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Protein

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

Gene

PTEN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 (PubMed:26504226). 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. Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability. In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement.1 Publication
Isoform alpha: Functional kinase, like isoform 1 it antagonizes the PI3K-AKT/PKB signaling pathway. Plays a role in mitochondrial energetic metabolism by promoting COX activity and ATP production, via collaboration with isoform 1 in increasing protein levels of PINK1.

Catalytic activityi

Phosphatidylinositol 3,4,5-trisphosphate + H2O = phosphatidylinositol 4,5-bisphosphate + phosphate.
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.
Protein tyrosine phosphate + H2O = protein tyrosine + phosphate.

Cofactori

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei124Phosphocysteine intermediatePROSITE-ProRule annotation1

GO - Molecular functioni

  • anaphase-promoting complex binding Source: BHF-UCL
  • enzyme binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity Source: UniProtKB
  • lipid binding Source: UniProtKB-KW
  • magnesium ion binding Source: InterPro
  • PDZ domain binding Source: UniProtKB
  • phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity Source: UniProtKB
  • phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity Source: UniProtKB
  • phosphatidylinositol-3-phosphatase activity Source: UniProtKB
  • phosphoprotein phosphatase activity Source: BHF-UCL
  • protein serine/threonine phosphatase activity Source: UniProtKB
  • protein tyrosine/serine/threonine phosphatase activity Source: InterPro
  • protein tyrosine phosphatase activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protein phosphatase

Keywords - Biological processi

Apoptosis, Lipid metabolism, Neurogenesis

Keywords - Ligandi

Lipid-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS10404-MONOMER.
ZFISH:HS10404-MONOMER.
BRENDAi3.1.3.16. 2681.
ReactomeiR-HSA-1257604. PIP3 activates AKT signaling.
R-HSA-1660499. Synthesis of PIPs at the plasma membrane.
R-HSA-1855204. Synthesis of IP3 and IP4 in the cytosol.
R-HSA-199418. Negative regulation of the PI3K/AKT network.
R-HSA-202424. Downstream TCR signaling.
R-HSA-5628897. TP53 Regulates Metabolic Genes.
R-HSA-5689880. Ub-specific processing proteases.
R-HSA-5689896. Ovarian tumor domain proteases.
SignaLinkiP60484.
SIGNORiP60484.

Chemistry databases

SwissLipidsiSLP:000000849.

Names & Taxonomyi

Protein namesi
Recommended name:
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (EC:3.1.3.16, EC:3.1.3.48, EC:3.1.3.67)
Alternative name(s):
Mutated in multiple advanced cancers 1
Phosphatase and tensin homolog
Gene namesi
Name:PTEN
Synonyms:MMAC1, TEP1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:9588. PTEN.

Subcellular locationi

  • Cytoplasm
  • Nucleus
  • NucleusPML body

  • Note: Monoubiquitinated form is nuclear. Nonubiquitinated form is cytoplasmic. Colocalized with PML and USP7 in PML nuclear bodies. XIAP/BIRC4 promotes its nuclear localization.
Isoform alpha :

GO - Cellular componenti

  • apical plasma membrane Source: UniProtKB
  • cell projection Source: UniProtKB
  • cytoplasm Source: UniProtKB
  • cytoplasmic side of plasma membrane Source: UniProtKB
  • cytosol Source: Reactome
  • dendritic spine Source: Ensembl
  • extracellular region Source: UniProtKB-SubCell
  • mitochondrion Source: Ensembl
  • myelin sheath adaxonal region Source: BHF-UCL
  • neuron projection Source: BHF-UCL
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
  • plasma membrane Source: UniProtKB
  • PML body Source: UniProtKB-SubCell
  • postsynaptic membrane Source: Ensembl
  • Schmidt-Lanterman incisure Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus, Secreted

