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Information on EC 3.1.3.64 - phosphatidylinositol-3-phosphatase and Organism(s) Homo sapiens and UniProt Accession Q13614
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3.1.3.64 phosphatidylinositol-3-phosphataseIUBMB Comments
This enzyme still works when the 2,3-bis(acyloxy)propyl group is removed, i.e., it hydrolyses Ins(1,3)P2 to Ins-1-P.
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Word Map
- 3.1.3.64
-
x-linked
- phosphatases
- charcot-marie-tooth
- endosomal
- neuropathy
- autophagosome
-
ptdins3,5p2
-
centronuclear
- phosphatidylinositol-3-phosphate
- xlmtm
-
demyelinate
-
ptdins3,4,5p3
- pten
-
endocytic
-
ptdins5p
-
beclin
-
autophagy-related
- hypotonia
- ulk1
-
myofibers
- dynamin
- 3-kinases
-
phagophore
-
sequestosome
-
3,4,5-trisphosphate
-
sqstm1
- 3,5-bisphosphate
-
pleckstrin
- pikfyve
- pik3c3
-
phosphoinositide-binding
-
uvrag
- amphiphysins
- 3-phosphoinositide
-
earl
-
excitation-contraction
-
polyphosphoinositides
- medicine
- phosphatidylinositol-3,5-bisphosphate
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
ptdins3p, myotubularin, mtmr2, mtmr3, mtmr14, mtmr6, mtmr4, mtmr13, mtmr7, myotubularin-related protein, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
D-myo-inositol 1,3-bisphosphate 3-phosphohydrolase
-
-
-
-
inositol 1,3-bisphosphate phosphatase
-
-
-
-
inositol-1,3-bisphosphate 3-phosphatase
-
-
-
-
inositol-polyphosphate 3-phosphatase
-
-
-
-
MTM1
myotubularin
phosphatase, phosphatidylinositol 3-
-
-
-
-
phosphatidyl-3-phosphate 3-phosphohydrolase
-
-
-
-
phosphoinositide 3-phosphatase
PtdIns 3-phosphatase
-
-
-
-
additional information
phosphoinositide 3-phosphatase
-
-
-
-
additional information
-
myotubularins are a family of phosphatidylinositol 3-phosphate phosphatases, e.g. MTM1, MTMR6, MTMR2 and MTMR3
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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
two-step reaction mechanism
-
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O = 1-phosphatidyl-1D-myo-inositol + phosphate
hJUMPY has a phosphatidylinositol 3-phosphatase activity and also shares the same substrate specificity as myotubularin
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of phosphoric ester
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
1-phosphatidyl-1D-myo-inositol-3-phosphate 3-phosphohydrolase
This enzyme still works when the 2,3-bis(acyloxy)propyl group is removed, i.e., it hydrolyses Ins(1,3)P2 to Ins-1-P.
CAS REGISTRY NUMBER
COMMENTARY
122653-77-4
formerly, EC 3.1.3.65
124248-47-1
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
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-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
-
-
-
?
phosphatidylinositol 3,4-bisphosphate + H2O
phosphatidylinositol 4-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
-
-
-
?
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-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
-
?
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
?
-
analysis of binding between recombinant MTMR2 and MTMR13, overview
-
-
?
additional information
?
-
-
analysis of binding between recombinant MTMR2 and MTMR13, overview
-
-
?
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
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-
?
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
?
-
-
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
?
-
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
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
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 3,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 5-phosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O
1-phosphatidyl-1D-myo-inositol + phosphate
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
-
phosphoinositide metabolism
-
?
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
-
-
-
?
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
?
-
enzyme deficiency is involved in XLMTM myopathies
-
-
?
additional information
?
-
-
enzyme deficiency is involved in XLMTM myopathies
-
-
?
