapse density and function. It causes a marked reduction in the frequency, but not amplitude, of miniature EPSCs. This effect is rescued by wild-type MTMR2 but not by a mutant MTMR2 lacking PSD-95 binding or 3-phosphatase activity. MTMR2 knockdown leads to a decrease in the intensity of EEA1-positive early endosomes in dendrites but increases the intensity in the cell body region. Moreover, MTMR2 suppression promotes endocytosis, but not recycling, of the GluR2 subunit of AMPA receptors, which is an endosomal cargo. MTMR2 knockdown reduces spine density by suppressing spine maintenance, and not formation
malfunction
-
MTMR2-deficient mice develop CMT4B1-like neuropathy and azoospermia. MTMR13-deficient mice manifest myelin outfoldings in peripheral nerves. Jumpy or MTMR14-/- mice display muscle weakness and fatigue similar to patients with centronuclear myopathy
malfunction
-
activity of SidP rescues the growth phenotype of a yeast strain defective in PI(3)P phosphatase activity
malfunction
-
inactivating mtm-1, blocks phagosome maturation
malfunction
-
reduction of MTMR6 accelerates the transport of vesicular stomatitis virus glycoprotein in which Rab1B is involved. Furthermore, reduction of MTMR6 or Rab1B inhibits the formation of the tubular omegasome that is induced by overexpression of DFCP1 in autophagy
metabolism
-
autophagy initiation depends on the balance between PI 3-kinase and PI 3-phosphatase activity
metabolism
-
autophagy initiation is strictly dependent on phosphatidylinositol 3-phosphate synthesis. PI3P production is under tight control of PI3Kinase, hVps34, in complex with Beclin-1. PI3P metabolism involved in autophagy initiation is further regulated by the PI3P phosphatases Jumpy and MTMR3, and other PI3P phosphatases might be involved in this process
metabolism
-
autophagy initiation is strictly dependent on phosphatidylinositol 3-phosphate synthesis. PI3P production is under tight control of PI3Kinase, hVps34, in complex with Beclin-1. PI3P metabolism involved in autophagy initiation is further regulated by the PI3P phosphatases Jumpy and MTMR3, and other PI3P phosphatases might be involved in this process
physiological function
-
autophagy initiation depends on the balance between PI 3-kinase and PI 3-phosphatase activity. Effect of MTMR3 on the cellular distribution of PtdIns3P, overview
physiological function
-
PSD-95 binding and phosphatase activities of MTMR2 are required for excitatory synapse maintenance. PSD-95-interacting MTMR2 contributes to the maintenance of excitatory synapses by inhibiting excessive endosome formation and destructive endosomal traffic to lysosomes. PSD-95 interacts with and promotes spine localization of MTMR2
physiological function
-
the enzyme plays central role in autophagy, overview
physiological function
-
the enzyme plays central role in autophagy, overview. MTM1 might be involved in membrane traffic and regulates intracellular trafficking of Glut-4 and EGF receptor, respectively, on ruffles at the plasma membrane, on early endosomes and partially on late endosomes. In muscle fibers, MTMR14 regulates Ca2+ homeostasis by dephosphorylating PI3,5P2, an activator of Ca2+ release channel ryanodine receptor 1. In Schwann cells MTMR2 plays an important role in membrane homeostasis at the plasma membrane during the process of myelination. MTMR2 binds to type III PI3K regulatory subunit, hVps15 (p150), which results in inhibition of phosphatase activity and in diminution of hVps34-Rab7 interaction important for PI3P synthesis. Regulation and cellular functions of PI3P phosphatases, protein interacting partners of active PI3P phosphatases, overview
physiological function
-
the enzyme plays central role in autophagy, overview. Regulation and cellular functions of PI3P phosphatases, protein interacting partners of active PI3P phosphatases, overview
physiological function
-
MTM-1 antagonizes the activities of piki-1 (PI 3-kinase) and vps-34 (PI 3-kinase) on phagosomes
physiological function
-
MTM-1 down-regulates phagosomal PtdIns(3)P, this is demonstrated in mtm-1 mutant embryos where the level of the PtdIns(3)P on phagosomes is significantly higher than in wild-type embryos
physiological function
-