Pathology & Biotechi

Involvement in diseasei

Cowden syndrome 1 (CWS1)13 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid.
See also OMIM:158350
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00873333Missing in CWS1. 1 Publication1
Natural variantiVAR_00803635M → R in CWS1. 1 PublicationCorresponds to variant rs121909225dbSNPEnsembl.1
Natural variantiVAR_01158747R → G in CWS1. 1 PublicationCorresponds to variant rs786204855dbSNPEnsembl.1
Natural variantiVAR_00746167I → R in CWS1. 1
Natural variantiVAR_00746268Y → H in CWS1 and BRRS; loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains the ability to bind phospholipid membranes. 4 PublicationsCorresponds to variant rs398123317dbSNPEnsembl.1
Natural variantiVAR_01810270L → P in CWS1. 1 PublicationCorresponds to variant rs121909226dbSNPEnsembl.1
Natural variantiVAR_02625471C → Y in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_02625593H → Y in CWS1. 1 Publication1
Natural variantiVAR_007807112L → P in CWS1 and LDD; loss of phosphatase activity towards Ins(1,3,4,5)P4. 3 PublicationsCorresponds to variant rs121909230dbSNPEnsembl.1
Natural variantiVAR_007463123H → R in CWS1. 2 PublicationsCorresponds to variant rs121909222dbSNPEnsembl.1
Natural variantiVAR_007464124C → R in CWS1. 3 PublicationsCorresponds to variant rs121909223dbSNPEnsembl.1
Natural variantiVAR_018104124C → S in CWS1; phosphatase-dead protein with neither lipid nor protein phosphatase activity. 2 Publications1
Natural variantiVAR_007465129G → E in CWS1; no lipid phosphatase activity but retains protein phosphatase activity; retains ability to inhibit focal adhesion formation. 5 PublicationsCorresponds to variant rs121909218dbSNPEnsembl.1
Natural variantiVAR_007467130R → L in CWS1 and endometrial hyperplasia; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes. 2 Publications1
Natural variantiVAR_007468130R → Q in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes. 2 PublicationsCorresponds to variant rs121909229dbSNPEnsembl.1
Natural variantiVAR_007808136C → Y in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P3. 2 PublicationsCorresponds to variant rs786204859dbSNPEnsembl.1
Natural variantiVAR_008737137A → AN in CWS1. 1 Publication1
Natural variantiVAR_026263155Y → C in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_008739165G → E in CWS1. 1 Publication1
Natural variantiVAR_008738165G → V in CWS1. Corresponds to variant rs786204863dbSNPEnsembl.1
Natural variantiVAR_008741289K → E in CWS1; reduced phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes; predominantly nuclear. 3 PublicationsCorresponds to variant rs562015640dbSNPEnsembl.1
Natural variantiVAR_026275331D → G in CWS1; reduced phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes. 1 Publication1
Natural variantiVAR_026276341F → V in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_026277342K → N in CWS1; reduced phosphatase activity towards Ins(1,3,4,5)P4 but PtdIns(3,4,5)P3 phosphatase activity is similar to wild-type. 1 PublicationCorresponds to variant rs398123314dbSNPEnsembl.1
Natural variantiVAR_008742343V → E in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4. 2 Publications1
Natural variantiVAR_008743347F → L in CWS1; reduced phosphatase activity towards Ins(1,3,4,5)P4. 2 Publications1
Lhermitte-Duclos disease (LDD)
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare disease characterized by the occurrence of a slowly enlarging mass within the cerebellar cortex corresponding histologically to a cerebellar hamartoma. It manifests, most commonly in the third and fourth decades of life, with increased intracranial pressure, headache, nausea, cerebellar dysfunction, occlusive hydrocephalus, ataxia, visual disturbances and other cranial nerve palsies. Various associated abnormalities may be present such as megalencephaly, microgyria, hydromyelia, polydactyly, partial gigantism, macroglossia. LDD is part of the PTEN hamartoma tumor syndromes spectrum that also includes Cowden syndrome.
See also OMIM:158350
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_007807112L → P in CWS1 and LDD; loss of phosphatase activity towards Ins(1,3,4,5)P4. 3 PublicationsCorresponds to variant rs121909230dbSNPEnsembl.1
Bannayan-Riley-Ruvalcaba syndrome (BRRS)4 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare hamartomatous disorder characterized by macrocephaly and multiple hemangiomas as well as subcutaneous and visceral lipomas. It belongs to the family of hamartomatous polyposis syndromes that includes Peutz Jeghers syndrome, juvenile polyposis, and Cowden syndrome.
See also OMIM:153480
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00873434A → D in BRRS. 2 Publications1
Natural variantiVAR_00746268Y → H in CWS1 and BRRS; loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains the ability to bind phospholipid membranes. 4 PublicationsCorresponds to variant rs398123317dbSNPEnsembl.1
Natural variantiVAR_026256105C → F in BRRS; loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_008735105C → Y in BRRS. 2 PublicationsCorresponds to variant rs587782343dbSNPEnsembl.1
Natural variantiVAR_026257107D → Y in BRRS and glioblastoma; loss of phosphatase activity towards Ins(1,3,4,5)P4. 2 Publications1
Natural variantiVAR_008736135I → V in BRRS. 2 PublicationsCorresponds to variant rs587782360dbSNPEnsembl.1
Natural variantiVAR_007470170S → R in BRRS; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4. 5 PublicationsCorresponds to variant rs121909221dbSNPEnsembl.1
Natural variantiVAR_008740246P → L in BRRS. 1 PublicationCorresponds to variant rs587782350dbSNPEnsembl.1
Squamous cell carcinoma of the head and neck (HNSCC)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA non-melanoma skin cancer affecting the head and neck. The hallmark of cutaneous SCC is malignant transformation of normal epidermal keratinocytes.
See also OMIM:275355
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_018103121A → G in HNSCC. 1 PublicationCorresponds to variant rs121909237dbSNPEnsembl.1
Endometrial cancer (ENDMC)
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids.
See also OMIM:608089

