Affinage

PTEN

Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN · UniProt P60484

Round 2 corrected
Length
403 aa
Mass
47.2 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTEN is a dual-specificity phosphatase that functions as a major tumor suppressor by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the D3 position, thereby antagonizing PI3K/AKT signaling to control cell survival, proliferation, and metabolism (PMID:9593664, PMID:9811831). Beyond its lipid phosphatase activity, PTEN directly dephosphorylates protein substrates including FAK (suppressing cell migration), PGK1 (inhibiting glycolysis), and PLK1 (preventing polyploidy), and it maintains genomic integrity through nuclear functions that include centromere association via CENP-C, stabilization of RPA1 at replication forks, and promotion of TOP2A-dependent DNA decatenation (PMID:9616126, PMID:31492635, PMID:17218262, PMID:26403191, PMID:26657567). PTEN activity is regulated by C-terminal tail phosphorylation-dependent autoinhibition, reversible oxidative inactivation through a Cys124–Cys71 disulfide, acetylation at Lys125/128 by PCAF, S-nitrosylation downstream of AMPK/eNOS, tankyrase-mediated PARylation leading to RNF146-dependent degradation, stabilization by the deubiquitinase USP13, and compartment-specific nuclear degradation by the E3 ligase FBXO22 at Lys221 (PMID:18794881, PMID:11916965, PMID:16829519, PMID:28306514, PMID:25547115, PMID:24270891, PMID:32249768). Germline PTEN mutations cause Cowden disease, a cancer predisposition syndrome (PMID:9140396).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    Positional cloning at 10q23 identified PTEN as a candidate tumor suppressor with a protein phosphatase domain, resolving the identity of a frequently deleted locus in diverse cancers and establishing a phosphatase-based tumor suppression paradigm.

    Evidence Homozygous deletion mapping and mutation screening in cancer cell lines by two independent groups

    PMID:9072974 PMID:9090379 PMID:9187108

    Open questions at the time
    • Physiological substrates unknown
    • Lipid phosphatase activity not yet recognized
    • In vivo tumor suppressor function not formally tested
  2. 1997 High

    Discovery that germline PTEN mutations cause Cowden disease established PTEN as a bona fide hereditary tumor suppressor, linking its phosphatase domain to human cancer predisposition.

    Evidence Germline mutational analysis of multiple Cowden disease kindreds

    PMID:9140396

    Open questions at the time
    • Genotype–phenotype correlations for specific mutations unresolved
    • Whether protein or lipid phosphatase activity is critical for tumor suppression unknown
  3. 1998 High

    Identification of PIP3 as the primary physiological substrate of PTEN, with D3-specific dephosphorylation, transformed understanding from a protein phosphatase to a lipid phosphatase that directly antagonizes PI3K signaling and controls AKT activation.

    Evidence In vitro phosphatase assay with purified recombinant PTEN, active-site C124S mutagenesis, cellular PIP3 measurement; Cowden mutation G129E selectively ablating lipid but not protein phosphatase activity

    PMID:9593664 PMID:9811831

    Open questions at the time
    • Structural basis for PIP3 recognition unresolved
    • Relative contribution of protein vs. lipid phosphatase activity to each tumor suppressor function unclear
  4. 1998 High

    Demonstration that PTEN suppresses cell migration by dephosphorylating FAK and inhibiting focal adhesion formation revealed a protein phosphatase-dependent function distinct from lipid phosphatase activity, establishing PTEN as a dual-function enzyme.

    Evidence Cell migration and focal adhesion assays, co-immunoprecipitation with FAK, phosphatase-dead mutant controls

    PMID:9616126

    Open questions at the time
    • Whether FAK dephosphorylation occurs in vivo at physiological PTEN levels not established
    • Relative importance of FAK vs. PIP3 regulation for tumor suppression unclear
  5. 1998 High

    Pten knockout mice confirmed essential developmental and tumor-suppressive roles in vivo, with embryonic lethality in homozygotes and spontaneous tumors in heterozygotes, validating the haploinsufficient tumor suppressor model.

    Evidence Homologous recombination knockout in mice, histopathology, tumor spectrum analysis

    PMID:9697695

    Open questions at the time
    • Tissue-specific contributions of PTEN loss not dissected
    • Nuclear vs. cytoplasmic functions not distinguished in vivo
  6. 1999 High

    The crystal structure revealed an enlarged active-site pocket accommodating PIP3 and a C2 domain mediating membrane recruitment, providing the structural basis for substrate specificity and explaining how cancer-associated mutations impair function.

