Information on EC 3.1.3.67 - phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

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The expected taxonomic range for this enzyme is: Eutheria

EC NUMBER
COMMENTARY
3.1.3.67
-
RECOMMENDED NAME
GeneOntology No.
phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O = 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of phosphoric ester
-
-
-
-
hydrolysis of phosphoric ester
-
-
hydrolysis of phosphoric ester
-
-
hydrolysis of phosphoric ester
-
-
phospho-group transfer
-
-
PATHWAY
KEGG Link
MetaCyc Link
3-phosphoinositide degradation
-
Inositol phosphate metabolism
-
SYSTEMATIC NAME
IUBMB Comments
1-phosphatidyl-1D-myo-inositol-3,4,5-trisphosphate 3-phosphohydrolase
Requires Mg2+. Does not dephosphorylate inositol 4,5-bisphosphate. This enzyme still works when the 2,3-bis(acyloxy)propyl group is removed, i.e., it hydrolyses Ins(1,3,4,5)P4 to Ins(1,4,5)P3
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
1-phosphatidylinositol-3,4,5-trisphosphate 3-phosphohydrolase
-
-
-
-
MMAC1/TEP1
-
-
phosphatase and tensin homolog
-
-
phosphatase and tensin homologue
-
-
phosphatase and tensin homologue deleted on chromosome 10
-
-
phosphatase and tensin homologue deleted on chromosome 10
-
-
phosphatidylinositol 3,4,5-trisphosphate-specific phosphatase
-
-
phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
-
-
PI 3-phosphatase
-
-
PTEN
-
-
PTEN
-
-
PTEN
-
tumor suppressor
PTEN
O54857
-
PTEN phosphatase
-
-
PTEN/MMAC
-
-
tumor suppressor PREN
-
-
CAS REGISTRY NUMBER
COMMENTARY
210488-47-4
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
mice heterozygous for PTEN (+/-) on the C57BL6 genetic background
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
thrombin transiently increases PTEN lipid phosphatase activity, while pretreatment of HPAE cells with bpV(pic) slightly reduces basal PTEN activity.Thrombin fails to induce PTEN activity in cells pretreated with bpV(pic). Inhibiting PTEN activity also decreases Akt phosphorylation, inhibiting PTEN phosphatase activity has no effect on thrombin-induced Ca2+ entry
physiological function
-
phosphatase and tensin homologue is a dual lipidprotein phosphatase that catalyzes the conversion of phosphoinositol 3,4,5-triphosphate to phosphoinositol 4,5-bisphosphate and thereby inhibits PI3K-Akt-dependent cell proliferation, migration, and tumor vascularization. But PTEN is indicated to play a role beyond suppressing PI3K signaling, it also plays a role in regulating Ca2+ entry through transient receptor potential canonical channel 6, TRPC6, that does not require PTEN phosphatase activity, overview. PTEN tail-domain residues 394-403 permit PTEN to associate with TRPC6. The inflammatory mediator thrombin promotes this association. Deletion of PTEN residues 394-403 prevents TRPC6 cell surface expression and Ca2+ entry, regulation, overview
malfunction
-
lentiviral infection of PTEN shRNA significantly inhibits Caco-2/15 cell polarization, functional differentiation and brush border development. A strong reduction in claudin 1, 3, 4 and 8 is also observed as well as a decrease in transepithelial resistance. Loss of PTEN phosphatase expression increases the spreading, migration and invasion capacities of colorectal cancer cells in vitro, role of PTEN in human colorectal cancer cells, phenotype, overview. Loss of PTEN expression in Caco-2/15 cells stimulates migration/invasion, promotes tumor growth but is not sufficient to confer metastatic potential in vivo
additional information
-
loss of PTEN expression in HCT116 and CT26, but not in Caco-2/15, leads to an increase in their metastatic potential following tail-vein injections in mice
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 3,4,5-triphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
dual-specific phosphatase
-
-
?
4-nitrophenyl phosphate + H2O
4-nitrophenol + phosphate
show the reaction diagram
-
-
-
?
D-myo-phosphatidylinositol 3,4,5-trisphosphate + H2O
D-myo-phosphatidylinositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
inositol 1,3,4,5-tetrakisphosphate + H2O
inositol 1,4,5-trisphosphate + phosphate
show the reaction diagram
-
-
-
?
phosphatidylinositol 3,4,5-triphosphate + H2O
phosphatidylinositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
phosphatidylinositol 3,4,5-triphosphate + H2O
phosphatidylinositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
phosphatidylinositol 3,4,5-triphosphate + H2O
phosphatidylinositol 4,5-biphosphate + phosphate
show the reaction diagram
-
-
-
-
?
phosphatidylinositol 3,4,5-trisphosphate + H2O
phosphatidyl inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
?
phosphatidylinositol 3,4,5-trisphosphate + H2O
phosphatidyl inositol 4,5-bisphosphate + phosphate
show the reaction diagram
O54857
-
-
-
?
phosphatidylinositol 3,4,5-trisphosphate + H2O
phosphatidyl inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
tumor suppressor function. Dephosphorylation of the second-messenger phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-diphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway
-
?
phosphatidylinositol 3,4,5-trisphosphate + H2O
phosphatidyl inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
dephosphorylating
-
-
?
phosphatidylinositol 3,4-bisphosphate + H2O
phosphatidylinositol 4-phosphate + phosphate
show the reaction diagram
-
-
-
-
?
phosphatidylinositol 3,4-bisphosphate + H2O
phosphatidylinositol 4-phosphate
show the reaction diagram
-
tumor suppressor function. Dephosphorylation of the second-messenger phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-diphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway
-
?
phosphatidylinositol 3-phosphate + H2O
phosphatidylinositol + phosphate
show the reaction diagram
-
at 20% of the activity with phosphatidylinositol-3,4,5-trisphosphate
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
Phosphatidyl inositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
Phosphatidyl inositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
Phosphatidyl inositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
Phosphatidylinositol-3,4,5-trisphosphate + H2O
Phosphatidyl inositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
it is possible that the enzyme acts in vivo as a phosphoinositide 3-phosphatase by regulating phosphatidylinositol-3,4,5-trisphosphate levels
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
Phosphatidyl inositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
PTEN regulates the phosphatidylinositol-3,4,5-trisphosphate and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle progression and cell survival
-
?
phosphatidylinositol-3,4,5-trisphosphate + H2O
phosphatidylinositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
?
phosphatidylinositol-3,4,5-trisphosphate + H2O
phosphatidylinositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
lipid phosphatase activity of PTEN is critical for its tumor suppressor function and the enzyme negatively regulates the phosphatidylinositol 3'-kinase-protein kinase B pathway
-
?
phosphatidylinositol-3,4,5-trisphosphate + H2O
phosphatidylinositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
PTEN/MMAC is a tumor suppressor that dephosphorylates phosphatidylinositol-3,4,5-trisphosphate, an intermediate in the PI 3-K/Akt signaling pathway
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
?
show the reaction diagram
-
the enzyme may play a critical role in the inositolphospholipid 3-kinase signalling
-
-
-
phosphatidylinositol-3,4-bisphosphate + H2O
phosphatidylinositol 4-phosphate
show the reaction diagram
-
tumor suppressor function. Dephosphorylation of the second-messenger phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-diphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway
-
?
phosphatidylinositol-3,4-bisphosphate + H2O
phosphatidylinositol-4-monophosphate + phosphate
show the reaction diagram
O54857
-
-
-
?
phosphatidylinostitol 3,4-bisphosphate + H2O
phosphatidylinositol 4-phosphate + phosphate
show the reaction diagram
-
at 20% of the activity with phosphatidylinositol-3,4,5-trisphosphate
-
?
inositol 1,3,4,5-tetrakisphosphate + H2O
inositol 1,4,5-trisphosphate
show the reaction diagram
-
-
-
?
additional information
?