PTEN mutations are found in a subset of patients with Proteus syndrome, a genetically heterogeneous condition. The molecular diagnosis of PTEN mutation positive cases classifies Proteus syndrome patients as part of the PTEN hamartoma syndrome spectrum. As such, patients surviving the early years of Proteus syndrome are likely at a greater risk of developing malignancies.

Glioma 2 (GLM2)
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionGliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.
See also OMIM:613028
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_018106234R → Q in GLM2; the patient also suffered from benign meningioma; 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. 1 PublicationCorresponds to variant rs121909235dbSNPEnsembl.1
VACTERL association with hydrocephalus (VACTERL-H)
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionVACTERL is an acronym for vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects.
See also OMIM:276950
Prostate cancer (PC)2 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma.
See also OMIM:176807
Macrocephaly/autism syndrome (MCEPHAS)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionPatients 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).
See also OMIM:605309
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03263493H → R in MCEPHAS. 1 PublicationCorresponds to variant rs121909238dbSNPEnsembl.1
Natural variantiVAR_076762131T → I in MCEPHAS. 1 Publication1
Natural variantiVAR_076763167T → N in MCEPHAS. 1 Publication1
Natural variantiVAR_032636241F → S in MCEPHAS. 1 PublicationCorresponds to variant rs121909240dbSNPEnsembl.1
Natural variantiVAR_032637252D → G in MCEPHAS. 1 PublicationCorresponds to variant rs121909239dbSNPEnsembl.1

A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi1M → I: Expression is restricted to isoform alpha. 1 Publication1
Mutagenesisi13K → E: Nuclear. Cytoplasmic; when associated with E-289. Shows less tumor suppressive ability; when associated with E-289. 1 Publication1
Mutagenesisi92D → A: 700-fold reduction in phosphatase activity towards PtdIns(3,4,5)P3. Loss of protein phosphatase activity. Unable to inhibit focal adhesion formation. 2 Publications1
Mutagenesisi93H → A: 75% reduction in phosphatase activity towards PtdIns(3,4,5)P3. Modest reduction in phosphatase activity towards PtdIns(3,4)P2. 1 Publication1
Mutagenesisi124C → A: Loss of protein phosphatase activity. Unable to inhibit focal adhesion formation. 1 Publication1
Mutagenesisi125K → M: Reduced phosphatase activity towards PtdIns(3,4,5)P3, PtdIns(3,4)P2 and PtdIns(3)P. 1 Publication1
Mutagenesisi126A → P: Does not reduce phosphatase activity towards PtdIns(3,4,5)P3 and PtdIns(3,4)P2. 1 Publication1
Mutagenesisi126A → S: Does not reduce phosphatase activity towards PtdIns(3,4,5)P3 and PtdIns(3,4)P2. 1 Publication1
Mutagenesisi126A → V: Does not reduce phosphatase activity towards PtdIns(3,4,5)P3 and PtdIns(3,4)P2. 1 Publication1
Mutagenesisi128K → M: 85% reduction in phosphatase activity towards PtdIns(3,4,5)P3. 1 Publication1
Mutagenesisi128K → R: Does not reduce phosphatase activity towards PtdIns(3,4,5)P3. 1 Publication1
Mutagenesisi130R → M: Does not affect the ability to inhibit AKT/PKB activation. 1 Publication1
Mutagenesisi167T → A or D: 60% reduction in phosphatase activity towards PtdIns(3,4,5)P3. 1 Publication1
Mutagenesisi171Q → A or E: 75% reduction in phosphatase activity towards PtdIns(3,4,5)P3. 1 Publication1
Mutagenesisi263 – 269KMLKKDK → AAGAADA: Reduces the growth suppression activity and cells show anchorage-independent growth. Reduces binding to phospholipid membranes in vitro. Phosphatase activity towards PtdIns(3,4,5)P3 is not affected. 1 Publication7
Mutagenesisi289K → E: Cytoplasmic; when associated with E-13. Shows less tumor suppressive ability; when associated with E-13. 1 Publication1
Mutagenesisi327 – 335KANKDKANR → AAGADAANA: Reduces growth suppression activity and promotes anchorage-independent growth. Reduces binding to phospholipid membranes in vitro; phosphatase activity towards PtdIns(3,4,5)P3 is not affected. 1 Publication9
Mutagenesisi336Y → F: Significantly lower phosphatase activity, reduced protein stability and decreased growth-inhibitory effect. 1 Publication1
Mutagenesisi366T → A: Decreased stability. 1 Publication1
Mutagenesisi370S → A: Decreased stability. 1 Publication1
Mutagenesisi401T → A: Loss of DLG1-binding. No effect on MAGI2- and MAST2-binding. 1
Mutagenesisi402K → A: No effect on MAGI2-, MAST2- and DLG1-binding. 1
Mutagenesisi402K → W: Loss of DLG1-, MAGI2-, MAGI3- and MAST2-binding. Decrease of protein stability. 1
Mutagenesisi403V → A: Loss of DLG1-, MAGI2-, MAGI3-, MAST1-, MAST2- and MAST3-binding. 1 Publication1

