Information on EC 3.1.3.66 - phosphatidylinositol-3,4-bisphosphate 4-phosphatase

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
3.1.3.66
-
RECOMMENDED NAME
GeneOntology No.
phosphatidylinositol-3,4-bisphosphate 4-phosphatase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
1-phosphatidyl-myo-inositol 3,4-bisphosphate + H2O = 1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
Mg2+-independent, the enzyme still works when the 2,3-bis(acyloxy)propyl group is removed, i.e., it hydrolyses Ins(1,3,4)P3 to Ins(1,3)P2, it also converts Ins(3,4)P2 to Ins-3-P
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of phosphoric ester
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
3-phosphoinositide degradation
-
Inositol phosphate metabolism
-
Metabolic pathways
-
SYSTEMATIC NAME
IUBMB Comments
1-phosphatidyl-1D-myo-inositol-3,4-bisphosphate 4-phosphohydrolase
Mg2+-independent. This enzyme still works when the 2,3-bis(acyloxy)propyl group is removed, i.e., it hydrolyses Ins(1,3,4)P3 to Ins(1,3)P2. It also converts Ins(3,4)P2 into Ins-3-P.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
4-ptase-1
-
-
D-myo-inositol-3,4-bisphosphate 4-phosphohydrolase
-
-
-
-
inositol polyphosphate 4 phosphatase A
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-
inositol polyphosphate 4-phosphatase
-
-
-
-
inositol polyphosphate 4-phosphatase 1
-
-
inositol polyphosphate 4-phosphatase II
-
-
inositol polyphosphate 4-phosphatase type I
-
-
inositol polyphosphate 4-phosphatase type II
-
-
-
-
inositol polyphosphate 4-phosphatase type II
-
-
inositol polyphosphate 4-phosphatase-1
-
-
inositol-3,4-bisphosphate 4-phosphatase
-
-
-
-
INPP4A
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-
INPP4A
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INPP4B
-
gene name
phosphatase, inositol 3,4-bisphosphate 4-
-
-
-
-
phosphatidylinositol 4-phosphatase type II
-
-
phosphatidylinositol-4-phosphate phosphatase
Q9C5G5
-
phosphoinositide 4-phosphatase
-
-
-
-
phosphoinositide 4-phosphatase
-
-
PI-4-phosphatase II
-
-
Sac1p-like phosphoinositide phosphatase
Q9C5G5
-
CAS REGISTRY NUMBER
COMMENTARY
122653-78-5
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
gene INPP4B
-
-
Manually annotated by BRENDA team
inositol polyphosphate 4-phosphatase type II
SwissProt
Manually annotated by BRENDA team
inositol polyphosphate 4-phosphatase type II
SwissProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
knocking down the expression of INPP4B in human epithelial cells, like knockdown of PTEN, results in enhanced Akt activation and anchorage-independent growth and enhanced overall motility. INPP4B knockdown results in increased migratory and invasive behavior of mammary epithelial cells. Dual knockdown of INPP4B and PTEN results in cellular senescence and causes a more prolonged phosphorylation of AKT at Thr308 than that caused by knocking down either protein alone. INPP4B knockdown in MCF-10A mammary epithelial cells results in distorted acini architecture in three-dimensional culture
malfunction
-
in mouse embryonic fibroblasts lacking 4-ptase-1 (-/-MEFs), the Akt-pleckstrin homology domain is constitutively membrane-associated both in serum-starved and agonist-stimulated cells. 4-Ptase-1-deficient cells show increased Akt signalling. Loss of 4-ptase-1 results in increased cell proliferation and decreased apoptosis. Loss of function of 4-ptase-1 leads to increased and sustained growth factor-stimulated levels of pSer473/Thr308-Akt and Akt phospho-substrates
malfunction
-
Inpp4a weeble mutant has a frame shift mutation in Inpp4a and is characterized by an early onset recessive cerebellar ataxia. In the Inpp4a weeble mutant, Purkinje cells are lost in a specific temporal and spatial pattern: Purkinje cells are lost at early perinatal timepoints. Prior to the appearance of climbing fibers in the developing molecular layer, the Inpp4a weeble mutant has a normal complement of Purkinje cells and they are properly positioned, degeneration and reactive gliosis are present at postnatal day 5 and progress rapidly in a defined pattern of patches. Purkinje cell loss in the Inpp4awbl mutant is due to glutamate excitotoxicity initiated by the climbing fiber, whereby Eaat4 may exert a protective effect
malfunction
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ananlysis of the role of 4-phosphatase I in the regulation of PtdIns(3,4)P2 in platelets in the weeble mouse model, the mice are viable, but lack platelet 4-phosphatase I, overview. Weeble chimeric mice have a propensity for thrombosis using a carotid artery injury model
malfunction
-
silenced INPP4B expression in malignant proerythroblast is associated with increased activated-Akt levels that can be alleviated by the reexpression of INPP4B. Knockdown of INPP4B in LNCaP cells enhances proliferation
physiological function
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overexpression of INPP4B in SUM149 cells in a xenograft mouse model results in reduced tumor growth. Loss of heterozygosity at the INPP4B locus in a majority of basal-like breast cancers, as well as in a significant fraction of ovarian cancers, which correlates with lower overall patient survival, suggesting that INPP4B is a tumor suppressor
physiological function
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4-ptase-1 controls the activation of Akt and thereby cell proliferation, survival and tumorigenesis. In mouse embryonic fibroblasts (+/+MEFs), the Akt-pleckstrin homology domain is detected at the plasma membrane following serum stimulation
physiological function
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PtdIns(3,4)P2 is important for platelet function and stabilizes platelet aggregates, role of inositol polyphosphate 4-phosphatase 1 in regulation of PtdIns(3,4)P2 and of platelet function, overview
physiological function
-
INPP4B regulates proliferation and Akt phosphorylation in prostate cancer cells
physiological function
-
quantitative real-time reverse-transcription PCR analysis, inositol polyphosphate 4-phosphatase-II , INPP4B, functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway, and that loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas
malfunction
-
inositol polyphosphate 4-phosphatase-II knockdown in estrogen receptor-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth
additional information
-
INPP4B is regulated by androgens at the level of transcription. INPP4B mRNA expression is induced in both LNCaP and VCaP AR-expressing prostate cancer cells. INPP4B and PTEN expression are correlated with the recurrence rate of patients with high and low expression levels of the proliferation marker Ki67
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
Q96PE3
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
Q62784
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
Q9QWG5
-
-
-
?