-
-
the enzyme does not hydrolyze phosphatidylinositol 4,5-bisphosphate
-
-
-
additional information
?
-
-
germline PTEN mutations are associated with several dominant growth disorders. The growth regulatory function is primarily mediated via its lipid phosphatase activity, which specifically reduces the cellular levels of phosphatidylinositol 3,4,5-trisphosphate. This activity antagonizes the effects of activated phosphatidylinositol 3-kinase in the nutritionally controlled insulin receptor pathway, thereby reducing protein synthesis and restraining cell and organismal growth, while also regulating other biological processes, such as fertility and ageing. PTEN also plays a role as specialized cytoskeletal regulator, which, for example, is involved in directional movement of some migratory cells and may be important in metastasis
-
?
additional information
?
-
-
phosphatase-independent domains of PTEN markedly reduce the invasive potential of glioma cells, defining a structural role for PTEN that regulates cell motility distinct of the PKB/Akt pathway
-
?
additional information
?
-
-
protein phosphatase activity may contribute to the cell cycle inhibitory and thereby tumor suppresive function of PTEN
-
?
additional information
?
-
-
PTEN is a tumor suppressor inactivated in a variety of cancers such as glioblastoma and endometrial and prostate carcinoma. It acts as a phosphatidylinositol 3,4,5-triphosphate phosphatase antagonizing the activity of the phosphatidylinositol 3-OH kinase. The C-terminal region of PTEN contains secondary structure elements that are essential for the tumor-suppressor function of the protein
-
?
additional information
?
-
-
PTEN might regulate cell-cycle progression by blocking activation of downstream targets of phosphatidylinositol 3-kinase such as the protooncogene Akt. PTEN is capable of inhibiting wild-type Akt kinase activity in cells
-
?
additional information
?
-
-
PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein
-
?
additional information
?
-
-
the enzyme plays a role in regulating the activity of the phosphatidylinositol 3-kinase pathway in malignant cells
-
?
additional information
?
-
-
depending on the cell type, PTEN is important for proper development, cell fate and cell function, as well as for protection from tumorigenesis
-
-
-
additional information
?
-
-
loss of PTEN in the liver creates a state in which the phosphatidylinositol-3 kinase pathway is constitutively active, leading to chronic suppression of apolipoprotein B 100 and mitogen-activated protein resulting in reduced very low-density lipoprotein assembly and hepatic secretion of triglyceride
-
-
-
additional information
?
-
-
lung-specific deletion of PTEN after birth results in bronchiolar and alveolar epithelial hyperplasia
-
-
-
additional information
?
-
-
most of the tumor suppressor function of PTEN has been attributed to its ability to dephosphorylate the second messenger, phosphatidylinositol 3,4,5-triphosphate, resulting in the biological control of the phosphatidylinositol 3-kinase/protein kinase B pathway
-
-
-
additional information
?
-
-
N-terminal domain of PTEN binds anionic lipids via nonspecific electrostatic interactions
-
-
-
additional information
?
-
-
nuclear PTEN is not the same as cytoplasmic PTEN, nuclear PTEN has diverse roles particularly in chromosome stability, DNA repair, cell cycle arrest and cellular stability
-
-
-
additional information
?
-
-
overexpression of PTEN modulates the basal activities of both phosphoinositide 3 kinase-AKT and mitogen-activated protein kinase-extracellular signal-regulated kinase cascades
-
-
-
additional information
?
-
-
PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor that is mutated or deleted in a variety of human tumors, and even loss of only one PTEN gene profoundly affects carcinogenesis
-
-
-
additional information
?
-
-
PTEN activity may control the stability and cellular availability of newly synthesized hepatic apolipoprotein B100 at least partially through modulation of microsomal triglyceride transfer protein
-
-
-
additional information
?
-
-
PTEN acts as an major tumor suppressor gene that is inacitvated in a wide variety of cancers
-
-
-
additional information
?
-
-
PTEN acts to suppress cell growth, proliferation and survival, and in a more cell-specific manner, PTEN plays a role in the establishment of polarity and inhibits the migration of several mammalian cell types
-
-
-
additional information
?
-
-
PTEN binds synergistically phosphatidylinositol 4,5-biphosphate and phosphatidylserine
-
-
-
additional information
?
-
-
PTEN controls FYN kinase activity through its protein phosphatase function in glioma cells, PTEN controls vitronectin-mediated migration through its protein phosphatase activity in glioma cells
-
-
-
additional information
?
-
-
PTEN directly downregulates neurotophin receptor (p75NTR) expression by decreasing DNA-binding activity of transcription factor Sp1
-
-
-
additional information
?
-
-
PTEN encodes a phosphatidylinositol phosphate phosphatase specific for the 3-position of the inositol ring, it influences many biological processes in both developing and adult organisms
-
-
-
additional information
?
-
-
PTEN exists in a high activity state when it binds transiently at membrane surfaces containing its substrate and other lipids, such as phosphatidylinositol 4,5-bisphosphate and phosphatidylserine
-
-
-
additional information
?
-
-
PTEN inactivation in pancreas results in increases insulin sensitivity and hypoglycemia and may result in cystic changes of this organ due to mucinous metaplasia. Thus, PTEN is important for the physiological function of the pancreas as well as for the conservation of normal organ structure
-
-
-
additional information
?
-
-
PTEN is a dual specificity phosphatase capable of dephosphorylating both lipid and protein substrates
-
-
-
additional information
?
-
-
PTEN is critical for insulin regulation and liver homeostasis under physiological conditions, and plays an important role in suppressing the devlopment of hepatic adenomas and hepatocellular carcinomas, PTEN is required for both maturation and activation of natural killer cells
-
-
-
additional information
?
-
-
PTEN liver-specific knockout mice have fatty liver, increased triglyceride content and reduced apolipoprotein B protein mass
-
-
-
additional information
?
-
-
PTEN negatively regulates the phosphorylation of the important cellsurvival kinase Akt, PTEN plays a role in controlling seum insulin and resistin levels, which in turn regulate insulin sensitivity and AMP kinase activity in the liver, PTEN plays a role in embryogenesis and in maintenance of the normal physiological functions of many organ systems, PTEN plays an important role for protection from both epithelial as well as melanocytic tumor formation in the skin
-
-
-
additional information
?
-
-
PTEN regulates basal activities of the phosphoinositide 3-kinase-AKT8 virus oncogene cellular homolog and extracellular signal-regulated kinase cascades, independent of insulin stimulation
-
-
-
additional information
?
