PTEN

This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms.

phosphatase and tensin homolog

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, PubMed:16824732).
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 MAGI2 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.
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.

Adult behaviorIEA:Ensembl
AngiogenesisIEA:Ensembl
Apoptotic processIEA:UniProtKB-KW
Brain morphogenesisISS:BHF-UCL
Canonical Wnt signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Cardiac muscle tissue developmentIEA:Ensembl
Cell migrationISS:UniProtKB
Cell motilityManual Assertion Based On ExperimentIBA:GO_Central
Cellular response to electrical stimulusManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to hypoxiaIEA:Ensembl
Central nervous system developmentISS:UniProtKB
Central nervous system myelin maintenanceISS:BHF-UCL
Central nervous system neuron axonogenesisISS:BHF-UCL
Dendritic spine morphogenesisISS:BHF-UCL
Dentate gyrus developmentISS:BHF-UCL
DephosphorylationManual Assertion Based On ExperimentIBA:GO_Central
Endothelial cell migrationIEA:Ensembl
Forebrain morphogenesisISS:BHF-UCL
Heart developmentISS:UniProtKB
Inositol phosphate dephosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Learning or memoryISS:BHF-UCL
Locomotor rhythmISS:BHF-UCL
Locomotory behaviorISS:BHF-UCL
Long-term synaptic potentiationIEA:Ensembl
Male mating behaviorIEA:Ensembl
Maternal behaviorIEA:Ensembl
Multicellular organismal response to stressISS:BHF-UCL
Negative regulation of apoptotic processIEA:Ensembl
Negative regulation of axon regenerationIEA:Ensembl
Negative regulation of axonogenesisISS:BHF-UCL
Negative regulation of cardiac muscle cell proliferationIEA:Ensembl
Negative regulation of cell agingIEA:Ensembl
Negative regulation of cell cycle G1/S phase transitionManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of cell migrationManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of cell population proliferationManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of cell sizeISS:BHF-UCL
Negative regulation of cyclin-dependent protein serine/threonine kinase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of dendritic spine morphogenesisISS:BHF-UCL
Negative regulation of epithelial cell proliferationIEA:Ensembl
Negative regulation of epithelial to mesenchymal transitionManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of ERK1 and ERK2 cascadeManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of excitatory postsynaptic potentialISS:BHF-UCL
Negative regulation of focal adhesion assemblyManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of G1/S transition of mitotic cell cycleManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of keratinocyte migrationManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of myelinationIEA:Ensembl
Negative regulation of neuron projection developmentBy SimilarityISS:ARUK-UCL
Negative regulation of organ growthISS:BHF-UCL
Negative regulation of peptidyl-serine phosphorylationManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of phosphatidylinositol 3-kinase signalingManual Assertion Based On ExperimentTAS:BHF-UCL
Negative regulation of protein kinase B signalingManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of protein phosphorylationManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of ribosome biogenesisIEA:Ensembl
Negative regulation of synaptic vesicle clusteringISS:BHF-UCL
Negative regulation of vascular associated smooth muscle cell proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of wound healing, spreading of epidermal cellsManual Assertion Based On ExperimentIMP:BHF-UCL
Neuron-neuron synaptic transmissionISS:BHF-UCL
Phosphatidylinositol 3-kinase signalingManual Assertion Based On ExperimentIBA:GO_Central
Phosphatidylinositol biosynthetic processTAS:Reactome
Phosphatidylinositol dephosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of cell population proliferationISS:BHF-UCL
Positive regulation of DNA-binding transcription factor activityManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of ERK1 and ERK2 cascadeIEA:Ensembl
Positive regulation of excitatory postsynaptic potentialISS:BHF-UCL
Positive regulation of TRAIL-activated apoptotic signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of ubiquitin protein ligase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIDA:BHF-UCL
Postsynaptic density assemblyISS:BHF-UCL
Prepulse inhibitionISS:BHF-UCL
Presynaptic membrane assemblyISS:BHF-UCL
Prostate gland growthIEA:Ensembl
Protein dephosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Protein kinase B signalingISS:UniProtKB
Protein stabilizationManual Assertion Based On ExperimentIDA:BHF-UCL
Regulation of B cell apoptotic processIEA:Ensembl
Regulation of cellular component sizeISS:BHF-UCL
Regulation of myeloid cell apoptotic processIEA:Ensembl
Regulation of neuron projection developmentISS:UniProtKB
Regulation of protein kinase B signalingManual Assertion Based On ExperimentIBA:GO_Central
Regulation of protein stabilityManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of synaptic transmission, GABAergicIEA:Ensembl
Rhythmic synaptic transmissionISS:BHF-UCL
Social behaviorISS:BHF-UCL
Synapse assemblyISS:BHF-UCL
Synapse maturationISS:BHF-UCL

Cytoplasm
Nucleus
Nucleus, PML body
Monoubiquitinated form is nuclear. Nonubiquitinated form is cytoplasmic. Colocalized with PML and USP7 in PML nuclear bodies (PubMed:18716620).
XIAP/BIRC4 promotes its nuclear localization (PubMed:19473982).
Isoform alpha
Secreted
May be secreted via a classical signal peptide and reenter into cells with the help of a poly-Arg motif.

Cowden syndrome 1 (CWS1):
An 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.
Lhermitte-Duclos disease (LDD):
A 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.
Squamous cell carcinoma of the head and neck (HNSCC):
A non-melanoma skin cancer affecting the head and neck. The hallmark of cutaneous SCC is malignant transformation of normal epidermal keratinocytes.
Endometrial cancer (ENDMC):
A 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.
Glioma 2 (GLM2):
Gliomas 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.
Prostate cancer (PC):
A 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.
Macrocephaly/autism syndrome (MCEPHAS):
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).

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.
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.