    Evidence X-ray crystallography, lipid binding assay, C2 domain mutagenesis, cell growth suppression assay

    PMID:10555148

    Open questions at the time
    • Full-length PTEN structure including C-terminal tail not resolved
    • Membrane-bound catalytic conformation unknown
  7. 2001 High

    Identification of p53 as a direct transcriptional activator of PTEN, with PTEN required for p53-mediated apoptosis, established a tumor suppressor signaling axis linking the two most frequently inactivated genes in cancer.

    Evidence PTEN promoter deletion and mutation analysis, p53 induction, apoptosis in PTEN-null MEFs

    PMID:11545734

    Open questions at the time
    • Whether p53-PTEN axis operates equivalently in all tissue contexts unknown
    • Post-translational crosstalk beyond transcription not addressed
  8. 2002 High

    Discovery of reversible oxidative inactivation through a Cys124–Cys71 disulfide bond, reactivated by thioredoxin, revealed that ROS directly regulate PTEN and link redox signaling to PI3K pathway activation.

    Evidence Purified PTEN oxidation, mass spectrometry of disulfide, cysteine mutant analysis, co-IP with thioredoxin, cell-based inhibitor studies

    PMID:11916965

    Open questions at the time
    • Quantitative contribution of oxidative inactivation to PTEN regulation in specific tissues unknown
    • Role of other reductases in vivo not fully excluded
  9. 2006 High

    Identification of PCAF-mediated acetylation at Lys125/128 within the catalytic cleft as an inhibitory modification demonstrated a growth-factor-responsive epigenetic switch that tunes PTEN activity independently of protein levels.

    Evidence Co-IP, acetylation assay, PCAF shRNA, acetylation-resistant K125R/K128R mutagenesis, PI3K signaling and cell cycle analysis

    PMID:16829519

    Open questions at the time
    • Identity of the deacetylase that reverses this modification not established
    • In vivo significance in tumorigenesis not tested
  10. 2007 High

    Nuclear PTEN was shown to associate with centromeres through CENP-C and maintain chromosomal stability independently of lipid phosphatase activity, establishing a phosphatase-independent genome guardian role.

    Evidence Co-immunoprecipitation of PTEN with CENP-C, immunofluorescence at centromeres, chromosome breakage analysis in Pten-null cells

    PMID:17218262

    Open questions at the time
    • Whether CENP-C interaction is direct or bridged unknown
    • Mechanism by which PTEN at centromeres prevents breakage not molecularly defined
  11. 2013 High

    Identification of USP13 as a PTEN-stabilizing deubiquitinase established that PTEN protein levels are actively maintained by deubiquitylation, providing a mechanism for PTEN downregulation in cancers without genomic loss.

    Evidence Systematic DUB screen, direct binding by co-IP, ubiquitylation assay, tumor suppression only in PTEN-positive cells

    PMID:24270891

    Open questions at the time
    • Which E3 ligase ubiquitylates PTEN in this context not identified
    • Tissue specificity of USP13-PTEN axis not resolved
  12. 2014 High

    Discovery that tankyrases PARylate PTEN to promote RNF146-mediated ubiquitination and degradation revealed a PARP-dependent proteolytic mechanism for PTEN turnover, connecting poly-ADP-ribosylation to PI3K/AKT signaling control.

    Evidence Co-IP, ADP-ribosylation assay, ubiquitination assay, tankyrase knockdown, AKT signaling, in vivo tumor model

    PMID:25547115

    Open questions at the time
    • Specific PARylation sites on PTEN not mapped
    • Interplay between tankyrase-mediated degradation and USP13-mediated stabilization not quantified
  13. 2015 High

    PTEN was shown to localize at replication forks, stabilize RPA1 through OTUB1-mediated deubiquitination, and maintain fork integrity under replication stress, extending its genome-protective role to DNA replication.

    Evidence iPOND, STORM super-resolution imaging, co-IP with RPA1, deubiquitylation assay, hydroxyurea-induced replication stress

    PMID:26403191

    Open questions at the time
    • Whether PTEN phosphatase activity is required for replication fork protection unclear
    • How PTEN is recruited to forks not defined
  14. 2017 High

    PTEN S-nitrosylation downstream of AMPK-activated eNOS was identified as a mechanism linking metabolic/energy stress to PTEN inactivation and subsequent PI3K pathway activation, mediated by PARK2 deficiency.

