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Information on EC 3.1.3.86 - phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase
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3.1.3.86 phosphatidylinositol-3,4,5-trisphosphate 5-phosphataseIUBMB Comments
This enzyme hydrolyses 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. The enzyme also shows activity toward (PtdIns(1,3,4,5)P4) . The enzyme is involved in several signal transduction pathways in the immune system leading to an adverse range of effects.
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Word Map
- 3.1.3.86
- phosphatases
- 3-kinase
- phosphoinositide
-
5\'-inositol
-
immunoreceptor
-
5'-phosphatase
-
tyrosine-based
-
ptdins3,4,5p3
- grb2
- syk
-
fcgammariib
- sorl1
-
pomerania
- 3,4-bisphosphate
-
phosphatase-like
-
ptdins3,4p2
-
picalm
-
fermt2
-
microrna-155
- trem2
- fcepsilonri
- medicine
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
ship-1, ship-2, inppl1, inpp5d, 5'-inositol phosphatase, sh2-containing inositol phosphatase, sh2 domain-containing inositol 5-phosphatase, ptdins(3,4,5)p3 5-phosphatase, phosphatidylinositol 5-phosphatase, pi 5-phosphatase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase
PtdIns(3,4,5)P3 5-phosphatase
SH2-containing inositol phosphatase
SHIP
SHIP-1
SHIP1
SHIP2
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O = 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
-
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SYSTEMATIC NAME
IUBMB Comments
1-phosphatidyl-1D-myo-inositol-3,4,5-trisphosphate 5-phosphohydrolase
This enzyme hydrolyses 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. The enzyme also shows activity toward (PtdIns(1,3,4,5)P4) [5]. The enzyme is involved in several signal transduction pathways in the immune system leading to an adverse range of effects.
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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 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4-phosphate + phosphate
1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
-
-
?
1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
substrate of isoform SHIP1 in vitro
-
?
1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
best substrate
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
preferred substrate
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
in vivo substrate of SHIP2
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
substrate of isoforms SHIP2 and SHIP1 in vitro
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
in vitro substrate of SHIP2
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4-phosphate + phosphate
-
-
?
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4-phosphate + phosphate
-
-
-
?
1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
-
-
-
?
1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
-
-
-
?
additional information
?
-
SHIP2 does not hydrolyze 1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate in vitro
-
?
additional information
?
-
SHIP2 does not hydrolyze 1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate in vitro
-
?
additional information
?
-
-
cytosolic Ptdlns(3,4,5)P3 5-phosphatase which associates with phosphoinositide 3-kinase does not metabolize phosphatidylinositol 4,5-bisphosphate, inositol 1,4,5-trisphosphate or inositol 1,3,4,5-tetraphosphate
-
?
additional information
?
-
-
synaptojanin accounts for the major part of the active PtdIns(3,4,5)P3 5-phosphatase activity in rat brain
-
?
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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-1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4-phosphate + phosphate
1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 1,3,4-trisphosphate + phosphate
substrate of isoform SHIP1 in vitro
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
preferred substrate
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
in vivo substrate of SHIP2
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
substrate of isoforms SHIP2 and SHIP1 in vitro
-
-
?
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate + phosphate
-
-
-
-
?
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4-phosphate + phosphate
-
-
-
?
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O
1-phosphatidyl-1D-myo-inositol 4-phosphate + phosphate
-
-
-
-
?
additional information
?
-
SHIP2 does not hydrolyze 1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate in vitro
-
-
?
additional information
?