Keywords - Diseasei

Autism spectrum disorder, Disease mutation, Tumor suppressor

Organism-specific databases

DisGeNETi5728.
MalaCardsiPTEN.
MIMi137800. phenotype.
153480. phenotype.
158350. phenotype.
176807. phenotype.
275355. phenotype.
276950. phenotype.
605309. phenotype.
608089. phenotype.
612242. phenotype.
613028. phenotype.
OpenTargetsiENSG00000171862.
Orphaneti109. Bannayan-Riley-Ruvalcaba syndrome.
201. Cowden syndrome.
145. Hereditary breast and ovarian cancer syndrome.
79076. Juvenile polyposis of infancy.
65285. Lhermitte-Duclos disease.
210548. Macrocephaly-autism syndrome.
744. Proteus syndrome.
2969. Proteus-like syndrome.
137608. Segmental outgrowth - lipomatosis - arteriovenous malformation - epidermal nevus.
67037. Squamous cell carcinoma of head and neck.
PharmGKBiPA33942.

Chemistry databases

ChEMBLiCHEMBL2052032.
GuidetoPHARMACOLOGYi2497.

Polymorphism and mutation databases

BioMutaiPTEN.
DMDMi42560209.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00002159042 – 403Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTENAdd BLAST402

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylthreonineCombined sources1
Cross-linki13Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki289Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei294PhosphoserineBy similarity1
Modified residuei336Phosphotyrosine; by FRK1 Publication1
Modified residuei366Phosphothreonine; by GSK3-beta and PLK3Combined sources2 Publications1
Modified residuei370Phosphoserine; by CK2 and PLK33 Publications1
Modified residuei380Phosphoserine; by ROCK1 and CK21 Publication1
Modified residuei382Phosphothreonine; by ROCK1 and CK21 Publication1
Modified residuei383Phosphothreonine; by ROCK1 and CK21 Publication1
Modified residuei385Phosphoserine; by CK22 Publications1
Modified residuei401Phosphothreonine1 Publication1

Post-translational modificationi

Constitutively phosphorylated by CK2 under normal conditions. Phosphorylated in vitro by MAST1, MAST2, MAST3 and STK11. Phosphorylation results in an inhibited activity towards PIP3. Phosphorylation can both inhibit or promote PDZ-binding. Phosphorylation at Tyr-336 by FRK/PTK5 protects this protein from ubiquitin-mediated degradation probably by inhibiting its binding to NEDD4. Phosphorylation by ROCK1 is essential for its stability and activity. Phosphorylation by PLK3 promotes its stability and prevents its degradation by the proteasome.9 Publications
Monoubiquitinated; monoubiquitination is increased in presence of retinoic acid. Deubiquitinated by USP7; leading to its nuclear exclusion. Monoubiquitination of one of either Lys-13 and Lys-289 amino acid is sufficient to modulate PTEN compartmentalization. Ubiquitinated by XIAP/BIRC4.2 Publications

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP60484.
MaxQBiP60484.
PaxDbiP60484.
PeptideAtlasiP60484.
PRIDEiP60484.

PTM databases

DEPODiP60484.
iPTMnetiP60484.
PhosphoSitePlusiP60484.

Miscellaneous databases

PMAP-CutDBP60484.