MTMR4 knockdown markedly suppresses the motility, fusion, and fission of phosphatidylinositol 3-phosphate-enriched structures, resulting in decreases in late endosomes, autophagosomes, and lysosomes, and enlargement of phosphatidylinositol 3-phosphate-enriched early and late endosomes. In amino acid- and serum-starved cells, MTMR4 knockdown decreases both autophagosomes and autolysosomes and markedly increased phosphatidylinositol 3-phosphate-containing autophagosomes and late endosome. MTMR4 knockdown inhibits the nuclear translocation of starvation stress responsive transcription factor-EB with reduced expression of lysosome-related genes in starved cells
additional information
-
PI3P is a substrate for PIP5-kinase, Fab1, also named PIKfyve, an enzyme that generates phosphoinositide 1-phosphatidyl-1D-myo-inositol 3,5-diphosphate
additional information
-
PI3P is a substrate for PIP5-kinase, Fab1, also named PIKfyve, an enzyme that generates phosphoinositide 1-phosphatidyl-1D-myo-inositol 3,5-diphosphate
additional information
-
WIPI-1alpha, a homologue of the yeast autophagy protein Atg18, directly binds PtdIns3P and forms puncta in mammalian cells in a PI 3-kinasedependent manner
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C330S
strong decrease in enzymatic activity (27% of wild type activity), mutant displays a similar localization pattern to the wild-type construct
C336S
-
inactive MTMR6 active site mutant
C407S
-
catalytically inactive
C413S
-
a dominant-negative inactive mutant of myotubularin-related phosphatase 3. The distribution of MTMR3C413S substantially overlaps with both autophagy-related PtdIns3P-binding proteins GST-2xFYVE and GFP-LC3, demonstrating that the amount of PtdIns3P is focally increased in areas of MTMR3C413S accumulation on autophagosomes
C417S
-
site-directed mutagenesis, a catalytically inactive MTMR2 variant
D278A
site-directed mutagenesis, inactive, substrate-trapping mutant
G103E
-
mutations in the PH-GRAM domain affect both binding to the membrane and the phosphatase activity, as demonstrated for the G103E mutation
R114A
-
MTM1 mutant, conserved residue, decreased response to the allosteric activator phosphatidylinositol 5-phosphate
R184G
-
MTM1 mutant with reduced activity
R220A
-
inactive MTM1 mutant, conserved residue
R241L
-
inactive MTM1 mutant
R421Q
-
MTM1 mutant with reduced activity
R69C
-
a disease-causing mutation of MTM1 falling within a putative pleckstrin homology domain, decreased response to the allosteric activator phosphatidylinositol 5-phosphate due to a reduced affinity for the activator, mutant with reduced activity due to a mutation in the allosteric regulatory site
S58A/C417S
-
site-directed mutagenesis, a catalytically inactive MTMR2 variant, which shows strong co-localization with markers for early endosomes including the PI(3)P marker generated from EEA1 and Rab5
S58A/C417S/S631A
-
catalytically inactive variant. Loss of catalytic activity (S58A/C417S/S631A) of dephosphorylated MTMR2 results in partial colocalization with PI(3)P endosomes. In contrast to double mutant S58A/S631A triple mutant S58A/C417S/S631A containing an additional mutated catalytic residue do not show enlarged viscles being positive for both MTMR2 and APPL1. This underlines that that the phosphatase activity of MTMR2 contributes to the observed enlargement of MTMR2/APPL1 positive vesicles
S58A/S631A
-
dephosphorylation at Ser58 and Ser631 in double mutant S58A/S631A prevents localization to PI(3)P-rich endosomes. MTMR2 localization shift upon administration of MAPK inhibitors is recapitulated in double mutant S58A/S631A. Expression of this double mutant leads to a more sustained and pronounced increase in ERK1/2 activation compared with mutant S58A. Further analysis of single mutant S58A and double mutant S58A/S631A demonstrate that it is the phosphorylation status of Ser58 that regulates general endosomal binding and that the phosphorylation status of Ser631 mediates the endosomal shuttling between Rab5 and APPL1 subtypes
S58E
-
site-directed mutagenesis, a phosphorylation-deficient mutant, which retains full catalytic activity toward PI(3)P and PI(3,5)P2 as compared to wild-type MTMR2. The mutant enzyme displays a similar localization pattern as wild-type in the cytoplasm
Y462C
decreased enzymatic activity (84% of wild type activity), mutant displays a similar localization pattern to the wild-type construct. This mutant is found as a non-conservative heterozygous Y462C missense in a patient suffering from centronuclear myopathy
C554S
-
mutant does not show any activity
D559N
-
mutant does not show any activity
R560K
-
mutant does not show any activity
E276X