1-phosphatidyl-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
-
-
-
-
?
D-myo-inositol 1,3,4-trisphosphate + H2O
D-myo-inositol 3,4-bisphosphate + phosphate
show the reaction diagram
Q96PE3
-
-
-
?
D-myo-inositol 1,3,4-trisphosphate + H2O
D-myo-inositol 3,4-bisphosphate + phosphate
show the reaction diagram
Q62784
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-
-
?
D-myo-inositol 1,3,4-trisphosphate + H2O
D-myo-inositol 3,4-bisphosphate + phosphate
show the reaction diagram
Q9QWG5
-
-
-
?
D-myo-inositol 3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
show the reaction diagram
-
-
-
?
D-myo-inositol 3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
show the reaction diagram
Q96PE3
-
-
-
?
D-myo-inositol 3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
show the reaction diagram
Q62784
-
-
-
?
D-myo-inositol 3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
show the reaction diagram
Q9QWG5
-
-
-
?
phosphatidylinositol-4-phosphate + H2O
?
show the reaction diagram
-, Q9C5G5
prefered substrate
-
-
?
D-myo-phosphatidylinositol-3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
show the reaction diagram
-
prefered substrate
-
-
-
additional information
?
-
Q96PE3
no substrate: inositol 1,4-bisphosphate
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-
-
additional information
?
-
Q62784
no substrate: inositol 1,4-bisphosphate
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-
-
additional information
?
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calpain-mediated inhibition of enzyme is involved in the phosphatidylinositol 3,4-bisphosphate accumulation in thrombin-stimulated platelets
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-
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additional information
?
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has no effect on phosphatidylinositol-1,3,4-triphosphate
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additional information
?
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-
inositol polyphosphate 4-phosphatase type II is a class II phosphatase that preferentially hydrolyzes the 4 position of PI(3,4)P2
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-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
-
-
-
-
?
1-phosphatidyl-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
show the reaction diagram
-
-
-
-
?
D-myo-inositol 3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
show the reaction diagram
-
-
-
?
additional information
?
-
-
calpain-mediated inhibition of enzyme is involved in the phosphatidylinositol 3,4-bisphosphate accumulation in thrombin-stimulated platelets
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
no Mg2+ requirement
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(NH4)2SO4
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-
5,5'-dithiobis(nitrobenzoic acid)
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-
Inositol hexakisphosphate
Q96PE3
50% inhibition at 0.05 mM
Inositol hexakisphosphate
Q9QWG5
50% inhibition at 0.05 mM
KCl
-
moderate salt concentrations
additional information
-
no inhibition by Li+
-
additional information
-
by using a cocktail of phosphatase inhibitors containing vanadate, molybdate, imidazole, fluoride and tartrate these inhibitors remarkably change the pattern of peroxisomal phosphoinositides
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KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.034
-
D-myo-Inositol 1,3,4-trisphosphate
Q9QWG5
-
0.046
-
D-myo-Inositol 1,3,4-trisphosphate
Q96PE3
-
0.028
-
D-myo-Inositol 3,4-bisphosphate
Q96PE3
-
0.039
-
D-myo-Inositol 3,4-bisphosphate
Q9QWG5
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7
8
Q96PE3
-
7
8
Q9QWG5
-
7.6
-
-
-
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
primary, the enzyme is expressed in nonproliferative estrogen receptor-positive cells in the normal breast, and in estrogen receptor-positive, but not negative, breast cancer cell lines
Manually annotated by BRENDA team
-
restricted to the Purkinje cell soma and their dendrites in the molecular layer
Manually annotated by BRENDA team
additional information
Q62784
highest levels of enzyme in brain, heart, skeletal muscle and spleen
Manually annotated by BRENDA team
additional information
-
phosphatidylinositol 4-phosphatase type II gene expression is turned off in malignant proerythroblasts of spi-1/PU.1 transgenic mice developing erythroleukemia. Stimulation of malignant cells with erythropoetin inudces PI-4-phosphatase II transcription pointing this gene as an erythropoetin-responsive gene
Manually annotated by BRENDA team
additional information
-
present in HMEC cells. Total level of INPP4B is approximately 2-3fold higher in SUM149 cells expressing Flag-INPP4B, compared with levels in control SUM149 cells