-
SHIP2 does not hydrolyze 1-phosphatidyl-1D-myo-inositol 1,3,4,5-tetrakisphosphate in vitro
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
additional information
-
Zn2+, Ca2+ and Mn2+ do not support enzyme activity
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R)-2-[(S)-hydroxy(2-phenylbenzo[h]quinolin-4-yl)methyl]piperidin-1-ium
-
(2R)-2-[(S)-[5,7-dichloro-3-adamantyl)naphthalen-1-yl](hydroxy)methyl]piperidin-1-ium
-
2-[1-(2,4-dichlorobenzyl)-2-methyl-5-(methylmercapto)-1H-indol-3-yl] ethanaminium chloride
-
2-[1-(2-chlorobenzyl)-2-methyl-5-(methylmercapto)-1H-indol-3-yl] ethanaminium chloride
-
2-[1-[(2,4-dichlorophenyl)methyl]-2-methyl-5-(methylsulfanyl)-1H-indol-3-yl]ethan-1-aminium
40% inhibition at 0.5 mM
2-[1-[(2-chlorophenyl)methyl]-2-methyl-5-(methylsulfanyl)-1H-indol-3-yl]ethan-1-aminium
-
3-[(2,4-dichlorophenyl)methoxy]-N-[(2,6-difluorophenyl)methyl]thiophene-2-carboxamide
AS1938909, competitive inhibitor of SHIP2
3-[(4-chlorophenyl)methoxy]-N-[(1S)-1-phenylethyl]thiophene-2-carboxamide
AS1949490, competitive inhibitor of SHIP2
N-(4-[[(4-chlorophenyl)methoxy]methyl]pyridin-2-yl)-3-phenylpropanamide
-
N-[4-[(4-chlorophenyl)methoxy]pyridin-2-yl]-2-(2,6-difluorophenyl)acetamide
-
phosphatidylinositol 4,5-bisphosphate
-
strong inhibition at low micromolar concentrations
phosphatidylinositol 4-phosphate
-
inhibition at low micromolar concentrations
additional information
an amine tethered to the quinoline core is required for SHIP inhibition
-
additional information
-
the enzyme is insensitive to N-ethylmaleimide, InsPh and 2,3-bisphosphoglycerate
-
additional information
-
N-ethylmaleimide, orthophosphate, 4-nitrophenylphosphate, glycerolbisphosphate, inositol hexakisphosphate and (1R,2R,4R)-cyclohexane-1,2,4-trismethylenesulfonate are without significant effect on the enzyme activity
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
SHIP2 enzyme activity with phosphatidylinositol 3,4,5-trisphosphate is 11fold stimulated in the presence of 0.02 mM vesicles of phosphatidylserine. 0.2 mM vesicles of phosphatidylcholine stimulate 2fold phosphatidylinositol 3,4,5-trisphosphate phosphatase activity of SHIP2
-
additional information
-
vinexin beta does not affect PtdIns(3,4,5)P3 5-phosphatase activity of SHIP2
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.001
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
in the presence of 5 mM MgCl2, 0.5 mM EGTA, 50 mM Tris, pH 7.4, temperature not specified in the publication
0.043
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
wild type enzyme, at pH 7.0 and 23°C
0.059
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
mutant enzyme R649A, at pH 7.0 and 23°C
0.061
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
mutant enzyme F593D/L597D, at pH 7.0 and 23°C
0.088
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
wild type enzyme, at pH 7.5 and 25°C
0.0316
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
-
mutant enzyme D360A/N362A, at pH 7.5 and 25°C
0.0738
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
-
wild type enzyme, at pH 7.5 and 25°C
0.1
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
-
in the presence of 5 mM MgCl2, 0.5 mM EGTA, 50 mM Tris, pH 7.4, temperature not specified in the publication
0.082
Inositol 1,3,4,5-tetrakisphosphate
mutant enzyme F593D/L597D, at pH 7.0 and 23°C
0.098
Inositol 1,3,4,5-tetrakisphosphate
wild type enzyme, at pH 7.0 and 23°C
0.126
Inositol 1,3,4,5-tetrakisphosphate
mutant enzyme R649A, at pH 7.0 and 23°C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.69
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
wild type enzyme, at pH 7.0 and 23°C
1.35
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
mutant enzyme R649A, at pH 7.0 and 23°C
4.44
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
mutant enzyme F593D/L597D, at pH 7.0 and 23°C
57.5
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
