Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN

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Reviewed, UniProtKB/Swiss-Prot P60484 (PTEN_HUMAN)

Last modified November 25, 2008. Version 65. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
    EC=3.1.3.67
    EC=3.1.3.16
    EC=3.1.3.48
Alternative name(s):
    Phosphatase and tensin homolog
    Mutated in multiple advanced cancers 1

Gene names

Name:	PTEN
Synonyms:	MMAC1, TEP1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	403 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Tumor suppressor. Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 > PtdIns(3,4)P2 > PtdIns3P > Ins(1,3,4,5)P4. The lipid phosphatase activity is critical for its tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form cooperates with AIP1 to suppress AKT1 activation. Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation. May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue.
Catalytic activity	Phosphatidylinositol 3,4,5-trisphosphate + H(2)O = phosphatidylinositol 4,5-bisphosphate + phosphate. A phosphoprotein + H(2)O = a protein + phosphate. Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.
Cofactor	Magnesium.
Subunit structure	Monomer. The unphosphorylated form interacts with the second PDZ domain of AIP1 and with DLG1 and MAST2 in vitro. Interacts with MAGI3.
Subcellular location	Cytoplasm.
Tissue specificity	Expressed at a relatively high level in all adult tissues, including heart, brain, placenta, lung, liver, muscle, kidney and pancreas.
Induction	Down-regulated by transforming growth factor beta (TGF-beta).
Domain	The C2 domain binds phospholipid membranes in vitro in a Ca(2+)-independent manner; this binding is important for its tumor suppressor function.
Post-translational modification	Phosphorylation results in an inhibited activity towards PIP3. Phosphorylation can both inhibit and promote PDZ-binding.
Involvement in disease	Mutations of PTEN are found in a large number of cancers. Defects in PTEN are a cause of Cowden disease (CD) [MIM:158350]; also known as Cowden syndrome (CS). CD is an autosomal dominant cancer predisposition syndrome associated with elevated risk for tumors of the breast, thyroid and skin. The predominant phenotype for CD is multiple hamartoma syndrome, in many organ systems including the breast (70% of CD patients), thyroid (40-60%), skin, CNS (40%), gastrointestinal tract. Affected individuals are at an increased risk of both breast and thyroid cancers. Trichilemmomas (benign tumors of the hair follicle infundibulum), and mucocutaneous papillomatosis (99%) are hallmarks of CD. Defects in PTEN are the cause of Lhermitte-Duclos disease (LDD) [MIM:158350]; also known as cerebelloparenchymal disorder VI. LDD is characterized by dysplastic gangliocytoma of the cerebellum which often results in cerebellar signs and seizures. LDD and CD seem to be the same entity, and are considered as hamartoma-neoplasia syndromes. Defects in PTEN are a cause of Bannayan-Zonana syndrome (BZS) [MIM:153480]; also known as Ruvalcaba-Riley-Smith or Bannayan-Riley-Ruvalcaba syndrome (BRRS). In BZS there seems not to be an increased risk of malignancy. It has a partial clinical overlap with CD. BZS is characterized by the classic triad of macrocephaly, lipomatosis and pigmented macules of the gland penis. Defects in PTEN are a cause of squamous cell carcinoma of the head and neck (HNSCC) [MIM:275355]. Defects in PTEN are a cause of susceptibility to endometrial cancer [MIM:608089]. Defects in PTEN are a cause of Proteus syndrome [MIM:176920]. Proteus syndrome is a hamartomatous disorder characterized by overgrowth of multiple tissues, connective tissue and epidermal naevi, and vascular malformations. These presentations are usually apparent at birth or soon after and continue to develop as the patient ages. It is named after the Greek god Proteus who, legend has it, could change his shape at will to avoid capture. Tumors, mostly benign but some malignant, have also been reported in Proteus syndrome, generally presenting by the age of 20 years and including papillary adenocarcinoma of the testis, meningioma, and cystadenoma of the ovaries. Defects in PTEN are a cause of oligodendroglioma [MIM:137800]; also called oligodendroblastoma or familial glioma of brain. Oligodendroglioma is a usually benign neoplasm derived from and composed of oligodendrogliocytes in varying stages of differentiation. The majority are seen in adults in the white matter of the brain. Defects in PTEN are a cause of VACTERL association with hydrocephalus [MIM:276950]; which includes also VATER association with hydrocephalus. VACTERL is an acronym for vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects. Defects in PTEN are involved in prostate cancer [MIM:176807]. Defects in PTEN are a cause of macrocephaly/autism syndrome [MIM:605309]. Patients have autism spectrum disorders and macrocephaly, with head circumferences ranging from +2.5 to +8 SD for age and sex (average head circumference +4.0 SD).
Sequence similarities	Contains 1 C2 tensin-type domain. Contains 1 phosphatase tensin-type domain.

