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Information on EC 3.1.3.66 - phosphatidylinositol-3,4-bisphosphate 4-phosphatase and Organism(s) Homo sapiens and UniProt Accession O15327
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3.1.3.66 phosphatidylinositol-3,4-bisphosphate 4-phosphataseIUBMB Comments
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.
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Word Map
- 3.1.3.66
- pten
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polyphosphate-4-phosphatase
- pik3ca
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basal-like
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ptdins3,4p2
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ptdins3,4,5p3
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5-phosphatase
- medicine
- phosphatidylinositol-3,4,5-trisphosphate
- 1,3,4-trisphosphate
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
inpp4b, inpp4a, inositol polyphosphate 4-phosphatase type ii, inositol polyphosphate 4-phosphatase, inositol polyphosphate 4-phosphatase type i, pi-4-phosphatase ii, 4-ptase-1, inositol polyphosphate 4-phosphatase ii, phosphoinositide 4-phosphatase, inositol polyphosphate 4-phosphatase-1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
D-myo-inositol-3,4-bisphosphate 4-phosphohydrolase
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inositol polyphosphate 4-phosphatase
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inositol polyphosphate 4-phosphatase type II
inositol-3,4-bisphosphate 4-phosphatase
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phosphatase, inositol 3,4-bisphosphate 4-
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phosphoinositide 4-phosphatase
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inositol polyphosphate 4-phosphatase type II
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of phosphoric ester
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-
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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.
CAS REGISTRY NUMBER
COMMENTARY
122653-78-5
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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 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
1-phosphatidyl-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
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-
-
-
?
D-myo-phosphatidylinositol-3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
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prefered substrate
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-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
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-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
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-
-
?
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
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-
-
-
?
D-myo-inositol 1,3,4-trisphosphate + H2O
D-myo-inositol 3,4-bisphosphate + phosphate
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-
-
?
D-myo-inositol 1,3,4-trisphosphate + H2O
D-myo-inositol 3,4-bisphosphate + phosphate
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-
-
-
?
D-myo-inositol 3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
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-
-
?
D-myo-inositol 3,4-bisphosphate + H2O
D-myo-inositol 4-phosphate + phosphate
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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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?
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 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-myo-inositol 3,4-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3-phosphate + phosphate
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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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-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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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
additional information
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
additional information
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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
additional information
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no expression in MDA MB 231 cells, Hs578T cells, and BT-549cells. Colocalization of INPP4B and the proliferation marker, Ki-67, in breast lobules
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
cells expressing wild-type, but not catalytically inactive inositol polyphosphate 4-phosphatase show impaired phosphatidylinositol-3,4-bisphosphate responses induced by chenomkine SDF-1 and reduced migration in Transwell chamber assays. Phosphatidylinositol-3,4-bisphosphate depletion in primary chronic lymphocytic leukemia cells significantly impairs their migration capacity. Phosphatidylinositol-3,4-bisphosphate depletion reduces both overall motility and migration directionality in the presence of a stable chemokine gradient
malfunction
physiological function
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
malfunction
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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
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inositol polyphosphate 4-phosphatase-II knockdown in estrogen receptor-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth
malfunction
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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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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
physiological function
INPP4a is secreted by airway epithelial cells and extracellular INPP4A critically inhibits airway inflammation and remodeling. INPP4A is present in blood and broncho-alveolar lavage fluid and is reduced in asthma patients. Cultured airway epithelial cells secrete enzymatically active INPP4A in extracellular vesicles and in a free form. Extracellular vesicles-mediated INPP4A is transferred from epithelial cells to fibroblasts. Inhibition of this transfer increases fibroblast proliferation
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). INP4B_HUMAN