    Evidence S-nitrosylation assay, AMPK activation, eNOS inhibition, ubiquitination assay, genetic validation in Park2/Pten compound mouse model

    PMID:28306514

    Open questions at the time
    • Specific cysteine residue(s) targeted by S-nitrosylation not fully resolved
    • Whether this mechanism operates outside Parkinson's-related contexts not established
  15. 2019 High

    Direct dephosphorylation of PGK1 at Y324 by PTEN's protein phosphatase activity was shown to suppress glycolysis and brain tumorigenesis, establishing a metabolic tumor suppressor function distinct from PIP3 regulation.

    Evidence In vitro phosphatase assay, co-IP, glycolysis measurement, PGK1-Y324F knockin mouse, human GBM specimen analysis

    PMID:31492635

    Open questions at the time
    • Whether PGK1 dephosphorylation contributes to tumor suppression outside brain not tested
    • Full scope of PTEN protein substrates in metabolism not surveyed
  16. 2020 High

    FBXO22 was identified as a compartment-specific E3 ligase that ubiquitylates nuclear PTEN at Lys221 for proteasomal degradation, resolving how nuclear and cytoplasmic PTEN pools are differentially regulated.

    Evidence Co-IP, ubiquitylation assay, K221 mutagenesis, nuclear/cytoplasmic fractionation, functional tumor assays

    PMID:32249768

    Open questions at the time
    • Signals that trigger FBXO22-mediated nuclear PTEN degradation not defined
    • Interplay with monoubiquitylation-dependent nuclear import unclear
  17. 2021 High

    A homeostatic feedback loop was identified in which PI3K activation increases PTEN translation through mTOR/4E-BP1, explaining pathway self-limitation and rebound signaling upon PI3K inhibitor withdrawal.

    Evidence 4E-BP1 genetic deletion, translational rate measurement, pharmacologic PI3K inhibition, in vitro and in vivo signaling assays

