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Reviewed, UniProtKB/Swiss-Prot P60484 (PTEN_HUMAN)

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

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length403 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

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.

Ontologies

Keywords

   Biological processCell cycle
Lipid metabolism
   Cellular componentCytoplasm
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   LigandLipid-binding
   Molecular functionAnti-oncogene
Hydrolase
Protein phosphatase
   PTMPhosphoprotein
   Technical term3D-structure

Gene Ontology (GO)

   Biological processcentral 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 componentcytosol Ref.11

Inferred from Experiment. Source: Reactome

nucleus

Inferred from direct assay. Source: UniProtKB

   Molecular functionPDZ 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...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Cenpc1P494521EBI-696162,EBI-1186252From a different organism.
Dlg1Q626961EBI-696162,EBI-389325From a different organism.
HSPA5P110211EBI-696162,EBI-354921
Magi2O883822EBI-696162,EBI-696179From a different organism.
Magi3Q9JK711EBI-696162,EBI-696226From a different organism.
Mast1Q9R1L52EBI-696162,EBI-491771From a different organism.
Mast2Q605922EBI-696162,EBI-493888From a different organism.
MAST3O603072EBI-696162,EBI-311420
PPP1CAP621362EBI-696162,EBI-357253
PtenO085861EBI-696162,EBI-1186266From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 403403Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
PRO_0000215904

Regions

Domain14 – 185172Phosphatase tensin-type
Domain190 – 350161C2 tensin-type
Region401 – 4033PDZ domain-binding

Sites

Active site1241Phosphocysteine intermediate Potential

Amino acid modifications

Modified residue3661Phosphothreonine
Modified residue3701Phosphoserine; by CK2
Modified residue3851Phosphoserine; by CK2
Modified residue4011Phosphothreonine

Natural variations

Natural variant101S → 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 variant151R → S in glioma.
VAR_007457
Natural variant161Y → C Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains the ability to bind phospholipid membranes.
VAR_026249
Natural variant191D → N in malignant melanoma; somatic mutation.
VAR_018100
Natural variant201G → E Reduced phosphatase activity towards Ins(1,3,4,5)P4; retains phosphatase activity towards PtdIns(3,4,5)P3.
VAR_026250
Natural variant271Y → S Loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026251
Natural variant331Missing in CD.
VAR_008733
Natural variant341A → D in BZS.
VAR_008734
Natural variant351M → R in CD.
VAR_008036
Natural variant361G → E in glioma.
VAR_007458
Natural variant361G → R in endometrial hyperplasia.
VAR_026252
Natural variant421L → 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 variant471R → G in CD.
VAR_011587
Natural variant571L → W in glioma; loss of protein phosphatase activity.
VAR_007460
Natural variant611H → D in VATER.
VAR_018101
Natural variant611H → R Loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026253
Natural variant671I → R in CD.
VAR_007461
Natural variant681Y → 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 variant701L → P in CD.
VAR_018102
Natural variant711C → Y in CD; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026254
Natural variant931H → R in macrocephaly/autism syndrome.
VAR_032634
Natural variant931H → Y in CD.
VAR_026255
Natural variant1051C → F in BZS; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026256
Natural variant1051C → Y in BZS.
VAR_008735
Natural variant1071D → Y in BZS and glioblastoma; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026257
Natural variant1121L → P in CD and LDD; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_007807
Natural variant1121L → R Loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026258
Natural variant1191V → L in multiple cancers.
VAR_011588
Natural variant1211A → G in HNSCC.
VAR_018103
Natural variant1211A → P in glioblastoma; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026259
Natural variant1231H → R in CD.
VAR_007463
Natural variant1231H → Y in endometrial cancer; loss of protein phosphatase activity.
VAR_026260
Natural variant1241C → R in CD.
VAR_007464
Natural variant1241C → S in CD; phosphatase-dead protein with neither lipid nor protein phosphatase activity.
VAR_018104
Natural variant1291G → E in CD; no lipid phosphatase activity but retains protein phosphatase activity; retains ability to inhibit focal adhesion formation.
VAR_007465
Natural variant1291G → R in glioblastoma; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_007466
Natural variant1301R → G Loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3.
VAR_026261
Natural variant1301R → 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 variant1301R → Q in CD; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.
VAR_007468
Natural variant1321G → V in one patient with clinical findings suggesting hamartoma tumor syndrome.
VAR_032635
Natural variant1331V → I Loss of phosphatase activity towards Ins(1,3,4,5)P3.
VAR_026262
Natural variant1341M → 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 variant1351I → V in BZS.
VAR_008736
Natural variant1361C → Y in CD; loss of phosphatase activity towards Ins(1,3,4,5)P3.
VAR_007808
Natural variant1371A → AN in CD.
VAR_008737
Natural variant1551Y → C in CD; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026263
Natural variant1581V → L in multiple cancers.
VAR_011589
Natural variant1651G → E in CD.
VAR_008739
Natural variant1651G → 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 variant1651G → V in CD.
VAR_008738
Natural variant1671T → P in breast cancer; severely reduced protein phosphatase activity.
VAR_026265
Natural variant1701S → N Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.
VAR_026266
Natural variant1701S → R in BZS; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_007470
Natural variant1731R → 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 variant1731R → H Loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026268
Natural variant1731R → P Loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026269
Natural variant1741Y → N Loss of phosphatase activity towards Ins(1,3,4,5)P4.
VAR_026270
Natural variant1911V → A in endometrial hyperplasia.
VAR_026271
Natural variant2171V → I in malignant melanoma; somatic mutation.
VAR_018105
Natural variant2271S → F Reduced phosphatase activity towards Ins(1,3,4,5)P4 but retains PtdIns(3,4,5)P3 phosphatase activity.
VAR_026272
Natural variant2341R → 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 variant2411F → S in macrocephaly/autism syndrome.
VAR_032636
Natural variant2461P → L in CD and BZS.
VAR_008740
Natural variant2511G → C Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes.
VAR_026273
Natural variant2521D → G in macrocephaly/autism syndrome.
VAR_032637