wild type enzyme, at pH 7.5 and 25°C
28.2
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
-
mutant enzyme D360A/N362A, at pH 7.5 and 25°C
140.5
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
-
wild type enzyme, at pH 7.5 and 25°C
1.2
Inositol 1,3,4,5-tetrakisphosphate
mutant enzyme F593D/L597D, at pH 7.0 and 23°C
1.32
Inositol 1,3,4,5-tetrakisphosphate
wild type enzyme, at pH 7.0 and 23°C
1.64
Inositol 1,3,4,5-tetrakisphosphate
mutant enzyme R649A, at pH 7.0 and 23°C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
653
1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
wild type enzyme, at pH 7.5 and 25°C
892
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
-
mutant enzyme D360A/N362A, at pH 7.5 and 25°C
1900
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
-
wild type enzyme, at pH 7.5 and 25°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.03
(2R)-2-[(S)-hydroxy(2-phenylbenzo[h]quinolin-4-yl)methyl]piperidin-1-ium
pH and temperature not specified in the publication
0.063
(2R)-2-[(S)-[5,7-dichloro-3-adamantyl)naphthalen-1-yl](hydroxy)methyl]piperidin-1-ium
pH and temperature not specified in the publication
0.5
2-[1-[(2-chlorophenyl)methyl]-2-methyl-5-(methylsulfanyl)-1H-indol-3-yl]ethan-1-aminium
pH and temperature not specified in the publication
0.00057
3-[(2,4-dichlorophenyl)methoxy]-N-[(2,6-difluorophenyl)methyl]thiophene-2-carboxamide
pH and temperature not specified in the publication
0.00062
3-[(4-chlorophenyl)methoxy]-N-[(1S)-1-phenylethyl]thiophene-2-carboxamide
pH and temperature not specified in the publication
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.03
(2R)-2-[(S)-hydroxy(2-phenylbenzo[h]quinolin-4-yl)methyl]piperidin-1-ium
Homo sapiens
pH and temperature not specified in the publication
0.063
(2R)-2-[(S)-[5,7-dichloro-3-adamantyl)naphthalen-1-yl](hydroxy)methyl]piperidin-1-ium
Homo sapiens
pH and temperature not specified in the publication
0.5
2-[1-[(2-chlorophenyl)methyl]-2-methyl-5-(methylsulfanyl)-1H-indol-3-yl]ethan-1-aminium
Homo sapiens
pH and temperature not specified in the publication
0.00057
3-[(2,4-dichlorophenyl)methoxy]-N-[(2,6-difluorophenyl)methyl]thiophene-2-carboxamide
Homo sapiens
pH and temperature not specified in the publication
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
cell adhesion to collagen-I-coated dishes is decreased in SHIP2-deicient MEF cells compared with wild type cells
malfunction
-
depletion of SHIP 5'-phosphatases increases neutrophil wound attraction and random motility through a PI3K-dependent pathway. Ectopic expression of the SHIP1 phosphatase domain impairs neutrophil migration
malfunction
apoptosis in MDA-MB-231 cells is increased in SHIP2-depleted cells as compared to control cells
malfunction
disruption of the enzyme-Mena interaction in cancer cells leads to attenuated capacity for extracellular matrix degradation and invasion in vitro, as well as reduced metastasis in vivo
malfunction
enzyme deficiency leads to myeloproliferation and B-cell lymphoma in mice
malfunction
enzyme depletion inhibits cell migration of glioblastoma cells
malfunction
enzyme mutations are associated with opsismodysplasia. Mice expressing a germline catalytically inactive SHIP2 mutant protein are viable, but have defects in the development of muscle, adipose tissue and the female genital tract, as well as in somatic growth
malfunction
isoform SHIP2 inhibition or knockdown inhibits cell migration and reduces phosphorylated protein kinase B levels, resulting in sensitivity to chemotherapeutics
physiological function
isoforms SHIP2 and SHIP1 have a different hierarchy of binding SH3-domain containing proteins
physiological function
-
PR130/Balpha1 and SHIP2 partially colocalize in untreated HeLa cells, and both translocate to the cell membrane on epidermal growth factor stimulation. Protein phosphatase 2A PR130/Balpha1 subunit binds to the SH2 domain-containing inositol polyphosphate 5-phosphatase 2 and prevents epidermal growth factor-induced epidermal growth factor receptor degradation sustaining epidermal growth factor-mediated signaling