another animal model for Charcot-Marie-Tooth type 4B1 is produced by introducing the E276X mutation in exon 9. Phosphatase activity is inactivated toward PtdIns3P and PtdIns(3,5)P2. Nerve morphology in these mice is similar to that observed in Mtmr2-null mice, although a huge variability in the number of myelin outfoldings between different mice is noted. In both mutants, Mtmr2-null and E276X, the dysmyelinating phenotype is less severe than that observed in human Charcot-Marie-Tooth type 4B1
Q426X
phosphatase activity is inactivated toward PtdIns3P and PtdIns(3,5)P2 in vitro
Q482X
phosphatase activity is inactivated toward PtdIns3P and PtdIns(3,5)P2 in vitro
C375S
-
inactive MTM1 mutant, catalytic cysteine
C375S
-
a phosphatase-dead mutant of MTM1 also localizes in early and late endosomes
R336Q
strong decrease in enzymatic activity (33% of wild type activity), mutant displays a similar localization pattern to the wild-type construct. This mutant is found as a heterozygous missense in a patient suffering from centronuclear myopathy. The Arg336 is conserved in all JUMPY protein orthologs and in all PTP/DSP phosphatases, as it is one of the compulsory amino acids for the enzymatic activity
R336Q
-
centronuclear myopathy, naturally occuring mutation within the catalytic site that abrogates phosphatase activity
S58A
-
site-directed mutagenesis, a phosphorylation-mimetic mutant, which retains full catalytic activity toward PI(3)P and PI(3,5)P2 as compared to wild-type MTMR2. The majority of the MTMR2 phosphorylation-deficient S58A mutant is localized to distinct punctate structures, indicative of endosomal localization, in contrast to the wild-type enzyme. The level of ERK1/2 phosphorylation/activation is also2-3fold higher in cells expressing MTMR2S58A in comparison to control cells
S58A
-
comparison with double mutant S58A/S631A shows that dephosphorylation of Ser58 is sufficient for targeting MTMR2 to endosomal structures
additional information
-
MTM-6 and MTM-9 have been identified in a genetic screening as proteins required for endocytosis in coelomocytes: a dramatical alteration in PtdIns3P localization is observed in coelomocyte from mtm-6 and mtm-9 mutants
additional information
MTM-6 and MTM-9 have been identified in a genetic screening as proteins required for endocytosis in coelomocytes: a dramatical alteration in PtdIns3P localization is observed in coelomocyte from mtm-6 and mtm-9 mutants
additional information
-
MTM1 overexpression in COS-7 cells extensively treated with EGF induces large endosomal vacuoles and inhibits EGFR trafficking from late endosome to lysosome, while, in myotubes, MTM1 overexpression leads to the displacement of early endosomal antigen 1 (EEA1) from early endosomes and to a decreased insulin-induced glucose uptake
additional information
-
X-linked myotubular myopathy (XLMTM) is a severe skeletal muscle disorder affecting newborn males, characterized by hypotonia and generalized muscle weakness. More than 200 mutations in MTM1 are identified thus far in XLMTM patients leading to loss of MTM1 protein. Lack of endogenous MTM1 in XLMTM patient myoblasts does not significantly affect the pool of PtdIns3P or the localization of early endosomal antigen 1 (EEA1)
additional information
-
mutation of His-469 to the amino acid found in the disease state inactivates
additional information
MTMR13-defective mutant cells show altered subcellular distribution of enzyme MTMR2 in the cytoplasmic and microsomal fraction
additional information
-
MTMR13-defective mutant cells show altered subcellular distribution of enzyme MTMR2 in the cytoplasmic and microsomal fraction
additional information
hJUMPY shows strong homology to the catalytic loop of myotubularin and is highly conserved through evolution
additional information
-
hJUMPY shows strong homology to the catalytic loop of myotubularin and is highly conserved through evolution
additional information
-
it is demonstrated that putative loss of function mutations in MTMR2 cause Charcot-Marie-Tooth type 4B1 (CMT4B1). Additional mutations are identified mainly in familial CMT4B1 cases. Most of the MTMR2 identified mutations affect the broad PTP domain, resulting in loss of the enzymatic activity, as has been functionally demonstrated for some of them
additional information
-
loss of endosomal phosphatidylinositol 3-phosphate upon overexpression of wild-type MTM1, but not a phosphatase-dead MTM1C375S mutant, results in altered early and late endosomal phosphatidylinositol 3-phosphate levels and rapid depletion of early endosome antigen-1
additional information
-