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
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
type III PI3K regulatory subunit hVps15
-
i.e. p150, MTMR2 binding results in inhibition of phosphatase activity and in diminution of hVps34-Rab7 interaction important for PI3P synthesis
-
additional information
-
in the presence of myotubularin-related protein 9 , both phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate have an inhibitory effect on myotubularin-related protein 6 activity in 50% phosphatidylserine, the 3-phosphatase activity decreases 30 and 40% for phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
myotubularin-related protein 9
-
myotubularin-related protein 9 increases the binding of myotubularin-related protein 6 to phospholipids without changing the lipid binding profile, myotubularin-related protein 9 increases the 3-phosphatase activity of myotubularin-related protein 6 up to 6fold, myotubularin-related protein 9 potentiates the effects of myotubularin-related protein 6 on apoptosis
-
phosphatidylinositol 3-phosphate
-
substrate is a weak allosteric activator of MTM1 capable of binding at a regulatory site on the monomeric enzyme, no physiological activator
phosphatidylinositol 4-phosphate
-
phosphatidylinositol 4-phosphate increases myotubularin-related protein 6 activity in the presence of myotubularin-related protein 9 in 100% phosphatidylserine
phosphatidylserine
-
myotubularin-related protein 6 activity increases 1.8fold in both 50% and 100% phosphatidylserine
additional information
-
myotubularin-related protein 6 is activated up to 28fold in the presence of phosphatidylserine liposomes, myotubularin-related protein 6 activity in the presence of myotubularin-related protein 9 and assayed in phosphatidylserine liposomes increases 84fold
-
phosphatidylinositol 5-phosphate
-
causes MTM1 to form a heptameric ring and is a specific allosteric activator of MTM1, MTMR3 and MTMR6, activates MTM1 activity toward both phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate
phosphatidylinositol 5-phosphate
-
allosteric activator, phosphatidylinositol 5-phosphate and increases myotubularin-related protein 6 activity in the presence of myotubularin-related protein 9 in 100% phosphatidylserine
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
adapter subunit 3-PAP mRNA, highest abundance in liver, kidney, lung and placenta, 2 transcripts of 5.5 and 2.5 kb
adapter subunit 3-PAP mRNA, highest abundance in liver, kidney, lung and placenta, 2 transcripts of 5.5 and 2.5 kb
adapter subunit 3-PAP mRNA, highest abundance in liver, kidney, lung and placenta, 2 transcripts of 5.5 and 2.5 kb
additional information
adapter subunit 3-PAP mRNA, highest abundance in liver, kidney, lung and placenta, 2 transcripts of 5.5 and 2.5 kb
-
peripheral and central neurons, MTMR2 is localized to excitatory synapses of central neurons
additional information
-
PSD-95 interacts with and promotes spine localization of MTMR2
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
when hypoosmotic stress is induced in COS7 cells, a condition that increases PtdIns(3,5)P2 levels, MTMR2 delocalizes to membranes of intracellular vacuoles
-
MTMR2 is localized to excitatory synapses of central neurons, localization in synaptic membrane, cytosol, and vesicles
additional information
-
MTM1 localizes to both early and late endosomes and associates with the hVPS15/hVPS34 complex. Both Rab7 and MTM1 bind to hVPS15, the hVPS34 adapter molecule that regulates hVPS34 activity through its interactions with Rab5 and Rab7. The WD40 domain of hVPS15 mediates binding to Rab5, Rab7 and MTM1. Consequently, binding of the hVPS15/hVPS34 complex to the Rab GTPases and MTM1 is mutually exclusive
-
MTM1 is present on ruffles at the plasma membrane, on early endosomes and partially on late endosomes
-
treatment with multiple MAPK inhibitors results in a MTMR2 localization shift from Rab5-positive endosomes to the more proximal APPL1-positive endosomes
-
immunofluorescent microscopy demonstrate that both the MTMR6 coiled-coil (CC)(aa 512-621) and pleckstrin homology/GRAM (PH/G) (aa 1-106) domains are required to co-localize MTMR6 to the plasma membrane with KCa3.1
-
MTM1 is present on ruffles at the plasma membrane, on early endosomes and partially on late endosomes
additional information
the enzyme associates with membranes where substrates are localized mediated by membrane-associated pseudophosphatase MTMR13, overview
-
additional information
-
the enzyme associates with membranes where substrates are localized mediated by membrane-associated pseudophosphatase MTMR13, overview
-
additional information
transient transfection in COS-1 cells: EYFP-tagged hJUMPY is localized to cytoplasmic reticular structures and displays a concentration near the nucleus, and plasma membrane ruffles also containes hJUMPY. Different variants described (C330S, R336Q and Y462C) display a similar localization pattern to the wild-type construct
-
additional information
-