-
-
PTEN regulates hepatic lipogenesis, microsomal triglyceride transfer protein and the secretion of apolipoprotein B-containing lipoproteins
-
-
-
additional information
?
-
-
PTEN signaling in Pimc neurons in the hypothlamus is vital for the regulation of food uptake and body weight
-
-
-
additional information
?
-
-
PTEN tumor suppressor negatively regulates the phosphatidylinositol 3-kinase-AKT pathway
-
-
-
additional information
?
-
-
PTEN, one of the most important tumor suppressors, must associate with the plasma membrane to maintain appropriate steady-state levels of phosphatidylinositol 3,4,5-triphosphate, the membrane binding of PTEN requires phosphatidylinositol 4,5-bisphosphate
-
-
-
additional information
?
-
-
the Par-3/PDZ3-PTEN binding is required for the enrichment of PTEN at the junctional membranes of Madin-Darby canine kidney cells, the junctional membrane-localized PTEN is specifically required for the polarization of Madin-Darby canine kidney cells
-
-
-
additional information
?
-
-
the protein phosphatase activity of PTEN regulates src family kinases and controls glioma migration
-
-
-
additional information
?
-
-
the PTEN tumor suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase-dependent signalling by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate
-
-
-
additional information
?
-
-
the regulatory function of PTEN in cell polarity is specifically mediated by its interaction with Par-3, the junctional membrane localization of PTEN depends on this specific Par-3/PDZ3-PTEN tail peptide interaction
-
-
-
additional information
?
-
-
oxidation of PTEN by H2O2 oxidative stress in vitro leads to the formation of a disulfide bond between the active site Cys124 and another very closely Cys71, activates the phosphoinositide 3-kinase-dependent pathway
-
-
-
additional information
?
-
-
the PTEN phosphatase acts on phosphatidylinositol 3,4,5-triphosphates resulting from phosphatidylinositol 3-kinase activation
-
-
-
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 3,4,5-triphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
dual-specific phosphatase
-
-
?
phosphatidylinositol 3,4,5-triphosphate + H2O
phosphatidylinositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
phosphatidylinositol 3,4,5-triphosphate + H2O
phosphatidylinositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
phosphatidylinositol 3,4,5-trisphosphate + H2O
phosphatidyl inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
tumor suppressor function. Dephosphorylation of the second-messenger phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-diphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway
-
?
phosphatidylinositol 3,4,5-trisphosphate + H2O
phosphatidyl inositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
dephosphorylating
-
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
Phosphatidyl inositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
it is possible that the enzyme acts in vivo as a phosphoinositide 3-phosphatase by regulating phosphatidylinositol-3,4,5-trisphosphate levels
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
Phosphatidyl inositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
PTEN regulates the phosphatidylinositol-3,4,5-trisphosphate and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle progression and cell survival
-
?
phosphatidylinositol-3,4,5-trisphosphate + H2O
phosphatidylinositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
lipid phosphatase activity of PTEN is critical for its tumor suppressor function and the enzyme negatively regulates the phosphatidylinositol 3'-kinase-protein kinase B pathway
-
?
phosphatidylinositol-3,4,5-trisphosphate + H2O
phosphatidylinositol-4,5-bisphosphate + phosphate
show the reaction diagram
-
PTEN/MMAC is a tumor suppressor that dephosphorylates phosphatidylinositol-3,4,5-trisphosphate, an intermediate in the PI 3-K/Akt signaling pathway
-
?
Phosphatidylinositol-3,4,5-trisphosphate + H2O
?
show the reaction diagram
-
the enzyme may play a critical role in the inositolphospholipid 3-kinase signalling
-
-
-
phosphatidylinositol-3,4-bisphosphate + H2O
phosphatidylinositol 4-phosphate
show the reaction diagram
-
tumor suppressor function. Dephosphorylation of the second-messenger phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-diphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway
-
?
D-myo-phosphatidylinositol 3,4,5-trisphosphate + H2O
D-myo-phosphatidylinositol 4,5-bisphosphate + phosphate
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
germline PTEN mutations are associated with several dominant growth disorders. The growth regulatory function is primarily mediated via its lipid phosphatase activity, which specifically reduces the cellular levels of phosphatidylinositol 3,4,5-trisphosphate. This activity antagonizes the effects of activated phosphatidylinositol 3-kinase in the nutritionally controlled insulin receptor pathway, thereby reducing protein synthesis and restraining cell and organismal growth, while also regulating other biological processes, such as fertility and ageing. PTEN also plays a role as specialized cytoskeletal regulator, which, for example, is involved in directional movement of some migratory cells and may be important in metastasis
-
?
additional information
?
-
-
phosphatase-independent domains of PTEN markedly reduce the invasive potential of glioma cells, defining a structural role for PTEN that regulates cell motility distinct of the PKB/Akt pathway
-
?
additional information
?
-
-
protein phosphatase activity may contribute to the cell cycle inhibitory and thereby tumor suppresive function of PTEN
-
?
additional information
?
-
-
PTEN is a tumor suppressor inactivated in a variety of cancers such as glioblastoma and endometrial and prostate carcinoma. It acts as a phosphatidylinositol 3,4,5-triphosphate phosphatase antagonizing the activity of the phosphatidylinositol 3-OH kinase. The C-terminal region of PTEN contains secondary structure elements that are essential for the tumor-suppressor function of the protein
-
?
additional information
?
-
-
PTEN might regulate cell-cycle progression by blocking activation of downstream targets of phosphatidylinositol 3-kinase such as the protooncogene Akt. PTEN is capable of inhibiting wild-type Akt kinase activity in cells
-
?
additional information
?
-
-
PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein
-
?
additional information
?
-
-
the enzyme plays a role in regulating the activity of the phosphatidylinositol 3-kinase pathway in malignant cells
-
?
additional information
?
-
-
depending on the cell type, PTEN is important for proper development, cell fate and cell function, as well as for protection from tumorigenesis
-
-
-
additional information
?
-
-
loss of PTEN in the liver creates a state in which the phosphatidylinositol-3 kinase pathway is constitutively active, leading to chronic suppression of apolipoprotein B 100 and mitogen-activated protein resulting in reduced very low-density lipoprotein assembly and hepatic secretion of triglyceride
-
-
-
additional information
?
-
-
lung-specific deletion of PTEN after birth results in bronchiolar and alveolar epithelial hyperplasia
-
-
-
additional information
?
-
-
most of the tumor suppressor function of PTEN has been attributed to its ability to dephosphorylate the second messenger, phosphatidylinositol 3,4,5-triphosphate, resulting in the biological control of the phosphatidylinositol 3-kinase/protein kinase B pathway
-
-
-
additional information
?
-
-
N-terminal domain of PTEN binds anionic lipids via nonspecific electrostatic interactions
-
-
-
additional information
?
-
-
nuclear PTEN is not the same as cytoplasmic PTEN, nuclear PTEN has diverse roles particularly in chromosome stability, DNA repair, cell cycle arrest and cellular stability
-
-
-
additional information
?