physiological function
-
SHIP is involved in platelet activation evoked by thrombin
physiological function
-
SHIP2 interaction with vinexin alpha promotes the localization of SHIP2 at the periphery of the cells leaving its catalytic site intact. SHIP2 is active both as a PtdIns(3,4,5)P3 5-phosphatase and as a modulator of focal contact formation
physiological function
-
the Src homology 2 domain containing inositol 5-phosphatase SHIP2 is recruited to the epidermal growth factor receptor and dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in epidermal growth factor-stimulated COS-7 cells
physiological function
-
SHIP phosphatases serve as a brake that limit neutrophil motility and inflammation, at least in part through their effects on PI3K signaling
physiological function
high glucose induces SHIP2 mRNA and protein levels in HepG2 cells. Overexpression of a dominant negative mutant SHIP2 ameliorates high glucose-induced de novo lipogenesis and secretion of apoB containing lipoprotein in HepG2 cells. Overexpression of the SHIP2 dominant negative mutant decreases high glucose-induced apoB containing lipoproteins secretion via reduction in reactive oxygen species generation, JNK phosphorylation and Akt activation. AMPK/mTOR/SREBP1 is the signaling pathway that mediates the effects of SHIP2 modulation on hepatic de novo lipogenesis
physiological function
isoform SHIP1 inhibits haematopoietic cell proliferation, inhibits Akt signalling and regulates immune cell function in vitro and in vivo
physiological function
isoform SHIP2 functions as oncogene in colorectal cancer by regulating protein kinase B activation
physiological function
isoform SHIP2 regulates Akt signalling in metabolic tissues
physiological function
overexpression of the wild-ype SHIP2 gene leads to a higher total lipid content (28%) compared to control, whereas overexpression of the dominant negative SHIP2 gene reduces total lipid content in oleate treated cells by 40%. Overexpression of SHIP2 wild-type also leads to a significant increase in both secretion of apoB100 containing lipoproteins and de novo lipogenesis. Overexpression of the SHIP2 dominant negative gene prevents oleate-induced de novo lipogenesis and secretion of apoB100 containing lipoproteins in HepG2 cells
physiological function
the enzyme acts as a negative regulator of immune response and haematopoietic progenitor cell proliferation/survival, and as an inducer of cellular apoptosis. Isoform SHIP-1 is also implicated both as a haematopoietic tumour suppressor and activator
physiological function
the enzyme acts as a negative regulator of immune response and haematopoietic progenitor cell proliferation/survival, and as an inducer of cellular apoptosis. Isoform SHIP-2 is a negative regulator of glucose homeostasis and is involved in the maturation and activation of mast cells as well as in phagocytosis directed by Fc receptors for immunoglobulin G, thus regulating allergic reactions and antibacterial defense
physiological function
the enzyme SHIP2 recruits Mena, but not vasodilator-stimulated phosphoprotein, to invadopodia
physiological function
-
the enzyme's activity controls 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate binding by RAP1 and, thus, transcriptional silencing of variant surface glycoprotein genes
Show AA Sequence and Transmembrane Helices (856 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
145000
150000
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
x * 500005, a fragment of human SHIP2 containing the phosphatase domain and a region proposed to resemble a C2 domain, SDS-PAGE
?
x * 52685, a fragment of human SHIP2 containing the phosphatase domain and a region proposed to resemble a C2 domain, electrospray ionization mass spectrometry
?