transient transfection in COS-1 cells: EYFP-tagged hJUMPY is localized to cytoplasmic reticular structures and displays a concentration near the nucleus, and plasma membrane ruffles also containes hJUMPY. Different variants described (C330S, R336Q and Y462C) display a similar localization pattern to the wild-type construct
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
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
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
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. 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
-
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
-
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MTMR2_HUMAN
643
0
73381
Swiss-Prot
other Location (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
86000
x * 86000 + x * ?, adapter subunit 3-PAP of phosphatidylinositol 3-phosphate phosphatase, forms a complex with a catalytic subunit of unknown MW, predicted from the amino acid sequence
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
-
MTM1 and MTMR6, catalytically inactive in absence of substrate, binding of substrate and of the allosteric activator phosphatidylinositol 5-phosphate triggers oligomerization and thus activates enzyme
oligomer
-
MTM1 and MTMR6, catalytically inactive monomer in absence of substrate, binding of substrate and of the allosteric activator phosphatidylinositol 5-phosphate triggers oligomerization and thus activates enzyme
additional information
additional information
x * 86000 + x * ?, adapter subunit 3-PAP of phosphatidylinositol 3-phosphate phosphatase, forms a complex with a catalytic subunit of unknown MW, predicted from the amino acid sequence
additional information
-
x * 86000 + x * ?, adapter subunit 3-PAP of phosphatidylinositol 3-phosphate phosphatase, forms a complex with a catalytic subunit of unknown MW, predicted from the amino acid sequence
additional information
-
domain structure of the myotubularin family members, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
ERK1/2 is the kinase responsible for phosphorylating MTMR2 at position Ser58, which suggests that the endosomal targeting of MTMR2 is regulated through an ERK1/2 negative feedback mechanism
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C330S
strong decrease in enzymatic activity (27% of wild type activity), mutant displays a similar localization pattern to the wild-type construct
C375S
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
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
R336Q
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
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
additional information
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
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
-
mutation of His-469 to the amino acid found in the disease state inactivates
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant FLAG-tagged and His-tagged wild-type and mutant enzymes from Escherichia coli lysates
-
recombinant GST-tagged enzyme from Escherichia coli strain DH5alpha by glutathione affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA and amino acid sequence analysis, phylogenetic analysis, coexpression of FLAG-tagged MTMR2 and MTMR13 in HEK-293A cells
cDNA encoding the adapter subunit 3-PAP of phosphatidylinositol 3-phosphate 3-phosphatase is cloned, sequenced and characterized, expression of 3-PAP in SF9 insect cells
cDNAs encoding MTM1 and MTMR6 are cloned and expressed in SF9 insect cells, MTM1 is also expressed in yeast
-
expression of GST-tagged enzyme in Escherichia coli strain DH5alpha, overexpression in COS-7 cells, HEK-293 cells, L6 cells, C2C12 cells, and Jurkat with 10-15% expression level in all cases
expression of wild-type myotubularin-related phosphatase in A-549 cells, overexpression of a dominant-negative inactive mutant of myotubularin-related phosphatase 3, that partially localizes to autophagosomes, and PtdIns3P and two autophagy-related PtdIns3P-binding proteins, GFPDFCP1 and GFP-WIPI-1alpha, in A-549 cells, the recombinant enzyme accumulates at sites of autophagosome formation
-
overexpression of wild-type MTMR2 in HeLa cells predominantly located to the cytosolic/perinuclear region, recombinant expression of FLAG-tagged and of His-tagged wild-type and mutant enzymes in Escherichia coli lysates
-
stable coexpression of human FLAG-tagged Ca2+-activated K+ channel KCa3.1 with GFP-tagged or FLAG-tagged MTMR6 in CHO cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
impairment of hJUMPY function is implicated in some cases of autosomal centronuclear myopathy (CNM)
medicine
-
loss of either MTMR2 or MTMR13 specifically causes Charcot-Marie-Tooth type 4B1 and B2 (CMT4B1 and CMT4B2) neuropathies, respectively
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Nandurkar, H.H.; Caldwell, K.K.; Whisstock, J.C.; Layton, M.J.; Gaudet, E.A.; Norris, F.A.; Majerus, P.W.; Mitchell, C.A.
Characterization of an adapter subunit to a phosphatidylinositol (3)P 3-phosphatase: Identification of a myotubularin-related protein lacking catalytic activity
Proc. Natl. Acad. Sci. USA
98
9499-9504
2001
Homo sapiens (Q9C0I1), Homo sapiens
Schaletzky, J.; Dove, S.K.; Short, B.; Lorenzo, O.; Clague, M.J.; Barr, F.A.