-
-
overexpression of PTEN modulates the basal activities of both phosphoinositide 3 kinase-AKT and mitogen-activated protein kinase-extracellular signal-regulated kinase cascades
-
-
-
additional information
?
-
-
PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor that is mutated or deleted in a variety of human tumors, and even loss of only one PTEN gene profoundly affects carcinogenesis
-
-
-
additional information
?
-
-
PTEN activity may control the stability and cellular availability of newly synthesized hepatic apolipoprotein B100 at least partially through modulation of microsomal triglyceride transfer protein
-
-
-
additional information
?
-
-
PTEN acts as an major tumor suppressor gene that is inacitvated in a wide variety of cancers
-
-
-
additional information
?
-
-
PTEN acts to suppress cell growth, proliferation and survival, and in a more cell-specific manner, PTEN plays a role in the establishment of polarity and inhibits the migration of several mammalian cell types
-
-
-
additional information
?
-
-
PTEN binds synergistically phosphatidylinositol 4,5-biphosphate and phosphatidylserine
-
-
-
additional information
?
-
-
PTEN controls FYN kinase activity through its protein phosphatase function in glioma cells, PTEN controls vitronectin-mediated migration through its protein phosphatase activity in glioma cells
-
-
-
additional information
?
-
-
PTEN directly downregulates neurotophin receptor (p75NTR) expression by decreasing DNA-binding activity of transcription factor Sp1
-
-
-
additional information
?
-
-
PTEN encodes a phosphatidylinositol phosphate phosphatase specific for the 3-position of the inositol ring, it influences many biological processes in both developing and adult organisms
-
-
-
additional information
?
-
-
PTEN exists in a high activity state when it binds transiently at membrane surfaces containing its substrate and other lipids, such as phosphatidylinositol 4,5-bisphosphate and phosphatidylserine
-
-
-
additional information
?
-
-
PTEN inactivation in pancreas results in increases insulin sensitivity and hypoglycemia and may result in cystic changes of this organ due to mucinous metaplasia. Thus, PTEN is important for the physiological function of the pancreas as well as for the conservation of normal organ structure
-
-
-
additional information
?
-
-
PTEN is a dual specificity phosphatase capable of dephosphorylating both lipid and protein substrates
-
-
-
additional information
?
-
-
PTEN is critical for insulin regulation and liver homeostasis under physiological conditions, and plays an important role in suppressing the devlopment of hepatic adenomas and hepatocellular carcinomas, PTEN is required for both maturation and activation of natural killer cells
-
-
-
additional information
?
-
-
PTEN liver-specific knockout mice have fatty liver, increased triglyceride content and reduced apolipoprotein B protein mass
-
-
-
additional information
?
-
-
PTEN negatively regulates the phosphorylation of the important cellsurvival kinase Akt, PTEN plays a role in controlling seum insulin and resistin levels, which in turn regulate insulin sensitivity and AMP kinase activity in the liver, PTEN plays a role in embryogenesis and in maintenance of the normal physiological functions of many organ systems, PTEN plays an important role for protection from both epithelial as well as melanocytic tumor formation in the skin
-
-
-
additional information
?
-
-
PTEN regulates basal activities of the phosphoinositide 3-kinase-AKT8 virus oncogene cellular homolog and extracellular signal-regulated kinase cascades, independent of insulin stimulation
-
-
-
additional information
?
-
-
PTEN regulates hepatic lipogenesis, microsomal triglyceride transfer protein and the secretion of apolipoprotein B-containing lipoproteins
-
-
-
additional information
?
-
-
PTEN signaling in Pimc neurons in the hypothlamus is vital for the regulation of food uptake and body weight
-
-
-
additional information
?
-
-
PTEN tumor suppressor negatively regulates the phosphatidylinositol 3-kinase-AKT pathway
-
-
-
additional information
?
-
-
PTEN, one of the most important tumor suppressors, must associate with the plasma membrane to maintain appropriate steady-state levels of phosphatidylinositol 3,4,5-triphosphate, the membrane binding of PTEN requires phosphatidylinositol 4,5-bisphosphate
-
-
-
additional information
?
-
-
the Par-3/PDZ3-PTEN binding is required for the enrichment of PTEN at the junctional membranes of Madin-Darby canine kidney cells, the junctional membrane-localized PTEN is specifically required for the polarization of Madin-Darby canine kidney cells
-
-
-
additional information
?
-
-
the protein phosphatase activity of PTEN regulates src family kinases and controls glioma migration
-
-
-
additional information
?
-
-
the PTEN tumor suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase-dependent signalling by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate
-
-
-
additional information
?
-
-
the regulatory function of PTEN in cell polarity is specifically mediated by its interaction with Par-3, the junctional membrane localization of PTEN depends on this specific Par-3/PDZ3-PTEN tail peptide interaction
-
-
-
additional information
?
-
-
the PTEN phosphatase acts on phosphatidylinositol 3,4,5-triphosphates resulting from phosphatidylinositol 3-kinase activation
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
in presence of 1 mM Mg2+, slight activation up to 0.01 mM, significant inhibition above 0.1 mM
Mg2+
-
divalent cation required, maximal activition at 1 mM, inhibition above 1 mM
Mn2+
-
divalent cation required, Mn2+ is less effective than Mg2+. 0.5 mM Mn2+ gives 30% of the maximal activity with 1 mM Mg2+
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
Ca2+
-
in presence of 1 mM Mg2+, slight activation up to 0.01 mM, significant inhibition above 0.1 mM
H2O2
-
H2O2 reversibly inhibits PTEN activity by covalently linking Cys-71 to Cys-124, inhibition partially reverses by inclusion of 100 mM dithiothreitol to the buffer
Laminin
-
laminin medium induces PTEN upregulation decreases transcription factor Sp1-binding activity
-
phosphatidylserine
-
0.2 mM, 75% loss of activity
reactive oxygen species
-
oxidation of the active site cysteine by reactive oxygen species inhibits PTEN
-
Mg2+
-
divalent cation required, maximal activition at 1 mM, inhibition above 1 mM
additional information
-
PTEN is inhibited by cyclic strain: cyclic strain increases phosphatidylinositol 3,4,5-trisphosphate immunofluorescence and peaks at 60 min after cyclic strain stimulation by 1.93fold in endothelial cells
-
additional information
-
PTEN function is very frequently lost during the development of epithelial-derived tumors, and many such tumors are believed to undergo a form of epithelial to mesenchymal transition before these metastasize
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
phosphatidylinositol 4,5-biphosphate
-
Enhances PTEN phosphatase activity by inducing conformational change by binding to the PTEN N-terminal domain. Binding constants are in accord with enzyme kinetic measurements showing that phosphatidylinositol 4,5-bisphosphate enhances phosphatidylinositol 3,4,5-triphosphate hydrolysis more effectively than phosphatidylserine, and the binding constant of phosphatidylinositol 4,5-biphosphate of 8.14 microM is in general agreement with the phosphatidylinositol 4,5-bisphosphate concentration requires to activate the PTEN phosphatase. The magnitude of this binding constant indicates that PTEN-phosphatidylinositol 4,5-bisphosphate interactions are physiologically relevant since the effective cellular concentration of phosphatidylinositol 4,5-bisphosphate is thought to be 10 microM, and local phosphatidylinositol 4,5-bisphosphate concentrations are likely to reach even higher levels. Increasing the phosphatidylserine concentration to 25 mol results in stronger binding, but even for these higher surface charge densities, binding constant is still lower than the corresponding values for the phosphatidylcholine/phosphatidylinositol 4,5-bisphosphate vesicle system.