    PMID:33606974

    Open questions at the time
    • Whether other translational regulators cooperate with 4E-BP1 for PTEN mRNA not tested
    • Clinical implications for PI3K inhibitor resistance not mechanistically validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length membrane-engaged PTEN structure, the complete inventory of direct protein substrates, the quantitative interplay among competing PTMs (phosphorylation, ubiquitylation, acetylation, PARylation, S-nitrosylation, oxidation) in specific tissue and signaling contexts, and how nuclear versus cytoplasmic PTEN pools are coordinately regulated to balance genome integrity and PI3K signaling functions.
  • Full-length PTEN structure with C-terminal tail and membrane not resolved
  • Systematic identification of protein phosphatase substrates incomplete
  • Quantitative modeling of competing PTM inputs not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005694 chromosome 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-1430728 Metabolism 1
Partners
CENP-CFAKPCAFPGK1PLK1RPA1TOP2AUSP13
Complex memberships
PTEN-associated complex (PAC, >600 kDa)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PTEN was identified as a candidate tumor suppressor gene at chromosome 10q23, encoding a protein with a protein tyrosine phosphatase domain and extensive homology to the cytoskeletal protein tensin, suggesting it may suppress tumor growth by antagonizing protein tyrosine kinases and regulating focal adhesions. Positional cloning, homozygous deletion mapping, mutation screening in cancer cell lines Science High 9072974
1997 PTEN (MMAC1) encodes a protein with homology to the catalytic domain of protein phosphatases and to cytoskeletal proteins tensin and auxilin; mutations were identified in glioma, prostate, kidney, and breast carcinoma cell lines/specimens. Positional cloning, homozygous deletion mapping, sequence analysis Nature genetics High 9090379
1997 TEP1 (identical to PTEN/MMAC1) possesses intrinsic protein tyrosine phosphatase activity; it is a cytoplasmic protein sharing homology with tensin and auxilin, and its expression is down-regulated by TGF-β. Biochemical phosphatase assay, immunofluorescence, Northern blot, chromosomal mapping Cancer research High 9187108
1997 Germline mutations in PTEN cause Cowden disease; mutations are found throughout the gene and predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain, establishing PTEN as a tumor suppressor in the germline. Germline mutational analysis of Cowden disease kindreds Nature genetics High 9140396
1998 PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) specifically at position 3 on the inositol ring; overexpression reduces insulin-induced PtdIns(3,4,5)P3, while the catalytically inactive C124S mutant causes PtdIns(3,4,5)P3 accumulation. PTEN also exhibits 3-phosphatase activity toward inositol 1,3,4,5-tetrakisphosphate. In vitro phosphatase assay with purified recombinant PTEN, transfection of wild-type and C124S mutant in 293 cells, lipid measurement The Journal of biological chemistry High 9593664
1998 The lipid phosphatase activity of PTEN is critical for its tumor suppressor function: a Cowden disease missense mutation (G129E) specifically ablates recognition of inositol phospholipid substrates without affecting protein phosphatase activity; wild-type PTEN expression in PTEN-deficient tumor cells inhibits PKB/Akt and regulates cell survival. In vitro lipid phosphatase assay, cell-based PIP3 measurement, PKB/Akt phosphorylation assay, ectopic expression in tumor cell lines Proceedings of the National Academy of Sciences of the United States of America High 9811831
1998 PTEN inhibits cell migration, integrin-mediated cell spreading, and the formation of focal adhesions; PTEN interacts with focal adhesion kinase (FAK) and reduces FAK tyrosine phosphorylation; overexpression of FAK partially antagonizes PTEN effects; the phosphatase domain is required for these effects. Cell migration assay, focal adhesion staining, co-immunoprecipitation, FAK phosphorylation assay, PTEN overexpression and antisense Science High 9616126
1998 Pten is essential for embryonic development; homozygous Pten knockout mice die early in embryogenesis; heterozygous mice develop hyperplastic-dysplastic changes and spontaneous tumors, demonstrating Pten is a bona fide tumor suppressor gene in vivo. Homologous recombination knockout in mice, histopathology, tumor analysis Nature genetics High 9697695
1999 Crystal structure of PTEN reveals a phosphatase domain with an enlarged active site accommodating phosphoinositide substrates, and a C2 domain that binds phospholipid membranes in vitro; mutation of basic residues in the C2 domain reduces membrane affinity and tumor cell growth suppression. X-ray crystallography, lipid binding assay, mutagenesis, cell growth assay Cell High 10555148
1999 PTEN directly dephosphorylates and inhibits focal adhesion kinase (FAK), thereby negatively regulating signals generated at focal adhesions; PTEN also inhibits the adaptor protein Shc to negatively regulate growth factor receptor signaling. In vitro phosphatase assay, co-immunoprecipitation, Western blot analysis of FAK phosphorylation European journal of biochemistry Medium 10469123
2000 PTEN PDZ binding domain (C-terminal) interacts with PDZ domains of hDLG and hMAST205; threonine phosphorylation of the PTEN PDZ binding domain inhibits interaction with hDLG and hMAST205 PDZ domains but promotes interaction with ~90 kDa and ~120 kDa proteins from cell lysates. Yeast two-hybrid, microtiter plate binding assay, peptide coprecipitation from cell lysates, Western blotting Cancer research Medium 10646847