Phosphatidylinositol-5-phosphate activation and conserved substrate specificity of the myotubularin phosphatidylinositol 3-phosphatases
Curr. Biol.
13
504-509
2003
Homo sapiens
Tronchere, H.; Laporte, J.; Pendaries, C.; Chaussade, C.; Liaubet, L.; Pirola, L.; Mandel, J.L.; Payrastre, B.
Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells
J. Biol. Chem.
279
7304-7312
2004
Homo sapiens (Q13496), Homo sapiens
Robinson, F.L.; Dixon, J.E.
The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-tooth disease
J. Biol. Chem.
280
31699-31707
2005
Homo sapiens (Q13614), Homo sapiens
Srivastava, S.; Li, Z.; Lin, L.; Liu, G.; Ko, K.; Coetzee, W.A.; Skolnik, E.Y.
The phosphatidylinositol 3-phosphate phosphatase myotubularin-related protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+ channel KCa3.1
Mol. Cell. Biol.
25
3630-3638
2005
Homo sapiens
Tosch, V.; Rohde, H.M.; Tronchere, H.; Zanoteli, E.; Monroy, N.; Kretz, C.; Dondaine, N.; Payrastre, B.; Mandel, J.L.; Laporte, J.
A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy
Hum. Mol. Genet.
15
3098-3106
2006
Homo sapiens (Q8NCE2), Homo sapiens
Choudhury, P.; Srivastava, S.; Li, Z.; Ko, K.; Albaqumi, M.; Narayan, K.; Coetzee, W.A.; Lemmon, M.A.; Skolnik, E.Y.
Specificity of the myotubularin family of phosphatidylinositol-3-phosphatase is determined by the PH/GRAM domain
J. Biol. Chem.
281
31762-31769
2006
Homo sapiens
Bolis, A.; Zordan, P.; Coviello, S.; Bolino, A.
Myotubularin-related (MTMR) phospholipid phosphatase proteins in the peripheral nervous system
Mol. Neurobiol.
35
308-316
2007
Chlorocebus aethiops, Caenorhabditis elegans, Caenorhabditis elegans (Q965W9), Homo sapiens, Mus musculus, Mus musculus (Q9Z2C4), Rattus norvegicus
Cao, C.; Laporte, J.; Backer, J.M.; Wandinger-Ness, A.; Stein, M.P.
Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomes
Traffic
8
1052-1067
2007
Homo sapiens
Zou, J.; Chang, S.C.; Marjanovic, J.; Majerus, P.W.
MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis
J. Biol. Chem.
284
2064-2071
2009
Homo sapiens
Vergne, I.; Roberts, E.; Elmaoued, R.A.; Tosch, V.; Delgado, M.A.; Proikas-Cezanne, T.; Laporte, J.; Deretic, V.
Control of autophagy initiation by phosphoinositide 3-phosphatase jumpy
EMBO J.
28
2244-2258
2009
Homo sapiens
Vergne, I.; Deretic, V.
The role of PI3P phosphatases in the regulation of autophagy
FEBS Lett.
584
1313-1318
2010
Saccharomyces cerevisiae, Homo sapiens, Mus musculus
Franklin, N.E.; Taylor, G.S.; Vacratsis, P.O.
Endosomal targeting of the phosphoinositide 3-phosphatase MTMR2 is regulated by an N-terminal phosphorylation site
J. Biol. Chem.
286
15841-15853
2011
Homo sapiens
Lee, H.W.; Kim, Y.; Han, K.; Kim, H.; Kim, E.
The phosphoinositide 3-phosphatase MTMR2 interacts with PSD-95 and maintains excitatory synapses by modulating endosomal traffic
J. Neurosci.
30
5508-5518
2010
Homo sapiens
Taguchi-Atarashi, N.; Hamasaki, M.; Matsunaga, K.; Omori, H.; Ktistakis, N.; Yoshimori, T.; Noda, T.
Modulation of local Ptdins3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy
Traffic
11
468-478
2010
Homo sapiens
Franklin, N.E.; Bonham, C.A.; Xhabija, B.; Vacratsis, P.O.
Differential phosphorylation of the phosphoinositide 3-phosphatase MTMR2 regulates its association with early endosomal subtypes
J. Cell Sci.
126
1333-1344
2013
Homo sapiens
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