Thrombin
-
transiently increases PTEN lipid phosphatase activity by about 2.5fold within 1 min, which remains elevated for 5 min
-
acidic lipids
-
acidic lipids, and phosphatidylinositol 4,5-bisphosphate in particular, cause a conformational change within the enzyme and allosteric activation
-
additional information
-
treatment of many cell types with proteasome inhibitors enhances the levels of PTEN protein
-
additional information
-
the enzyme is activated by the phosphatidylinositol 3-kinase
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
25.6
-
4-nitrophenyl phosphate
-
-
0.0989
-
Inositol 1,3,4,5-tetrakisphosphate
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6.7
-
O54857
-
additional information
-
-
-
additional information
-
-
PTEN is inactivated in bovine aortic endothelial cells exposed to cyclic strain. Inhibition of PTEN activity has no effect on cyclic strain-mediated cell proliferation but inhibits cyclic strain mediated suppression of apoptosis
additional information
-
-
loss of PTEN activity in the Hep-G2 cell line leads to activation of lipogenesis, as evidenced from increased mRNA levels for sterol regulatory element binding protein 1c, fatty acid synthase and acetyl-CoA carboxylase; modulation of PTEN influences the microsomal triglyceride transfer protein mass and lipid transfer activity; PTEN protein levels are significantly increased in a dose-dependent manner with PTEN wildtype and PTEN C124S mutant overexpression at both 5 and 20 multiplicity of infection (moi) in Hep-G2 cells
additional information
-
-
loss of PTEN activity in knockout mice modell leads to activation of lipogenesis, as evidences from increased mRNA levels for sterol regulatory element binding protein 1c, fatty acid synthase and acetyl-CoA carboxylase; modulation of PTEN influences the microsomal triglyceride transfer protein mass and lipid transfer activity; protein levels of PTEN in the liver of 13-week-old male mice with PTEN liver-specific knockout are significantly decreased to 16% of that in the control mice; PTEN overactivity have a profound inhibitory effect on insulin signaling downstream of phosphatidylinositol-3 kinase and can readily induce insulin resistance
additional information
-
-
PTEN is an interfacially activated enzyme. PTEN can exist in 2 active states, one favouring metabolism of soluble substrates and the interfacially activity state is necessary for efficient metabolism of phosphatidylinositol 3,4,5-trisphosphate.; regulation of PTEN activity and expression serves not only to modulate the temporal and spatial distribution of phosphatidylinositol 3,4,5-trisphosphate but also its availability for an alternative route of metabolism to phosphatidylinositol 4,5-bisphosphate by 5-phosphatases; the scale of the interfacial activation when PTEN associates with a membrane or vesicular substrate depends largely on the composition of the membrane and particularly its surface characteristics, these includes the overall surface charge, largely determined both by its phosphatidylserine content and on the presence of phosphatidylinositol 4,5-bisphosphate
additional information
-
-
activity of PTEN is dependent on extent of membrane binding, phosphorylation of the C-terminal cluster has an inhibitory effect on membrane association and activity; alanine substituted PTEN is 7fold more active than wildtype PTEN; PTEN cellular activity is proportional to the extent of membrane association
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
8
-
-
-
8
-
O54857
assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
O54857
assay at
37
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
primary astrocyte, expression of wild-type enzyme
Manually annotated by BRENDA team
-
cultures are established from wildtype, PTEN heterozygous (+/-) mice and PTEN and Fyn kinase double heterozygous (+/-) mice
Manually annotated by BRENDA team
-
decreased enzyme in colorectal cancer
Manually annotated by BRENDA team
-
aortic endothelial cells, no change in PTEN protein expression in endothelial cells exposed to up to 24 h of cyclic strain
Manually annotated by BRENDA team
-
embryonic fibroblast
Manually annotated by BRENDA team
-
tissue from patients with sporadic gastric carcinoma
Manually annotated by BRENDA team
-
expression of mutant forms of PTEN
Manually annotated by BRENDA team
-
human embryonic kidney cell
Manually annotated by BRENDA team
-
infiltrative glioma cell line
Manually annotated by BRENDA team
-
Madin-darby canine kidney cell
Manually annotated by BRENDA team
O54857
amplified by PCR from
Manually annotated by BRENDA team
-
the disruption of the PTEN/MMAC1 gene is not a frequent event in neuroblastoma. This disruption may be responsible for malignant progression in only a limited proportion of cases of neuroblastoma
Manually annotated by BRENDA team
-
papillomavirus-infected laryngeal papillomas overexpress PTEN/MMAC1
Manually annotated by BRENDA team
-
pheochromocytoma cells
Manually annotated by BRENDA team
-
gastric cancer cell, PTEN negative and phospho-Akt-positive
Manually annotated by BRENDA team
-
glioblastoma-astrocytoma, epithelial-like cell line
Manually annotated by BRENDA team
additional information
-
infiltrative glioma cell line U87MG lacks functional PTEN
Manually annotated by BRENDA team
additional information
-
the enzyme is mutated in a wide range of human cancers
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
stably, but transiently bound
Manually annotated by BRENDA team
-
although the main substrate of PTEN is at the plasma membrane, the enzyme is mainly found in cytosol and the nucleus, but a small fraction is dynamically associated with the inner face of the plasma membrane
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
50000
-
O54857
50-53 kDa, SDS-PAGE
120000
-
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
monomer
-
1 * 120000, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
phosphoprotein
-
exposure of bovine aortic endothelial cells to cyclic strain results in a time-dependent PTEN phosphorylation. Maximal phosphorylation occurres at 10 min after the cyclic strain stimulation by 2.21fold relative to static condition
acetylation
-
inhibiton of PTEN
phosphoprotein
-
the 50-amino-acid C-terminal domain, the tail, is necessary for maintaining protein stability and it also acts to inhibit PTEN function. The tail-dependent regulation of stability and activity is linked to the phosphorylation of three residues, S380, T382, and T383 within the tail. Therefor, the tail is likely to mediate the regulation of PTEN function through phosphorylation
phosphoprotein
-
phosphorylation of several serine and threonine residues in the C-terminus of the protein inhibits PTEN, e.g., suppressing of membrane association, nuclear localization, PDZ-binding, ubiquitination, degradation and phosphatase activity. The phosphorylation sites form 2 separable groups comprising a close cluster of 4 residues, Ser380, Thr382, Thr383 and Ser385, and a pair of residues slightly more N-terminal, Thr366 and Ser370. The 380-385 cluster sites all appear to be phosphorylated by protein kinase CK2.; tyrosine residues, present in most examples of a rare subset of lung tumours, but not detected in the great majority. PTEN tyrosine phosphorylation may occur only in certain cell types and circumstances, or that only an extremely small proportion of the cellular PTEN becomes tyrosine phosphorylated
phosphoprotein
-
C-terminal 51 amino acids contains a cluster of phosphorylation sites which regulates protein stability and function in cells, a phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN, phosphorylation of the C-terminal cluster has an inhibitory effect on membrane association and activity
phosphoprotein
-
the enzyme is activated by the phosphatidylinositol 3-kinase
ubiquitination
-
mono-ubiquitination-mediated PTEN stabilization is essential for its tumor suppression activity
ubiquitination
-
regulation of activity, mono- and polyubiquitinated, PTEN has 2 canonical PEST motifs, a signature in many short-lived proteins degraded by ubiquitin-proteasome pathway, controlling of nuclear localization and PTEN stability
phosphoprotein
O54857
recombinant PTEN is phosphorylated in the infected insect cells at Ser-380, Thr-382, and Thr-383 at the C-terminal tail
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
the 50-amino-acid C-terminal domain, the tail, is necessary for maintaining protein stability
-
the PDZ-binding domain binds to several proteins, including MAGI-2 and MAST205, these interactions appear to enhance the stability of PTEN, as interference with either these binding partners or the ability of PTEN to bind them greatly reduces stability. A protein named PICT-1 (protein interacting with the C-tail-1) interacts with the C-terminus of PTEN, promoting both phosphorylation and stability of PTEN
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
fusion-protein is purified by Glutathione-Sepharose-4B affinity chromatography
-
Poly-His tag proteins are purified with a HisTrap HP kit using buffers with 10 mM mercaptoethanol, enzymes are further purified with a gel filtration column in 100 mM NaCl, 10 mM Tris, pH 7.4, and 1 mM dithiothreitol. Final purification is done with a anion exchange column in 10 mM Tris, pH 7.4 with a linear gradient from 50-600 mM NaCl.