x * 52688, a fragment of human SHIP2 containing the phosphatase domain and a region proposed to resemble a C2 domain, calculated from amino acid sequence
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
phosphoprotein
-
in COS-7 cells, SHIP2 is tyrosine-phosphorylated at least at two separated tyrosine phosphorylation sites in response to epidermal growth factor
phosphoprotein
isoforms SHIP2 and SHIP1 are constitutively tyrosine phosphorylated in chronic myelogenous leukemia progenitor cells
phosphoprotein
isoforms SHIP2 and SHIP1 are constitutively tyrosine phosphorylated in chronic myelogenous leukemia progenitor cells. Stimulation of human hematopoietic growth factor responsive cell lines with stem cell factor, interleukin-3, and granulocyte-macrophage colony-stimulating factor leads to rapid tyrosine phosphorylation of SHIP2 and its resulting association with src homologous and collagen gene
phosphoprotein
-
thrombin stimulation induces a tyrosine phosphorylation of SHIP
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
a fragment of human SHIP2 containing the phosphatase domain and a region proposed to resemble a C2 domain is crystallized by the hanging drop vapor diffusion method, using 0.1 M Bis-Tris propane pH 7.0, 0.2 M NaNO3, 20% (w/v) PEG 3350, 0.025 % (w/v) CH2Cl2, 2 mM Tris(2-carboxyethyl)phosphine
using 100 mM Bis-Tris propane, pH 7.0, 0.2 M NaNO3, 20% (w/v) PEG3350, 0.025% (v/v) CH2Cl2
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
R649A
the mutation removes C2 domain effects on inositol 1,3,4,5-tetrakisphosphate but not 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate kinetics
D360A/N362A
-
the mutations completely eliminate enzyme activity toward 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate and significantly decrease the dephosphorylation activity of the enzyme for 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
GST resin column chromatography, Source 15S column chromatography, and Superdex 200 gel filtration
HiTrap S column chromatography, phosphocellulose column chromatography, heparin-HiTrap column chromatography, Q-HiTrap column chromatography, and S-300 gel filtration
-
the enzyme is co-purified with the p85/pll0 form of PI 3-kinase, by Q-Sepharose column chromatography, S-Sepharose column chromatography, hydroxyapatite column chromatography and Mono S column chromatography
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in COS-7 cells
expressed in Escherichia coli BL21(DE3) cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Jackson, S.P.; Schoenwaelder, S.M.; Matzaris, M.; Brown, S.; Mitchell, C.A.
Phosphatidylinositol 3,4,5-trisphosphate is a substrate for the 75 kDa inositol polyphosphate 5-phosphatase and a novel 5-phosphatase which forms a complex with the p85/p110 form of phosphoinositide 3-kinase
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Homo sapiens
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Vandeput, F.; Backers, K.; Villeret, V.; Pesesse, X.; Erneux, C.
The influence of anionic lipids on SHIP2 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase activity
Cell. Signal.
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2006
Homo sapiens
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Drayer, A.L.; Pesesse, X.; De Smedt, F.; Woscholski, R.; Parker, P.; Erneux, C.
Cloning and expression of a human placenta inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase
Biochem. Biophys. Res. Commun.
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243-249
1996
Homo sapiens
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Drayer, A.; Pesesse, X.; De Smedt, F.; Communi, D.; Moreau, C.; Erneux, C.
The family of inositol and phosphatidylinositol polyphosphate 5-phosphatases
Biochem. Soc. Trans.
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Homo sapiens, Rattus norvegicus
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Wisniewski, D.; Strife, A.; Swendeman, S.; Erdjument-Bromage, H.; Geromanos, S.; Kavanaugh, W.M.; Tempst, P.; Clarkson, B.
A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells
Blood
93
2707-2720
1999
Homo sapiens (O15357), Homo sapiens (Q92835)
brenda
Zwaenepoel, K.; Goris, J.; Erneux, C.; Parker, P.J.; Janssens, V.
Protein phosphatase 2A PR130/Balpha1 subunit binds to the SH2 domain-containing inositol polyphosphate 5-phosphatase 2 and prevents epidermal growth factor (EGF)-induced EGF receptor degradation sustaining EGF-mediated signaling
FASEB J.
24
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2010
Homo sapiens
brenda
Paternotte, N.; Zhang, J.; Vandenbroere, I.; Backers, K.; Blero, D.; Kioka, N.; Vanderwinden, J.M.; Pirson, I.; Erneux, C.