Expressioni

Tissue specificityi

Expressed at a relatively high level in all adult tissues, including heart, brain, placenta, lung, liver, muscle, kidney and pancreas.1 Publication

Inductioni

Down-regulated by TGFB1.1 Publication

Gene expression databases

BgeeiENSG00000171862.
CleanExiHS_PTEN.
HS_TEP1.
ExpressionAtlasiP60484. baseline and differential.
GenevisibleiP60484. HS.

Organism-specific databases

HPAiCAB004076.
HPA031335.

Interactioni

Subunit structurei

Monomer. The unphosphorylated form interacts with the second PDZ domain of AIP1 and with DLG1 and MAST2 in vitro. Interacts with MAGI2, MAGI3, MAST1 and MAST3, but neither with MAST4 nor with DLG5; interaction with MAGI2 increases protein stability. Interacts with NEDD4. Interacts with NDFIP1 and NDFIP2; in the presence of NEDD4 or ITCH, this interaction promotes PTEN ubiquitination. Interacts (via C2 domain) with FRK. Interacts with USP7; the interaction is direct. Interacts with ROCK1 (By similarity). Interacts with XIAP/BIRC4. Interacts with STK11; the interaction phosphorylates PTEN.By similarity12 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself9EBI-696162,EBI-696162
BMI1P352263EBI-696162,EBI-2341576
CDC27P302607EBI-696162,EBI-994813
DBN1Q166435EBI-696162,EBI-351394
Dlg1Q626962EBI-696162,EBI-389325From a different organism.
FRKP426857EBI-696162,EBI-1383583
Magi2O883823EBI-696162,EBI-696179From a different organism.
Magi3Q9JK713EBI-696162,EBI-696226From a different organism.
Mast1Q9R1L53EBI-696162,EBI-491771From a different organism.
Mast2Q605924EBI-696162,EBI-493888From a different organism.
MAST3O603073EBI-696162,EBI-311420
NCOA3Q9Y6Q92EBI-696162,EBI-81196
NEDD4P469344EBI-696162,EBI-726944
PDGFRBP096193EBI-696162,EBI-641237
PPP1CAP621362EBI-696162,EBI-357253
PRDX1Q068307EBI-696162,EBI-353193
SLC9A3R1O147457EBI-696162,EBI-349787
SLC9A3R2Q155995EBI-696162,EBI-1149760
Slc9a3r2Q9JHL12EBI-696162,EBI-538451From a different organism.
SPOPO437914EBI-696162,EBI-743549

GO - Molecular functioni

  • anaphase-promoting complex binding Source: BHF-UCL
  • enzyme binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • PDZ domain binding Source: UniProtKB

Protein-protein interaction databases

BioGridi111700. 259 interactors.
DIPiDIP-35019N.
IntActiP60484. 52 interactors.
MINTiMINT-127351.
STRINGi9606.ENSP00000361021.

Chemistry databases

BindingDBiP60484.

Structurei

Secondary structure

1403
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni19 – 22Combined sources4
Beta strandi23 – 29Combined sources7
Beta strandi32 – 35Combined sources4
Beta strandi39 – 41Combined sources3
Beta strandi44 – 47Combined sources4
Helixi50 – 60Combined sources11
Beta strandi61 – 63Combined sources3
Beta strandi65 – 73Combined sources9
Helixi78 – 80Combined sources3
Beta strandi81 – 83Combined sources3
Beta strandi85 – 90Combined sources6
Helixi98 – 100Combined sources3
Helixi101 – 112Combined sources12
Turni113 – 115Combined sources3
Beta strandi118 – 123Combined sources6
Beta strandi125 – 128Combined sources4
Helixi129 – 141Combined sources13
Helixi148 – 159Combined sources12
Beta strandi161 – 163Combined sources3
Helixi169 – 184Combined sources16
Beta strandi192 – 202Combined sources11
Beta strandi206 – 209Combined sources4
Beta strandi213 – 219Combined sources7
Beta strandi222 – 226Combined sources5
Beta strandi232 – 235Combined sources4
Beta strandi238 – 259Combined sources22
Beta strandi262 – 264Combined sources3
Beta strandi268 – 276Combined sources9
Helixi277 – 279Combined sources3
Beta strandi280 – 284Combined sources5
Beta strandi310 – 312Combined sources3
Beta strandi315 – 321Combined sources7
Helixi322 – 324Combined sources3
Helixi328 – 330Combined sources3
Beta strandi335 – 337Combined sources3
Beta strandi342 – 349Combined sources8
Beta strandi395 – 403Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1D5RX-ray2.10A8-353[»]
2KYLNMR-B391-403[»]
4O1VX-ray2.00B354-368[»]
5BUGX-ray2.40A/B/C/D14-351[»]
5BZXX-ray2.50A/B/C/D14-351[»]
5BZZX-ray2.20A/B/C/D14-351[»]
ProteinModelPortaliP60484.
SMRiP60484.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP60484.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini14 – 185Phosphatase tensin-typePROSITE-ProRule annotationAdd BLAST172
Domaini190 – 350C2 tensin-typePROSITE-ProRule annotationAdd BLAST161