924
0
104738
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
104000
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x * 104000, SDS-PAGE, enzyme forms a complex with phosphatidylinositiol 3-kinase
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
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x * 104000, SDS-PAGE, enzyme forms a complex with phosphatidylinositiol 3-kinase
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
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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
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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
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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
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
pLXSN-Flag-INPP4B expressed in 293T cells or in SUM149 cells subcutaneously injected into nude mice
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
optimal induction of INPP4B by an androgen receptor required the expression of the transcriptional coactivator NCoR
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
medicine
colorectal carcinoma cell lines HCT-116, SW-620, DLD-1, and WiDr express significantly lower levels of INPP4B protein than the normal colonic epithelial cell lines CCD-841 CoTr and FHC. INPP4B mRNA expression in the colorectal carcinoma cell lines is significantly lower than in the normal colonic epithelial cells. Normal colonic mucosa displays uniform and strong-to-moderate INPP4B immunoreactivity, whereas 60.7% and 76.5% of the primary and metastatic colorectal carcinoma tissue samples exhibit reduced INPP4B expression, respectively
medicine
in acute myeloid leukemia, isoform IPNPP4B is significantly overexpressed, in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B confers leukemic resistance to cytosine arabinoside, daunorubicin, and etoposide. Expression of phosphatase inert variant C842A fails to abrogate resistance of acute myeloid leukemiacells to chemotherapy in vitro or in vivo. Targeted suppression of endogenously overexpressed INPP4B by RNAi sensitizes acute myeloid leukemia cell lines and primary acute myeloid leukemia to chemotherapy
medicine
in prostate cancer cell lines INPP4B regulates androgen recetor transcriptional activity and the oncogenic signaling pathways Akt and PKC. In prostate cancer patient cohorts, a positive correlation between INPP4B expression and both androgen receptor mRNA levels and transcriptional output exists
medicine
in Triple-negative breast cancer cells, which lack expression of estrogen receptor, progesterone receptor, and amplification of HER2/Neu, silencing isoform INPP4B decreases basal phospho-Akt (pAkt) and cellular proliferation, and in most cases sensitizes cells to phosphatidylinositol-3-kinase PI3K-alpha and PI3K-beta isoform-specific inhibitors. Overexpression of INPP4B desensitizes cells to PI3K inhibitors in a phosphatase activity-dependent manner
medicine
inositol polyphosphate 4-phosphatase type II is a direct target of microRNA-590-3p. Enforced expression of microRNA-590-3p leads to repression of inositol polyphosphate 4-phosphatase type II messenger RNA and protein expression, as well as upregulation of p-Akt, p-FoxO3a, and cyclin D1 and downregulation of p21 expression in prostate cancer cell lines. Overexpression of inositol polyphosphate 4-phosphatase type II can reduce microRNA-590-3p-induced cell proliferation and invasion as well as tumor growth, and decrease microRNA-590-3p-mediated upregulation of cyclin D1 and downregulation of p21 expression in prostate cancer cells
medicine
INPP4B is low expressed in osteosarcoma tissues and in osteosarcoma cell lines. INPP4B overexpression significantly decreases cell viability and induces apoptosis in SaOS2 and U2OS cells. Combination of INPP4B overexpression and poly-ADP ribose polymerase inhibitor rucaparib declines Myc, cyclin E1 and cyclin D1 expressions, enhances Bad, Bax, and cleaves caspase3 expressions, and blocks PI3K/AKT signal pathway in SaOS2 and U2OS cells. Combination of INPP4B overexpression and rucaparib inhibits tumor formation in vivo
medicine
INPP4B manipulates cadherin switch in certain pancreatic ductal adenocarcinoma cell lines through a phosphorylated AKT-inactivation. The knockdown of INPP4B in AsPC-1 cells results in a more invasive phenotype, and overexpression of INPP4B in PANC-1 leads to partial reversion of mesenchymal status and impediment of in vitro invasion but not migration. E-cadherin is enriched in the early and sorting endosomes containing INPP4B which enables its recycling rather than degradation. INPP4B acts as an tumor suppressor in pancreatic ductal adenocarcinomas which attenuates AKT activation and participates in preservation of E-cadherin in endocytic pool and cellular membrane
medicine
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calpain-mediated inhibition of enzyme is involved in the phosphatidylinositol 3,4-bisphosphate accumulation in thrombin-stimulated platelets
medicine
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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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Munday, A.D.; Norris, F.A.; Caldwell, K.K.; Brown, S.; Majerus, P.W.; Mitchell, C.A.
The inositol polyphosphate 4-phosphatase forms a complex with phosphatidylinositol 3-kinase in human platelet cytosol
Proc. Natl. Acad. Sci. USA
96
3640-3645
1999
Homo sapiens
Norris, F.A.; Auethavekiat, V.; Majerus, P.W.
The isolation and characterization of cDNA encoding human and rat brain inositol polyphosphate 4-phosphatase
J. Biol. Chem.
270
16128-16133
1995
Homo sapiens (Q96PE3), Homo sapiens, Rattus norvegicus (Q62784)
Norris, F.A.; Atkins, R.C.; Majerus, P.W.
The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family
J. Biol. Chem.
272
23859-23864
1997
Homo sapiens (Q96PE3), Homo sapiens, Rattus norvegicus (Q9QWG5)
Norris, F.A.; Atkins, R.C.; Majerus, P.W.
Inositol polyphosphate 4-phosphatase is inactivated by calpain-mediated proteolysis in stimulated human platelets
J. Biol. Chem.
272
10987-10989
1997
Homo sapiens
Ivetac, I.; Munday, A.D.; Kisseleva, M.V.; Zhang, X.M.; Luff, S.; Tiganis, T.; Whisstock, J.C.; Rowe, T.; Majerus, P.W.; Mitchell, C.A.