SHIP2 interaction with the cytoskeletal protein Vinexin
FEBS J.
272
6052-6066
2005
Mus musculus
brenda
Pesesse, X.; Moreau, C.; Drayer, A.L.; Woscholski, R.; Parker, P.; Erneux, C.
The SH2 domain containing inositol 5-phosphatase SHIP2 displays phosphatidylinositol 3,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate 5-phosphatase activity
FEBS Lett.
437
301-303
1998
Homo sapiens
brenda
Lioubin, M.N.; Algate, P.A.; Tsai, S.; Carlberg, K.; Aebersold, A.; Rohrschneider, L.R.
p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity
Genes Dev.
10
1084-95
1996
Homo sapiens
brenda
Woscholski, R.; Waterfield, M.D.; Parker, P.J.
Purification and biochemical characterization of a mammalian phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase
J. Biol. Chem.
270
31001-31007
1995
Rattus norvegicus
brenda
Giuriato, S.; Payrastre, B.; Drayer, A.L.; Plantavid, M.; Woscholski, R.; Parker, P.; Erneux, C.; Chap, H.
Tyrosine phosphorylation and relocation of SHIP are integrin-mediated in thrombin-stimulated human blood platelets
J. Biol. Chem.
272
26857-26863
1997
Homo sapiens
brenda
Woscholski, R.; Finan, P.M.; Radley, E.; Totty, N.F.; Sterling, A.E.; Hsuan, J.J.; Waterfield, M.D.; Parker, P.J.
Synaptojanin is the major constitutively active phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase in rodent brain
J. Biol. Chem.
272
9625-9628
1997
Rattus norvegicus
brenda
Pesesse, X.; Dewaste, V.; De Smedt, F.; Laffargue, M.; Giuriato, S.; Moreau, C.; Payrastre, B.; Erneux, C.
The Src homology 2 domain containing inositol 5-phosphatase SHIP2 is recruited to the epidermal growth factor (EGF) receptor and dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in EGF-stimulated COS-7 cells
J. Biol. Chem.
276
28348-28355
2001
Homo sapiens
brenda
Ooms, L.M.; Dyson, J.M.; Kong, A.M.; Mitchell, C.A.
Analysis of phosphatidylinositol 3,4,5 trisphosphate 5-phosphatase activity by in vitro and in vivo assays
Methods Mol. Biol.
462
223-239
2009
Chlorocebus aethiops
brenda
Damen, J.E.; Liu, L.; Rosten, P.; Humphries, R.K.; Jefferson, A.B.; Majerus, P.W.; Krystal, G.
The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase
Proc. Natl. Acad. Sci. USA
93
1689-1693
1996
Mus musculus
brenda
Kuehbacher, A.; Dambournet, D.; Echard, A.; Cossart, P.; Pizarro-Cerda, J.
Phosphatidylinositol 5-phosphatase oculocerebrorenal syndrome of Lowe protein (OCRL) controls actin dynamics during early steps of Listeria monocytogenes infection
J. Biol. Chem.
287
13128-13136
2012
Danio rerio
brenda
Ijuin, T.; Takenawa, T.
Regulation of insulin signaling and glucose transporter 4 (GLUT4) exocytosis by phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase, skeletal muscle, and kidney enriched inositol polyphosphate phosphatase (SKIP)
J. Biol. Chem.
287
6991-6999
2012
Mus musculus
brenda
Tu, W.J.; Liu, X.Y.; Dong, H.; Yu, Y.; Wang, Y.; Chen, H.
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1: a meaningful and independent marker to predict stroke in the Chinese population
J. Mol. Neurosci.
52
507-514
2014
Homo sapiens
brenda
Ramos, A.R.; Elong Edimo, W.; Erneux, C.
Phosphoinositide 5-phosphatase activities control cell motility in glioblastoma Two phosphoinositides PI(4,5)P2 and PI(3,4)P2 are involved
Adv. Biol. Regul.
67
40-48
2018
Homo sapiens (O15357)
brenda
Gorgani-Firuzjaee, S.; Adeli, K.; Meshkani, R.
Inhibition of SH2-domain-containing inositol 5-phosphatase (SHIP2) ameliorates palmitate induced-apoptosis through regulating Akt/FOXO1 pathway and ROS production in HepG2 cells
Biochem. Biophys. Res. Commun.
464
441-446
2015
Homo sapiens (O15357)
brenda
Eramo, M.J.; Mitchell, C.A.
Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases
Biochem. Soc. Trans.
44
240-252
2016
Homo sapiens (O15357), Homo sapiens (Q92835)
brenda
Russo, C.M.; Adhikari, A.A.; Wallach, D.R.; Fernandes, S.; Balch, A.N.; Kerr, W.G.; Chisholm, J.D.
Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5-phosphatase (SHIP)
Bioorg. Med. Chem. Lett.
25
5344-5348
2015
Homo sapiens (Q92835)
brenda
Thomas, M.P.; Erneux, C.; Potter, B.V.
SHIP2 structure, function and inhibition
ChemBioChem
18
233-247
2017
Homo sapiens (O15357)
brenda
Le Coq, J.; Camacho-Artacho, M.; Velazquez, J.V.; Santiveri, C.M.; Gallego, L.H.; Campos-Olivas, R.; Doelker, N.; Lietha, D.
Structural basis for interdomain communication in SHIP2 providing high phosphatase activity
eLife
6
e26640
2017
Homo sapiens (O15357)
brenda
Gorgani-Firuzjaee, S.; Meshkani, R.
SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells
Free Radic. Biol. Med.
89
679-689
2015
Homo sapiens (O15357)
brenda
Rajadurai, C.V.; Havrylov, S.; Coelho, P.P.; Ratcliffe, C.D.; Zaoui, K.; Huang, B.H.; Monast, A.; Chughtai, N.; Sangwan, V.; Gertler, F.B.; Siegel, P.M.; Park, M.
5-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion
J. Cell Biol.
214
719-734
2016
Homo sapiens (O15357)
brenda
Elong Edimo, W.; Ghosh, S.; Derua, R.; Janssens, V.; Waelkens, E.; Vanderwinden, J.M.; Robe, P.; Erneux, C.
SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration in 1321 N1 glioblastoma cells
J. Cell Sci.
129
1101-1114
2016
Homo sapiens (O15357)
brenda
Ghosh, S.; Scozzaro, S.; Ramos, A.R.; Delcambre, S.; Chevalier, C.; Krejci, P.; Erneux, C.
Inhibition of SHIP2 activity inhibits cell migration and could prevent metastasis in breast cancer cells
J. Cell Sci.
131
jcs216408
2018
Homo sapiens (O15357)
brenda
Cestari, I.; McLeland-Wieser, H.; Stuart, K.
Nuclear phosphatidylinositol 5-phosphatase is essential for allelic exclusion of variant surface glycoprotein genes in trypanosomes
Mol. Cell. Biol.
39
e00395-18
2019
Trypanosoma brucei
brenda
Dempke, W.C.M.; Uciechowski, P.; Fenchel, K.; Chevassut, T.
Targeting SHP-1, 2 and SHIP pathways a novel strategy for cancer treatment?
Oncology
95
257-269
2018
Homo sapiens (O15357), Homo sapiens (Q92835)
brenda
Hoekstra, E.; Das, A.M.; Willemsen, M.; Swets, M.; Kuppen, P.J.; van der Woude, C.J.; Bruno, M.J.; Shah, J.P.; Ten Hagen, T.L.; Chisholm, J.D.; Kerr, W.G.; Peppelenbosch, M.P.; Fuhler, G.M.
Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation
Oncotarget
7
73525-73540
2016
Homo sapiens (O15357)
brenda
Le Coq, J.; Heredia Gallego, L.; Lietha, D.
Expression, purification, crystallisation and X-ray crystallographic analysis of a truncated form of human Src homology 2 containing inositol 5-phosphatase 2
Protein J.
35
225-230
2016
Homo sapiens (O15357)
brenda
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