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni401 – 403PDZ domain-binding3

Domaini

The C2 domain binds phospholipid membranes in vitro in a Ca2+-independent manner; this binding is important for its tumor suppressor function.2 Publications

Sequence similaritiesi

Contains 1 C2 tensin-type domain.PROSITE-ProRule annotation
Contains 1 phosphatase tensin-type domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG2283. Eukaryota.
COG2453. LUCA.
GeneTreeiENSGT00760000119113.
HOGENOMiHOG000008008.
HOVERGENiHBG000239.
InParanoidiP60484.
KOiK01110.
OMAiYSPCESD.
OrthoDBiEOG091G09VG.
PhylomeDBiP60484.
TreeFamiTF324513.

Family and domain databases

Gene3Di3.90.190.10. 1 hit.
InterProiIPR017361. Bifunc_PIno_P3_Pase/Pase_PTEN.
IPR000008. C2_dom.
IPR000340. Dual-sp_phosphatase_cat-dom.
IPR029021. Prot-tyrosine_phosphatase-like.
IPR014020. Tensin_C2-dom.
IPR029023. Tensin_lipid_phosphatase_dom.
IPR016130. Tyr_Pase_AS.
IPR003595. Tyr_Pase_cat.
[Graphical view]
PfamiPF00782. DSPc. 1 hit.
PF10409. PTEN_C2. 1 hit.
[Graphical view]
PIRSFiPIRSF038025. PTEN. 1 hit.
SMARTiSM01326. PTEN_C2. 1 hit.
SM00404. PTPc_motif. 1 hit.
[Graphical view]
SUPFAMiSSF49562. SSF49562. 1 hit.
SSF52799. SSF52799. 1 hit.
PROSITEiPS51182. C2_TENSIN. 1 hit.
PS51181. PPASE_TENSIN. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing and alternative initiation. AlignAdd to basket

Isoform 1 (identifier: P60484-1) [UniParc]FASTAAdd to basket
Also known as: 55kDa

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MTAIIKEIVS RNKRRYQEDG FDLDLTYIYP NIIAMGFPAE RLEGVYRNNI
60 70 80 90 100
DDVVRFLDSK HKNHYKIYNL CAERHYDTAK FNCRVAQYPF EDHNPPQLEL
110 120 130 140 150
IKPFCEDLDQ WLSEDDNHVA AIHCKAGKGR TGVMICAYLL HRGKFLKAQE
160 170 180 190 200
ALDFYGEVRT RDKKGVTIPS QRRYVYYYSY LLKNHLDYRP VALLFHKMMF
210 220 230 240 250
ETIPMFSGGT CNPQFVVCQL KVKIYSSNSG PTRREDKFMY FEFPQPLPVC
260 270 280 290 300
GDIKVEFFHK QNKMLKKDKM FHFWVNTFFI PGPEETSEKV ENGSLCDQEI
310 320 330 340 350
DSICSIERAD NDKEYLVLTL TKNDLDKANK DKANRYFSPN FKVKLYFTKT
360 370 380 390 400
VEEPSNPEAS SSTSVTPDVS DNEPDHYRYS DTTDSDPENE PFDEDQHTQI

TKV
Length:403
Mass (Da):47,166
Last modified:February 16, 2004 - v1
Checksum:i75F97C3DD6802BA9
GO
Isoform alpha (identifier: P60484-2) [UniParc]FASTAAdd to basket
Also known as: 70kDa, PTEN-long

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MERGGEAAAA...FFFSHRLPDM

Note: Produced by alternative initiation at a CTG start codon of isoform 1. May contain a signal peptide at positions 1-21.
Show »
Length:576
Mass (Da):64,882
Checksum:iE0A3C5E42AEC150D
GO
Isoform 3 (identifier: P60484-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     55-70: RFLDSKHKNHYKIYNL → S
     165-190: GVTIPSQRRYVYYYSYLLKNHLDYRP → ADPTGGIPDKGIIVIGDGSSMDVIAP
     191-403: Missing.