MTMR6 specifically inhibits the Ca2+-activated K+ channel, KCa3.1, by dephosphorylating phosphatidylinositol-3-phosphate. Chimeric MTMs containing both the MTMR6 coiled-coil (CC)(aa 512-621) and pleckstrin homology/GRAM (PH/G) (aa 1-106) domains function like MTMR6 to inhibit KCa3.1 channel activity, whereas chimeric MTMs containing either domain alone do not
additional information
-
myotubularins all share a PH-GRAM (Pleckstrin Homology-Glucosyltransferase, Rab-like GTPase Activators and Myotubularins) domain at the N-terminus, a protein tyrosine phosphatase domain and a coiled-coil region at the C-terminus. The PHGRAM domain binds to poliphosphoinositides, mainly PtdIns5P and PtdIns(3,5)P2 and in MTMR2, it has been shown to mediate the targeting of the phosphatase to the membrane of vacuoles formed under hypoosmotic stress
additional information
-
putative loss of function mutations in MTMR13, encoding a catalytically inactive phosphatase, cause Charcot-Marie-Tooth type 4B2 (CMT4B2). The first reported mutation is an in frame deletion removing part of the DENN domain at the N-terminus of the protein. DENN/GEF/AEX-3 is a well-conserved motif in signaling molecules. Cytoplasmic proteins lacking part of this domain delocalize to the nucleus where they might activate other proteins
additional information
-
several interactions between active and inactive myotubularins have been demonstrated. The active MTMR2 phosphatase binds to MTMR5 and MTMR13, which are both inactive enzymes
additional information
-
generation of an MTMR2 shRNA (sh-M1) that reduces exogenous MTMR2 expression in HEK 293T cells by about 80%, and endogenous MTMR2 expression in cultured hippocampal neurons by about 55%. MTMR2 knockdown in cultured hippocampal neurons leading to a marked reduction in the number of excitatory synapses, defined as PSD-95-positive dendritic spines, compared with neurons expressing empty shRNA vector
additional information
-
knockdown of MTMR3 increases autophagosome formation, and overexpression of wild-type MTMR3 led to significantly smaller nascent autophagosomes and a net reduction in autophagic activity
additional information
-
Mtm1 deficient mice have, after birth, normal muscle fibers with nuclei located at the periphery. Starting at 4 weeks of age, these mice develop a progressive myopathy characterized by hypotrophy and an increasing number of fibers with centrally located nuclei
additional information
Mtm1 deficient mice have, after birth, normal muscle fibers with nuclei located at the periphery. Starting at 4 weeks of age, these mice develop a progressive myopathy characterized by hypotrophy and an increasing number of fibers with centrally located nuclei
additional information
-
Mtmr2-null mouse are created as an animal model for Charcot-Marie-Tooth type 4B1 by removing exon 4, which encodes part of the PH-GRAM domain. Mice are viable. In both motor and sensory nerves of mutant mice, myelin outfoldings are observed starting at 3-4 weeks after birth. Semithin analysis is performed in longitudinal section of nerves. Myelin outfoldings predominantly arise at paranodal regions extending throughout the internode. At 12-15 months of age, myelin outfoldings also arise at Schmidt-Lanterman incisures, other regions enriched in Schwann cell cytoplasm. Axonal loss is observed only in Mtmr2-null mice at later stages (around 15 months) in more distal nerves. Dysmyelinating phenotype is less severe than that observed in human Charcot-Marie-Tooth type 4B1. Mtmr2-null mice have also defects in spermatogenesis, again, starting at 3-4 weeks of age
additional information
Mtmr2-null mouse are created as an animal model for Charcot-Marie-Tooth type 4B1 by removing exon 4, which encodes part of the PH-GRAM domain. Mice are viable. In both motor and sensory nerves of mutant mice, myelin outfoldings are observed starting at 3-4 weeks after birth. Semithin analysis is performed in longitudinal section of nerves. Myelin outfoldings predominantly arise at paranodal regions extending throughout the internode. At 12-15 months of age, myelin outfoldings also arise at Schmidt-Lanterman incisures, other regions enriched in Schwann cell cytoplasm. Axonal loss is observed only in Mtmr2-null mice at later stages (around 15 months) in more distal nerves. Dysmyelinating phenotype is less severe than that observed in human Charcot-Marie-Tooth type 4B1. Mtmr2-null mice have also defects in spermatogenesis, again, starting at 3-4 weeks of age
additional information
-
deletion of the GRAM domain (amino acids 142-617) abolishes the binding of Rab1B
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