-
recombinant enzyme
-
recombinant PTEN is purified to near homogeneity using four sequential column chromatographic steps: a diethylaminoethyl (DEAE) Sepharose anion exchange column, a bio-gel hydroxyapatite HT (HAP) column, a Mono-S cation exchange column, and a Mono-Q anion exchange column; treatment with alkaline phosphatase fully dephosphorylates the phosphorylation sites. Unphosphorylated PTEN and alkaline phosphatase can be separated by ion exchange column chromatography
O54857
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
C-terminal domain of enzyme is expressed in BL21 (DE3) Escherichia coli cells as glutathione S-transferase-protein. Par-3/PDZ3-PTEN peptide single chain fusion protein contains a thrombin cleavage site (LVPRGS) between the C-terminus of PDZ3 domain and the PTEN peptide (DEDQSHQITKV), production of a canine knockdown
-
adenovirus expressing PTEN wild-type, encoding full-length human wild-type PTEN cDNA and AdPTENC/S, encoding a dominant negative human PTEN cDNA mutant (cysteine 124 changed to serine within the catalytic domain) are used for the transduction of cell cultures, overexpression of PTEN and its mutant
-
cDNA is subcloned into bicistronic pIRES vector, which also codes for GFP expression and transiently transfected into the following cell lines: HaCaT, MCA3D, NIH 3T3, 3T3 Ki ras and 3T3 v-src
-
expression in Escherichia coli
-
overexpressed in MCF-7 breast cancer cell line
-
PTEN-null U87 cells are transiently transfected with either wild-type PTEN-green fluorescent protein or PTEN-alanine substituted-green fluorescent protein. U87 cells expressing PH-AKT1-green fluorescent protein are co-transfected with either wildtype PTEN or PTEN-alanine substituted enzyme. Whereas two cells co-expressing wild-type PTEN and PH-AKT1-green fluorescent protein fails to respond to epidermal growth factor stimulation, all PTEN-alanine substituted proteins co-transfected cells fail to respond. HeLa cells are transiently co-transfected with cyan fluorescent protein-FKBP-inositol polyphosphate-5-phosphatase and PTEN-C124S-alanine substituted-yellow fluorescent protein. Expression of PTEN-C124Salanine substituted-yellow fluorescent protein in HeLa cells.
-
The cDNA encoding full-length 1-403 PTEN is cloned into the NdeI and XhoI sites of the pET30b vector, thereby introducing a poly-His tag at the C-terminus. Point mutations are introduced with the Quick-Change site-directed mutagenesis kit. Deletion mutant 16-403 is prepared by PCR with the Phusion DNA polymerase. PTEN proteins are expressed in Escherichia coli BL21 (DE3) cells.
-
Wild type and mutant cDNA is subcloned in the vector pcDNA3.1 to generate expression vectors, transduction of recombinant PTEN and PTEN mutant into TMK-1 cells. Recombinant PTEN effectively downregulates phospho-Akt levels as well as the LY294002 phosphatidylinositol 3-kinase inhibitor
-
By crossing CD18-Cre recombinase transgenic mice with mice with a conditional point mutation of the pten gene, pten gene is specifically deleted in the B-cell lineage. Mutant animals do not develop B-cell malignancies.; Conditionally deleted pten in oocytes using transgenic mice expressing Cre recombinase under the control of the growth differentiation factor 9 promoter. Pten deficiency in murine oocytes causes the entire oocyte pool to become activated in life.; Creating of a conditional mutant with a combined deletion of Smad4 and Pten, the double mutant shows skin tumor onset; crossing of mice expressing Cre recombinase under the control of the nestin promoter to conditional PTEN mice, mice show a continous increase in brain size throughout embryonal development, individual cells from mutant brain are larger than that of wild type brains; deletion of pten gene in the urothelium results in an increased susceptibility to chemically induced carcinogenesis; female pten-deficient +/- mice develop multifocal endometrial complex atypical hyperplasia between the age of 18 and 39 weeks; Generating of mice with a complete ablation of PTEN is achieved by crossing mice with a conditional point mutation of the pten gene with two transgenic strains in which Cre recmbinase is under the control of the probasin promoter. Mice with complete loss of PTEN in the prostate show 100% penetrance of invasive prostate cancer starting st the age of 6 month; generating of Pten-deficient mice leads to an increasing rate of fatty acid synthesis that is 2.5 times higher than in wild types, furthermore an increase in insulin sensitivity in liver-specifiv Pten-deficient mice is observed, which results in lower fasting plasma glucose levels and reduced serum insulin; Generating of pten +/hyp mice that carry only one hypomorphic pten allele and thus expresses half of the wild type level of one wild type allele. Pten +/hyp mice are crossed with pten +/- mice to generate pten +/+, pten +/-, pten +/hyp and pten hyp/- mice. The pten hyp/- mice are not born at the expected Mendelian ratio, indicating that the hypomorphic pten allele is insufficient to rescue development in all embryos. Surviving male pten hyp/- mice have a much higher incidence of pathological changes in the prostate; Generating of thyroid-specific PTEN-deficient mice using TpoCre transgenic mice,PTEN deletion does not affect normal thyroid development and function, but may contribute to adenoma development; generation of mice with conditional inactivation of PTEN in the mammary epithelium using two different MMTV-Cre recombinase mouse strains results in developmental defects of the mammary gland, mammary ducts in the mutant mice grow much faster than in wild type mice and exhibit excessive side branching and precocious lobuloalveolar budding; homozygous conditional inactivation of PTEN in endothelial and endocardial cells results in embryonic lethality; mice heterozygous for a null mutation of pten gene shows a higher risk for the development of breast and endometrial cancers, by 30-49 weeks of age, 61% female PTEN +/- mice have developed mammary tumors that are mainly adenocarcinomas or small fibroadenomas; mice which deleted pten gene in all T lineage cells show lymphadenopathy, splenomegaly and an enlarged thymus at 6-8 weeks of age, tumor formation is observed from 10 weeks onward and all mice died of malignant T-cell lymphoma by week 17; mice with a conditional null mutation of the pten gene are crossed to transgenic mice in which Cre recombinase expression is driven by the glial fibrillary acidic protein promoter; Mutant mice with brain-specific PTEN deficiency are generated. One transgenic mouse strain expressed Cre recombinase under the control of the engrailed-2 promoter. Crossing of this strain to mice with a conditional null mutation of the pten gene results in the inactivation of PTEN in cells that localize to the dorsal midbrain-hindbrain junction and give rise to cells that populate the vermis of the cerebellum.; Strain of mice with a prostate-specfic deletion of pten is created using Cre recombinase under the control of the prostate-specific antigen promoter, all mutant mice show prostate hyperplasia with focal PIN at the age of 4-5 months. By 7-9 months, PIN is widespread and focal microinvasion is observed. All mutant mice aged 10-14 months show invasive prostate cancer.; the keratin 5 promotor-cren recombinase-driven deletion of pten gene induces hyperplasia of both skin and esophageal squamous epithelium, the esophageal hyperplasia in malnutrition of pups during lactation, 90% of them died within 21 days of birth; To explore PTEN function in the liver, two groups cross PTEN mice containing a conditional point mutation, with AlbCre mice, which express Cre recombinase under the control of albumin promoter. Striking hepatomegaly is observed, which progressed with age. Mutants show accumulation of cytoplasmatic triglycerides that expand over time to severe steatohepatits. In addition, inflammatory cell infiltrates are observed in mutant livers at 24 weeks; transgenic mouse strain expressing Cre recombinase under the control of the L7 promoter, which results in the selective inactivation of PTEN in Purkinje cells