Show »
Length:175
Mass (Da):19,796
Checksum:iEB3BBB17D7302085
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02624810S → N Retains phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains the ability to bind phospholipid membranes. 1 Publication1
Natural variantiVAR_00745715R → S in glioma. 1 Publication1
Natural variantiVAR_02624916Y → C Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains the ability to bind phospholipid membranes. 1 Publication1
Natural variantiVAR_01810019D → N in malignant melanoma; somatic mutation. 1 PublicationCorresponds to variant rs121909233dbSNPEnsembl.1
Natural variantiVAR_02625020G → E Reduced phosphatase activity towards Ins(1,3,4,5)P4; retains phosphatase activity towards PtdIns(3,4,5)P3. 1 Publication1
Natural variantiVAR_02625127Y → S Loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_00873333Missing in CWS1. 1 Publication1
Natural variantiVAR_00873434A → D in BRRS. 2 Publications1
Natural variantiVAR_00803635M → R in CWS1. 1 PublicationCorresponds to variant rs121909225dbSNPEnsembl.1
Natural variantiVAR_00745836G → E in glioma. 1 Publication1
Natural variantiVAR_02625236G → R in endometrial hyperplasia. 1 PublicationCorresponds to variant rs786204854dbSNPEnsembl.1
Natural variantiVAR_00745942L → 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. 1 Publication1
Natural variantiVAR_01158747R → G in CWS1. 1 PublicationCorresponds to variant rs786204855dbSNPEnsembl.1
Natural variantiVAR_00746057L → W in glioma; loss of protein phosphatase activity. 2 PublicationsCorresponds to variant rs786202398dbSNPEnsembl.1
Natural variantiVAR_01810161H → D in VATER. 1 PublicationCorresponds to variant rs121909236dbSNPEnsembl.1
Natural variantiVAR_02625361H → R Loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 PublicationCorresponds to variant rs398123316dbSNPEnsembl.1
Natural variantiVAR_00746167I → R in CWS1. 1
Natural variantiVAR_00746268Y → H in CWS1 and BRRS; loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3; retains the ability to bind phospholipid membranes. 4 PublicationsCorresponds to variant rs398123317dbSNPEnsembl.1
Natural variantiVAR_01810270L → P in CWS1. 1 PublicationCorresponds to variant rs121909226dbSNPEnsembl.1
Natural variantiVAR_02625471C → Y in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_03263493H → R in MCEPHAS. 1 PublicationCorresponds to variant rs121909238dbSNPEnsembl.1
Natural variantiVAR_02625593H → Y in CWS1. 1 Publication1
Natural variantiVAR_026256105C → F in BRRS; loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_008735105C → Y in BRRS. 2 PublicationsCorresponds to variant rs587782343dbSNPEnsembl.1
Natural variantiVAR_026257107D → Y in BRRS and glioblastoma; loss of phosphatase activity towards Ins(1,3,4,5)P4. 2 Publications1
Natural variantiVAR_007807112L → P in CWS1 and LDD; loss of phosphatase activity towards Ins(1,3,4,5)P4. 3 PublicationsCorresponds to variant rs121909230dbSNPEnsembl.1
Natural variantiVAR_026258112L → R Loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_011588119V → L in multiple cancers. 1 PublicationCorresponds to variant rs139767111dbSNPEnsembl.1
Natural variantiVAR_018103121A → G in HNSCC. 1 PublicationCorresponds to variant rs121909237dbSNPEnsembl.1
Natural variantiVAR_026259121A → P in glioblastoma; loss of phosphatase activity towards Ins(1,3,4,5)P4. 2 Publications1
Natural variantiVAR_007463123H → R in CWS1. 2 PublicationsCorresponds to variant rs121909222dbSNPEnsembl.1
Natural variantiVAR_026260123H → Y in endometrial cancer; loss of protein phosphatase activity. 1 PublicationCorresponds to variant rs786204931dbSNPEnsembl.1
Natural variantiVAR_007464124C → R in CWS1. 3 PublicationsCorresponds to variant rs121909223dbSNPEnsembl.1
Natural variantiVAR_018104124C → S in CWS1; phosphatase-dead protein with neither lipid nor protein phosphatase activity. 2 Publications1
Natural variantiVAR_076551126A → G in a patient with prostate cancer; reduced phosphatase activity towards PtdIns(3,4,5); shifts its activity from phosphatidylinositol phosphate 3-phosphatase to phosphatidylinositol phosphate 5-phosphatase; disrupts PI3K/ATK signaling; reduced cell migration. 1 Publication1
Natural variantiVAR_007465129G → E in CWS1; no lipid phosphatase activity but retains protein phosphatase activity; retains ability to inhibit focal adhesion formation. 5 PublicationsCorresponds to variant rs121909218dbSNPEnsembl.1