Manually annotated by BRENDA team
additional information
-
INPP4B expression is evaluated by quantitative RT-PCR
Manually annotated by BRENDA team
additional information
-
INPP4B protein expression is frequently lost in primary human breast carcinomas, associated with high clinical grade and tumor size and loss of hormone receptors and is lost most commonly in aggressive basal-like breast carcinomas; no expression in MDA MB 231 cells, Hs578T cells, and BT-549cells. Colocalization of INPP4B and the proliferation marker, Ki-67, in breast lobules
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
early and recycling endosome
Manually annotated by BRENDA team
-, Q9C5G5
RHD4 is selectively recruited to RabA4-blabeled membranes that are involved in polarized expansion of root hair cells. In conjunction with the phosphoinositide kinase PI-4Kb1, RHD4 regulates the accumulation of phosphatidylinositol-4-phosphate on membrane compartments at the tips of growing root hairs
Manually annotated by BRENDA team
-
and endosome, after growth factor stimulation
Manually annotated by BRENDA team
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 104000, SDS-PAGE, enzyme forms a complex with phosphatidylinositiol 3-kinase
?
-
x * 105700, deduced from gene sequence
?
Q62784
x * 105600, deduced from gene sequence
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
by gel filtration
-, Q9C5G5
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
wild-type RHD4 and the mutant rhd4-2 N-terminal catalytic domains expressed from Escherichia coli Rosetta cells or BL21 cells as GST fusion proteins. EYFP-wild-type fusion protein transformed into Arabidopsis under control of the native RHD4 promoter
-, Q9C5G5
pLXSN-Flag-INPP4B expressed in 293T cells or in SUM149 cells subcutaneously injected into nude mice
-
full-length 4-ptase-1 cDNA subcloned into the EcoRI site of pWzl-Hygromycin vector
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
knockdown of INPP4B expression by shRNA
-
optimal induction of INPP4B by an androgen receptor required the expression of the transcriptional coactivator NCoR
-
level of 4-ptase-1 protein expressed in reconstituted embryonic fibroblasts reveals a 5fold increase relative to endogenous 4-ptase-1 in +/+MEFs
-
expression of INPP4A is uniform across the cerebellum and the Purkinje cells
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
G449S
-, Q9C5G5
rhd4-2 mutant containing a mutation in motif VII of the SAC phosphatase domain, reduces the phosphatidylinositol-4-phosphate phosphatase activity to residual levels
additional information
-, Q9C5G5
rhd4-1 mutant, mutation results in root hairs that are shorter and randomly form bulges along their length. Stochastic loss and recovery of the RabA4b compartment in the tips of growing root hairs, altered subcellular distribution of phosphatidylinositol-4-phosphate within the root hair cell. EYFPRHD4 is capable of rescuing the rhd4-1 mutant phenotype
additional information
-
C2-domain deletion mutant, loss of enzyme activity, no localization to endosomes, no TAPP1 PH domain membrane recruitment
additional information
-
a nonsynonymous single nucleotide polymorphism +110832A/G (Thr/Ala) present within a PEST sequence (peptide sequence rich in proline, glutamic acid, serine and threonine), shows a significant association with atopic asthma. INPP4A alpha3 protein variant from platelets of individuals with AA genotype is found to be more susceptible to degradation, whereas the protein from individuals with GG genotype is less susceptible. Also, the basal levels of INPP4A protein in platelets from individuals with AA genotypes is found to be lower, suggesting poor stability in vivo as well
additional information
-
rescue construct pLXSN/Flag-INPP4BR harbors two silent mutations at Ser687 to render it resistant to shRNA-INPP4B-1 knockdown. The catalytic-dead pLXSN/Flag-INPP4BR construct harbors a Cys842Ala mutation to abolish phosphatase activity as well as two silent mutations at Ser687 to avoid knockdown
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
calpain-mediated inhibition of enzyme is involved in the phosphatidylinositol 3,4-bisphosphate accumulation in thrombin-stimulated platelets
medicine
-
INPP4A is identified as a novel asthma candidate gene
medicine
-
decreased expression of INPP4B correlates with poor outcome in both breast cancer and ovarian cancer patients, whereby the PI3K pathway is likely to play a major role in driving this subset of cancers. Loss of INPP4B expression may provide a marker for selecting patients who will respond to PI3K drugs
medicine
-
physiological role of PI-4-phosphatase II in the proerythroblast by controlling erythropoetin-resonsiveness through a negative regualtion of the PI3K/Akt pathway is demonstrated