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Ontologies

Keywords
Biological process	Cell cycle Lipid metabolism
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	Lipid-binding
Molecular function	Anti-oncogene Hydrolase Protein phosphatase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	central nervous system development Inferred from sequence or structural similarity. Source: UniProtKB induction of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB inositol phosphate dephosphorylation Ref.11 Inferred from direct assay. Source: UniProtKB negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of cell migration Ref.13 Inferred from mutant phenotype. Source: UniProtKB negative regulation of cell proliferation Ref.14 Inferred from mutant phenotype. Source: UniProtKB negative regulation of focal adhesion formation Ref.13 Inferred from mutant phenotype. Source: UniProtKB negative regulation of protein kinase B signaling cascade Ref.17 Inferred from mutant phenotype. Source: UniProtKB phosphoinositide dephosphorylation Ref.11 Ref.12 Inferred from direct assay. Source: UniProtKB protein amino acid dephosphorylation Ref.10 Inferred from direct assay. Source: UniProtKB regulation of cyclin-dependent protein kinase activity Traceable author statement. Source: UniProtKB regulation of protein stability Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cytosol Ref.11 Inferred from Experiment. Source: Reactome nucleus Inferred from direct assay. Source: UniProtKB
Molecular function	PDZ domain binding Ref.15 Ref.17 Inferred from physical interaction. Source: UniProtKB inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity Ref.11 Inferred from direct assay. Source: UniProtKB lipid binding Inferred from electronic annotation. Source: UniProtKB-KW phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity Ref.11 Ref.12 Inferred from direct assay. Source: UniProtKB phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity Ref.12 Inferred from direct assay. Source: UniProtKB phosphatidylinositol-3-phosphatase activity Ref.12 Inferred from direct assay. Source: UniProtKB protein serine/threonine phosphatase activity Ref.10 Inferred from direct assay. Source: UniProtKB protein tyrosine phosphatase activity Ref.10 Inferred from direct assay. Source: UniProtKB protein tyrosine/serine/threonine phosphatase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
Cenpc1	P49452	1	EBI-696162,EBI-1186252	From a different organism.
Dlg1	Q62696	1	EBI-696162,EBI-389325	From a different organism.
HSPA5	P11021	1	EBI-696162,EBI-354921
Magi2	O88382	2	EBI-696162,EBI-696179	From a different organism.
Magi3	Q9JK71	1	EBI-696162,EBI-696226	From a different organism.
Mast1	Q9R1L5	2	EBI-696162,EBI-491771	From a different organism.
Mast2	Q60592	2	EBI-696162,EBI-493888	From a different organism.
MAST3	O60307	2	EBI-696162,EBI-311420
PPP1CA	P62136	2	EBI-696162,EBI-357253
Pten	O08586	1	EBI-696162,EBI-1186266	From a different organism.

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 403

403

Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN

PRO_0000215904

Regions

Domain

14 – 185

172

Phosphatase tensin-type

Domain

190 – 350

161

C2 tensin-type

Region

401 – 403

PDZ domain-binding

Sites

Active site

124

Phosphocysteine intermediate Potential

Amino acid modifications

Modified residue

366

Phosphothreonine

Modified residue

370

Phosphoserine; by CK2

Modified residue

385

Phosphoserine; by CK2

Modified residue

401

Phosphothreonine

Natural variations

Natural variant

S → N Retains phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains the ability to bind phospholipid membranes.

VAR_026248

Natural variant

R → S in glioma.

VAR_007457

Natural variant

Y → C Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains the ability to bind phospholipid membranes.

VAR_026249

Natural variant

D → N in malignant melanoma; somatic mutation.

VAR_018100

Natural variant

G → E Reduced phosphatase activity towards Ins(1,3,4,5)P4; retains phosphatase activity towards PtdIns(3,4,5)P3.

VAR_026250

Natural variant

Y → S Loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026251

Natural variant

Missing in CD.

VAR_008733

Natural variant

A → D in BZS.

VAR_008734

Natural variant

M → R in CD.

VAR_008036

Natural variant

G → E in glioma.

VAR_007458

Natural variant

G → R in endometrial hyperplasia.