-
glioma cell lines U-87MG and U-373MG are stably transfected with wildtype PTEN or catalytically altered mutants of PTEN
-
overexpressed in 3T3L1 adipocytes
-
PTEN liver-specific knock-out mice are generated
-
GFP-tagged wild-type, C124S and G129E mutant PTEN are constructed
-
PTEN is ligated into the pBacPAK9 baculovirus transfer vector. Sf9 cells are infected with the recombinant PTEN baculovirus
O54857
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
380-385A
-
in endothelial cells transfected with 380-385A (mutation on the PTEN phosphorylation site) phosphatidylinositol 3,4,5-trisphosphate immunofluorescence intensity is than in wildtype or G129R transfected cells. Phosphatidylinositol 3,4,5-trisphosphate intensity in endothelial cells transfected with 380–385A is weak but gradually increases to a maximum at 240 min after cyclic strain stimulation by 1.48fold relative to static condition
G129R
-
in endothelial cells transfected with G129R, that lacks both protein and lipid phosphatase activities, phosphatidylinositol 3,4,5-trisphosphate immunofluorescence intensity is higher than transfection with wildtype PTEN. phosphatidylinositol 3,4,5-trisphosphate immunofluorescence in endothelial cells transfected with G129R rapidly increases and is maximum at 60 min after cyclic strain stimulation by 2.14fold relative to static condition
DELTA394-403
-
removal of the last 10 residues of PTEN leads to the complete diffusion of PTEN in MDCK cells, failing to restore the junctional localization of phosphatidylinositol 4,5-bisphosphate
A121P
-
inactive mutant enzyme
C105F
-
inactive mutant enzyme
C124R
-
inactive mutant enzyme
C124S
-
catalytically inactive mutant enzyme
C124S
-
complete loss of activity towards inositol 1,3,4,5-tetrakisphosphate
C124S
-
catalytically inert mutant enzyme
C124S
-
adenovirus encoding a dominant negative human PTEN cDNA is used for the transduction of cell cultures
C124S
-
mutant PTEN-C124S-A4-YFP lacks lipid and protein phosphatase activity, great localization to the plasma membrane than other mutants
C124S
-
phosphatase-deficient
C124S
-
the PTEN mutant lacks phosphatase activity, but is not altered in TRPC6 activity
C136Y
-
inactive mutant enzyme
C71Y
-
inactive mutant enzyme
D107Y
-
inactive mutant enzyme
D331G
-
mutant enzyme with partial activity
D92A
-
catalytically inert mutant enzyme, retains partial ability to induce cells to accumulate in G1
DELTA1-15
-
phosphatidylinositol 4,5-biphosphate has no effect on binding of PTEN16-403
DELTA352-403
-
truncated enzyme binds strongly to the plasma membrane, an effect that is reversed by co-expression of the remainder of the molecule, PTEN 352-403
F342N
-
mutant enzyme with partial activity
F347L
-
mutant enzyme with partial activity
G129E
-
inactive mutant enzyme
G129E
-
mutant enzyme is selectively deficient in the lipid phosphatase activity but still blocks the cell cycle of MCF-7 cells
G129E
-
mutant enzyme associated with Cowden‘s disease has protein phosphatase activity yet is defective in dephosphorylating inositol 1,3,4,5-tetrakisphosphate in vitro and fails to arrest cells in G1
G129E
-
transduction of recombinant PTEN in to TMK-1 cells promotes nuclear localization with increased mRNA levels of CDX2 and intestinal claudins, whereas the G129 dead phosphatase mutant has no effect
G129E
-
phosphatase-deficient
G129R
-
inactive mutant enzyme
G129R
-
the enzyme fails to induce a G1 block
G165R
-
inactive mutant enzyme
G20E
-
mutant enzyme with partial activity
G251C
-
inactive mutant enzyme
H123Y
-
mutant enzyme lacking phosphatase activity is ineffective in blocking the cell cycle of MCF-7 cells
H129R
-
mutant enzyme lacking phosphatase activity is ineffective in blocking the cell cycle of MCF-7 cells
H61R
-
inactive mutant enzyme
H93Y
-
inactive mutant enzyme
K13E
-
the binding of the PTEN mutant K13E, which is a tumor-derived mutation that renders PTEN inactive, is not affected by phosphatidylinositol 4,5-biphosphate
K289E
-
mutant enzyme with partial activity
L112P
-
inactive mutant enzyme
L112R
-
inactive mutant enzyme
L345Q
-
inactive mutant enzyme
L42R
-
activity is comparable with or even higher than that of wild-type enzyme
PTEN1-274
-
when produced as glutathione S-transferase fusion protein, the protein is defective in catalyzing the release of phosphate from either a phosphate-labeled poly(Glu4-Tyr1) substrate or inositol 1,3,4,5-tetrakisphosphate
PTEN1-336
-
when produced as glutathione S-transferase fusion protein, the protein is defective in catalyzing the release of phosphate from either a phosphate-labeled poly(Glu4-Tyr1) substrate or inositol 1,3,4,5-tetrakisphosphate
PTENDELTA274-342
-
when produced as glutathione S-transferase fusion protein, the protein is defective in catalyzing the release of phosphate from either a phosphate-labeled poly(Glu4-Tyr1) substrate or inositol 1,3,4,5-tetrakisphosphate
R130G
-
inactive mutant enzyme
R130L
-
inactive mutant enzyme
R130Q
-
inactive mutant enzyme
R173C
-
inactive mutant enzyme
R173H
-
inactive mutant enzyme
R173P
-
inactive mutant enzyme
S10N
-
activity is comparable with or even higher than that of wild-type enzyme
S170N
-
inactive mutant enzyme
S170R
-
inactive mutant enzyme
S227F
-
mutant enzyme with partial activity
S380A
-
greater catalytic activity than an unphosphorylated, bacterially expressed wild type enzyme
S380A
-
PTEN-green fluorescent protein mutant shows significant localization to the plasma membrane, the effect requires no catalytic activity
S383A
-
PTEN-green fluorescent protein mutant shows significant localization to the plasma membrane, the effect requires no catalytic activity
T382A
-
greater catalytic activity than an unphosphorylated, bacterially expressed wild type enzyme
T382A
-
PTEN-green fluorescent protein mutant shows significant localization to the plasma membrane, the effect requires no catalytic activity
T383A
-
greater catalytic activity than an unphosphorylated, bacterially expressed wild type enzyme
T385A
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PTEN-green fluorescent protein mutant shows significant localization to the plasma membrane, the effect requires no catalytic activity
T401I