The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane
Mol. Biol. Cell
16
2218-2233
2005
Homo sapiens
Sharma, M.; Batra, J.; Mabalirajan, U.; Sharma, S.; Nagarkatti, R.; Aich, J.; Sharma, S.K.; Niphadkar, P.V.; Ghosh, B.
A genetic variation in inositol polyphosphate 4 phosphatase A enhances susceptibility to asthma
Am. J. Respir. Crit. Care Med.
177
712-719
2008
Homo sapiens (Q96PE3), Homo sapiens
Gewinner, C.; Wang, Z.C.; Richardson, A.; Teruya-Feldstein, J.; Etemadmoghadam, D.; Bowtell, D.; Barretina, J.; Lin, W.M.; Rameh, L.; Salmena, L.; Pandolfi, P.P.; Cantley, L.C.
Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling
Cancer Cell
16
115-125
2009
Homo sapiens
Hodgson, M.C.; Shao, L.J.; Frolov, A.; Li, R.; Peterson, L.E.; Ayala, G.; Ittmann, M.M.; Weigel, N.L.; Agoulnik, I.U.
Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer
Cancer Res.
71
572-582
2011
Homo sapiens
Fedele, C.G.; Ooms, L.M.; Ho, M.; Vieusseux, J.; OToole, S.A.; Millar, E.K.; Lopez-Knowles, E.; Sriratana, A.; Gurung, R.; Baglietto, L.; Giles, G.G.; Bailey, C.G.; Rasko, J.E.; Shields, B.J.; Price, J.T.; Majerus, P.W.; Sutherland, R.L.; Tiganis, T.; McLean, C.A.; Mitchell, C.A.
Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers
Proc. Natl. Acad. Sci. USA
107
22231-22236
2010
Homo sapiens
Khanna, K.; Chaudhuri, R.; Aich, J.; Pattnaik, B.; Panda, L.; Prakash, Y.S.; Mabalirajan, U.; Ghosh, B.; Agrawal, A.
Secretory inositol polyphosphate 4-phosphatase protects against airway inflammation and remodeling
Am. J. Respir. Cell Mol. Biol.
60
399-412
2018
Homo sapiens (Q96PE3), Homo sapiens, Mus musculus (Q9EPW0)
Sung, J.Y.; Na, K.; Kim, H.S.
Down-regulation of inositol polyphosphate 4-phosphatase type II expression in colorectal carcinoma
Anticancer Res.
37
5525-5531
2017
Homo sapiens (O15327), Homo sapiens
Rijal, S.; Fleming, S.; Cummings, N.; Rynkiewicz, N.K.; Ooms, L.M.; Nguyen, N.Y.; Teh, T.C.; Avery, S.; McManus, J.F.; Papenfuss, A.T.; McLean, C.; Guthridge, M.A.; Mitchell, C.A.; Wei, A.H.
Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML
Blood
125
2815-2824
2015
Homo sapiens (O15327), Homo sapiens
Zhang, B.; Wang, W.; Li, C.; Liu, R.
Inositol polyphosphate-4-phosphatase type II plays critical roles in the modulation of cadherin-mediated adhesion dynamics of pancreatic ductal adenocarcinomas
Cell Adh. Migr.
12
548-563
2018
Homo sapiens (O15327), Homo sapiens
Li, D.; Yang, J.; Ma, H.; Sun, C.; Feng, R.
Inositol polyphosphate-4-phosphatase type II and rucaparib treatment inhibit the growth of osteosarcoma cells dependent on phosphoinositide 3-kinase/protein kinase B pathway
J. Cell. Biochem.
119
9899-9909
2018
Homo sapiens (O15327), Homo sapiens
Li, H.; Wu, X.; Hou, S.; Malek, M.; Kielkowska, A.; Noh, E.; Makondo, K.J.; Du, Q.; Wilkins, J.A.; Johnston, J.B.; Gibson, S.B.; Lin, F.; Marshall, A.J.
Phosphatidylinositol-3,4-bisphosphate and its binding protein lamellipodin regulate chemotaxis of malignant B lymphocytes
J. Immunol.
196
586-595
2016
Homo sapiens (O15327)
Reed, D.E.; Shokat, K.M.
INPP4B and PTEN loss leads to PI-3,4-P2 accumulation and inhibition of PI3K in TNBC
Mol. Cancer Res.
15
765-775
2017
Homo sapiens (O15327), Homo sapiens
Zhang, M.; Suarez, E.; Vasquez, J.L.; Nathanson, L.; Peterson, L.E.; Rajapakshe, K.; Basil, P.; Weigel, N.L.; Coarfa, C.; Agoulnik, I.U.
Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity
Oncogene
38
1121-1135
2018
Homo sapiens (O15327), Homo sapiens, Mus musculus (Q6P1Y8), Mus musculus
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