VAR_026252

Natural variant

L → R in glioma; retains phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains the ability to bind phospholipid membranes.

VAR_007459

Natural variant

R → G in CD.

VAR_011587

Natural variant

L → W in glioma; loss of protein phosphatase activity.

VAR_007460

Natural variant

H → D in VATER.

VAR_018101

Natural variant

H → R Loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026253

Natural variant

I → R in CD.

VAR_007461

Natural variant

Y → H in CD and BZS; loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains the ability to bind phospholipid membranes.

VAR_007462

Natural variant

L → P in CD.

VAR_018102

Natural variant

C → Y in CD; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026254

Natural variant

H → R in macrocephaly/autism syndrome.

VAR_032634

Natural variant

H → Y in CD.

VAR_026255

Natural variant

105

C → F in BZS; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026256

Natural variant

105

C → Y in BZS.

VAR_008735

Natural variant

107

D → Y in BZS and glioblastoma; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026257

Natural variant

112

L → P in CD and LDD; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_007807

Natural variant

112

L → R Loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026258

Natural variant

119

V → L in multiple cancers.

VAR_011588

Natural variant

121

A → G in HNSCC.

VAR_018103

Natural variant

121

A → P in glioblastoma; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026259

Natural variant

123

H → R in CD.

VAR_007463

Natural variant

123

H → Y in endometrial cancer; loss of protein phosphatase activity.

VAR_026260

Natural variant

124

C → R in CD.

VAR_007464

Natural variant

124

C → S in CD; phosphatase-dead protein with neither lipid nor protein phosphatase activity.

VAR_018104

Natural variant

129

G → E in CD; no lipid phosphatase activity but retains protein phosphatase activity; retains ability to inhibit focal adhesion formation.

VAR_007465

Natural variant

129

G → R in glioblastoma; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_007466

Natural variant

130

R → G Loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3.

VAR_026261

Natural variant

130

R → L in CD and endometrial hyperplasia; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.

VAR_007467

Natural variant

130

R → Q in CD; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.

VAR_007468

Natural variant

132

G → V in one patient with clinical findings suggesting hamartoma tumor syndrome.

VAR_032635

Natural variant

133

V → I Loss of phosphatase activity towards Ins(1,3,4,5)P3.

VAR_026262

Natural variant

134

M → L in prostate cancer; no effect on protein phosphatase activity; reduced phosphatase activity towards Ins(1,3,4,5)P3 but retains PtdIns(3,4,5)P3 phosphatase activity.

VAR_007469

Natural variant

135

I → V in BZS.

VAR_008736

Natural variant

136

C → Y in CD; loss of phosphatase activity towards Ins(1,3,4,5)P3.

VAR_007808

Natural variant

137

A → AN in CD.

VAR_008737

Natural variant

155

Y → C in CD; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026263

Natural variant

158

V → L in multiple cancers.

VAR_011589

Natural variant

165

G → E in CD.

VAR_008739

Natural variant

165

G → R in glioblastoma; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.

VAR_026264

Natural variant

165

G → V in CD.

VAR_008738

Natural variant

167

T → P in breast cancer; severely reduced protein phosphatase activity.

VAR_026265

Natural variant

170

S → N Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.

VAR_026266

Natural variant

170

S → R in BZS; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_007470

Natural variant

173

R → C in endometrial hyperplasia; loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains ability to bind phospholipid membranes.

VAR_026267

Natural variant

173

R → H Loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026268

Natural variant

173

R → P Loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026269

Natural variant

174

Y → N Loss of phosphatase activity towards Ins(1,3,4,5)P4.

VAR_026270

Natural variant

191

V → A in endometrial hyperplasia.

VAR_026271

Natural variant

217

V → I in malignant melanoma; somatic mutation.

VAR_018105

Natural variant

227

S → F Reduced phosphatase activity towards Ins(1,3,4,5)P4 but retains PtdIns(3,4,5)P3 phosphatase activity.

VAR_026272

Natural variant

234

R → Q in oligodendroglioma; not capable of inducing apoptosis; induced increased cell proliferation; led to high constitutive AKT1 activation which could not be increased further by stimulation with insulin.

VAR_018106

Natural variant

241

F → S in macrocephaly/autism syndrome.

VAR_032636

Natural variant

246

P → L in CD and BZS.

VAR_008740

Natural variant

251

G → C Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.

VAR_026273

Natural variant

252

D → G in macrocephaly/autism syndrome.

VAR_032637

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations