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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
-
tyrosine-based
-
immunoreceptor
-
5'-phosphatase
-
ptdins3,4,5p3
- syk
-
tyrosine-phosphorylated
- grb2
-
pomerania
-
fcgammariib
-
phosphatase-like
- sorl1
- 3,4-bisphosphate
-
picalm
- fcepsilonri
-
ptdins3,4p2
-
microrna-155
- trem2
-
fermt2
- medicine
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
ship-1, ship-2, inpp5d, inppl1, 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, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
SHIP2
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.
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
-
-
-
?
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
substrate of isoforms SHIP2 and SHIP1 in vitro
-
-
?
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
-
-
?
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 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
preferred substrate
-
-
?
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
-
-
?
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
-
-
?
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
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
0.082
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
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
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
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
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
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
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
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 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-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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SHIP2_HUMAN
1258
0
138599
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
GST resin column chromatography, Source 15S column chromatography, and Superdex 200 gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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)
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)
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)
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)
Thomas, M.P.; Erneux, C.; Potter, B.V.
SHIP2 structure, function and inhibition
ChemBioChem
18
233-247
2017
Homo sapiens (O15357)
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)
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)
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)
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)
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)
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)
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)
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