Natural variantiVAR_007466129G → R in glioblastoma; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4. 4 PublicationsCorresponds to variant rs786204929dbSNPEnsembl.1
Natural variantiVAR_026261130R → G Loss of phosphatase activity towards Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3. 1 PublicationCorresponds to variant rs121909224dbSNPEnsembl.1
Natural variantiVAR_007467130R → L in CWS1 and endometrial hyperplasia; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes. 2 Publications1
Natural variantiVAR_007468130R → Q in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes. 2 PublicationsCorresponds to variant rs121909229dbSNPEnsembl.1
Natural variantiVAR_076762131T → I in MCEPHAS. 1 Publication1
Natural variantiVAR_032635132G → V in one patient with clinical findings suggesting hamartoma tumor syndrome. 1 PublicationCorresponds to variant rs121909241dbSNPEnsembl.1
Natural variantiVAR_026262133V → I Loss of phosphatase activity towards Ins(1,3,4,5)P3. 1 Publication1
Natural variantiVAR_007469134M → 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. 3 Publications1
Natural variantiVAR_008736135I → V in BRRS. 2 PublicationsCorresponds to variant rs587782360dbSNPEnsembl.1
Natural variantiVAR_007808136C → Y in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P3. 2 PublicationsCorresponds to variant rs786204859dbSNPEnsembl.1
Natural variantiVAR_008737137A → AN in CWS1. 1 Publication1
Natural variantiVAR_026263155Y → C in CWS1; loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 Publication1
Natural variantiVAR_011589158V → L in multiple cancers. 1 Publication1
Natural variantiVAR_008739165G → E in CWS1. 1 Publication1
Natural variantiVAR_026264165G → 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. 3 Publications1
Natural variantiVAR_008738165G → V in CWS1. Corresponds to variant rs786204863dbSNPEnsembl.1
Natural variantiVAR_076763167T → N in MCEPHAS. 1 Publication1
Natural variantiVAR_026265167T → P in breast cancer; severely reduced protein phosphatase activity. 1 Publication1
Natural variantiVAR_026266170S → N Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes. 1 Publication1
Natural variantiVAR_007470170S → R in BRRS; severely reduced protein phosphatase activity; loss of phosphatase activity towards Ins(1,3,4,5)P4. 5 PublicationsCorresponds to variant rs121909221dbSNPEnsembl.1
Natural variantiVAR_026267173R → 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. 2 PublicationsCorresponds to variant rs121913293dbSNPEnsembl.1
Natural variantiVAR_026268173R → H Loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 PublicationCorresponds to variant rs121913294dbSNPEnsembl.1
Natural variantiVAR_026269173R → P Loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 PublicationCorresponds to variant rs121913294dbSNPEnsembl.1
Natural variantiVAR_026270174Y → N Loss of phosphatase activity towards Ins(1,3,4,5)P4. 1 PublicationCorresponds to variant rs587782316dbSNPEnsembl.1
Natural variantiVAR_026271191V → A in endometrial hyperplasia. 1 Publication1
Natural variantiVAR_018105217V → I in malignant melanoma; somatic mutation. 1 PublicationCorresponds to variant rs121909234dbSNPEnsembl.1
Natural variantiVAR_026272227S → F Reduced phosphatase activity towards Ins(1,3,4,5)P4 but retains PtdIns(3,4,5)P3 phosphatase activity. 1 Publication1
Natural variantiVAR_018106234R → Q in GLM2; the patient also suffered from benign meningioma; 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. 1 PublicationCorresponds to variant rs121909235dbSNPEnsembl.1
Natural variantiVAR_032636241F → S in MCEPHAS. 1 PublicationCorresponds to variant rs121909240dbSNPEnsembl.1
Natural variantiVAR_008740246P → L in BRRS. 1 PublicationCorresponds to variant rs587782350dbSNPEnsembl.1
Natural variantiVAR_026273251G → C Loss of phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes. 1 Publication1
Natural variantiVAR_032637252D → G in MCEPHAS. 1 PublicationCorresponds to variant rs121909239dbSNPEnsembl.1
Natural variantiVAR_008741289K → E in CWS1; reduced phosphatase activity towards Ins(1,3,4,5)P4; retains ability to bind phospholipid membranes; predominantly nuclear. 3 PublicationsCorresponds to variant rs562015640dbSNPEnsembl.1
Natural variantiVAR_025167290V → L.1 PublicationCorresponds to variant rs35600253dbSNPEnsembl.1
Natural variantiVAR_026274319Missing in glioma; reduced tumor suppressor activity; fails to inactivate AKT/PKB. 2 Publications