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activity is comparable with or even higher than that of wild-type enzyme
V133I
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inactive mutant enzyme
V343E
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inactive mutant enzyme
V369G
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activity is comparable with or even higher than that of wild-type enzyme
Y155C
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inactive mutant enzyme
Y16C
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inactive mutant enzyme
Y174N
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inactive mutant enzyme
Y27S
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inactive mutant enzyme
Y68H
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inactive mutant enzyme
R130M
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kinase dead mutant, expression of R130M mutant of PTEN in U-87MG cells has no effect on the phosphorylation status of protein kinase B, the mutant displays 5% of wildtype lipid phosphatidylinositol 3,4,5-trisphosphate-phosphatase activitiy and 12% of wild-type protein phosphatase activitiy in glioma cells
C124S
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PTEN mutant is devoid of phosphatase activity and fails to modulate p75NTR expression, indicating that phosphatase activity is required for PTEN regulation of neurotophin receptor p75NTR
G129E
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PTEN mutant which is lipid phosphatase dead but which retains protein phosphatase activity, significantly reduces the expression of p75NTR, suggesting that it is the protein phosphatase activity of PTEN that is able to regulate neurotophin receptor p75NTR expression
M134L
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mutant enzyme with partial activity
additional information
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PTEN overexpression in MCF-7 breast cancer cell line prevents ERK1/2 phosphorylation in response to insulin. Inhibition of ERK1/2 activation is not only caused by a reduction in PtdIns(3,4,5)P3 level but also by a decreased association of Shc with Grb2/Sos complex and Ras activation
additional information
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lentiviral infection of PTEN shRNA significantly inhibited Caco-2/15 cell polarization, functional differentiation and brush border development
G129E
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protein phosphatase-active, lipid phosphatase inactive mutant, expression of G129E mutant of PTEN in U-87MG cells has no effect on the phosphorylation status of protein kinase B, the mutant displays 7% of wildtype lipid phosphatidylinositol 3,4,5-trisphosphate-phosphatase activitiy and 65% wild type protein phosphatase activitiy in glioma cells
additional information
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adipose tissue-specific depletion of PTEN in mice results in improved glucose tolerance and insulin sensitivity rendering mice resistant to streptozotocin-induced diabetes. Increased recruitment of Glut4 transporters at the plasma membrane of adipocytes,whereas the contrary is observed in muscle of the same animals. Decreased expression of resistin is shown; deletion of one PTEN allele in insulin receptor substrate 2 (IRS2) in mice is able to restore pancreatic beta-cell function, peripheral insulin sensitivity, glucose tolerance and significantly increases life span of the animals, indicating that PTEN controls insulin sensitivity in peripheral tissues and pancreatic beta-cell growth and function; liver-specific deletion of PTEN in mice results in enhanced insulin sensitivity, hypoinsulinemia, hypoleptinemia and overall improved glucose tolerance. Adult mice lacking PTEN in liver also develop hepatomegaly syndromes, steatohepatitis and hepatocellular carcinomas; muscle-specific depletion of PTEN in mice results in improved glucose metabolism in animals with diabetes and insulin resistance. Elevated fasting glucose levels are prevented and insulin sensitivity and glucose tolerance in high-fat fed animals are improved. Insulin stimulated Akt-activation is enhanced. PTEN depletion in muscle is not associated with increased tumorigenesis; overexpresion of catalytically inactive or dominant-negative PTEN mutants in 3T1-L1 adipocytes show that it is the lipid phosphatase activity of PTEN which is required to downregulate Akt/PKB signaling and glucose uptake in response to insulin; PTEN downregulation in 3T1-L1 adipocytes by small interfering RNAs enhances Akt/PKB activation and glucose uptake in response to insulin; PTEN null mutations in mice are lethal at embryonic stages and even a 50% reduction in PTEN expression leads to increased tumorigenesis; PTEN overexpression in 3T1-L1 adipocytes causes inhibition of insulin-induced PtdIns(3,4)P2 and PtdIns(3,4,5)P3 production, Akt/PKB activation, GLUT4 translocation to the cell membrane and glucose uptake
additional information
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CA1 synapses in hippocampal slices from PTEN-deficient mice exhibit activity-induced long-term potentiation of synaptic transmission but are resistant to long-term depression. PTEN reduces phosphatidylinositol-3-kinase activity and pharmacological inhibition of phosphatidylinositol-3-kinase restores long-term depression of synaptic transmission in PTEN-deficient mice, suggesting that inhibition of phosphatidylinositol-3-kinase is necessary for induction of long term depression
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
diagnostics
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putative biomarker, nuclear localization of PTEN is important for intestinal differentiation of gastric carcinomas, the loss of cytoplasmatic PTEN expression is correlated with poor gastric carcinoma prognosis
drug development
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This study is a direct evidence for a model in which PTEN switches between open and closed states and phosphorylation favors the closed conformation, thereby regulating localization and function. Small molecules targeting these interactions can potentially serve as therapeutic agents in antagonizing Ras or phosphoinositide 3-kinase-driven tumors.
medicine
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PTEN plays an important role in insulin-dependent signaling pathways controlling glucose and lipid metabolsim in vivo. A fine tuning of PTEN expression/activation in target organs is likely to be beneficial to correct metabolic dysfunctions in pathological conditions such as insulin resistance diabetes melitus and obesity
medicine
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results demonstrate an important role of PTEN in long term depression and suggest that alterations in PTEN can have an impact on learning and memory process
analysis
O54857
availability of the phosphorylated and unphosphorylated forms of recombinant PTEN permits future investigations into the three-dimensional structures of the phosphorylated and unphosphorylated forms of PTEN, and the role of phosphorylation in regulating PTEN activity, phospholipid- and protein-binding affinities