2001 PTEN suppresses Bcl-2 expression via its lipid phosphatase activity acting through the Akt/CREB pathway; PTEN reduces Bcl-2 mRNA and protein, downregulates Bcl-2 promoter activity through decreased CREB phosphorylation at Ser133, and loss of PTEN leads to chemoresistance that is rescued by Bcl-2 overexpression. Transfection, RT-PCR, Western blot, Bcl-2 promoter-reporter assay, cell death assay The Journal of biological chemistry Medium 11495901
2001 p53 transcriptionally activates PTEN through a p53 binding element directly upstream of the PTEN gene; PTEN is required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts, placing PTEN downstream of p53 in a tumor suppressor signaling axis. Deletion and mutation analysis of PTEN promoter, p53 induction assays, mRNA measurement, apoptosis assay in PTEN-null MEFs Molecular cell High 11545734
2002 PTEN is reversibly inactivated by H2O2 through formation of an intramolecular disulfide bond between the catalytic Cys124 and Cys71; thioredoxin, not glutaredoxin or glutathione, is the primary cellular reductant that restores PTEN activity; thioredoxin co-immunoprecipitates with PTEN from cell lysates. Purified PTEN oxidation assay, mass spectrometry of tryptic peptides, cysteine mutant analysis, co-immunoprecipitation, inhibitor studies in cells The Journal of biological chemistry High 11916965
2004 PTEN negatively regulates MDM2 transcription by suppressing its P1 promoter activity through its lipid phosphatase activity (independent of p53), thereby reducing L-Mdm2 expression and p90(MDM2) isoform production. Reporter assays, RT-PCR, Western blot, lipid phosphatase-dead PTEN mutant analysis, Pten-null cell lines and prostate cancer tissues The Journal of biological chemistry Medium 15090541
2006 PCAF histone acetyltransferase physically interacts with PTEN and acetylates Lys125 and Lys128 within the catalytic cleft of PTEN in a growth factor-dependent manner; acetylation of these residues inhibits PTEN's ability to down-regulate PI3K signaling and induce G1 cell cycle arrest; acetylation-resistant K125R/K128R PTEN mutants retain PI3K regulatory activity even with forced PCAF expression. Co-immunoprecipitation, acetylation assay, shRNA knockdown of PCAF, cell cycle analysis, PI3K signaling measurement, site-directed mutagenesis The Journal of biological chemistry High 16829519
2007 Nuclear PTEN is essential for chromosomal integrity; PTEN localizes at centromeres and physically associates with CENP-C; disruption of Pten leads to centromere breakage and chromosomal translocations; PTEN regulates Rad51 expression to reduce spontaneous DNA double-strand breaks. Chromosome analysis, co-immunoprecipitation of PTEN with CENP-C, immunofluorescence localization, Rad51 expression analysis, Pten-null cells Cell High 17218262
2008 PTEN exists as a monomer or as part of a >600-kDa PTEN-associated complex (PAC); PTEN associates with p85, the regulatory subunit of PI3K, and the p110β isoform of PI3K; this association involves unphosphorylated PTEN within the PAC and is enhanced by trastuzumab treatment. Gel filtration, co-immunoprecipitation with specific antibodies, AKT phosphorylation assay, trastuzumab treatment Molecular and cellular biology Medium 19635806
2008 PTEN activity is regulated by its C-terminal tail phosphorylation: when phosphorylated, the unstructured C-terminal tail interacts with the phosphatase-C2 superdomain to inactivate PTEN by preventing membrane association; oxidation of the active site cysteine by ROS and C-terminal Ser/Thr phosphorylation inhibit PTEN and regulate its stability and localization. Biochemical assays, mutagenesis, membrane association assays, review of structural and regulatory data Oncogene Medium 18794881
2008 PTEN enters the nucleus by multiple mechanisms including simple diffusion, active shuttling, cytoplasmic-localization-signal-dependent export, and monoubiquitylation-dependent import; nuclear PTEN has phosphatase-independent roles in chromosome stability, DNA repair, and cell cycle arrest distinct from cytoplasmic PTEN. Review of experimental data including nuclear localization studies, ubiquitylation assays, and chromosome stability assays Journal of cell science Medium 18216329
2008 A novel Akt-EGR1-ARF-PTEN axis exists in which PTEN transcriptional activation requires p14ARF-mediated sumoylation of EGR1; Akt phosphorylates EGR1 at S350 and T309, promoting EGR1 interaction with ARF and subsequent sumoylation at K272; ARF-deficient mice exhibit reduced PTEN, establishing a regulatory circuit. In vivo sumoylation assay, co-immunoprecipitation, site-directed mutagenesis, ARF-null mouse analysis, Western blot The EMBO journal Medium 19057511
2013 USP13 is a deubiquitylase that stabilizes PTEN by direct binding and deubiquitylation; USP13 loss in breast cancer cells promotes AKT phosphorylation and tumorigenesis through PTEN downregulation; USP13 overexpression suppresses tumorigenesis only in PTEN-positive cells. DUB screen (30 DUBs tested), co-immunoprecipitation, ubiquitylation assay, cell proliferation and tumor growth assays, human breast tumor correlation Nature cell biology High 24270891
2014 Tankyrases (PARP family members) interact with PTEN, poly-ADP-ribosylate it, and promote its recognition by the PAR-binding E3 ubiquitin ligase RNF146, leading to PTEN ubiquitination and proteasomal degradation; tankyrase knockdown stabilizes PTEN and suppresses AKT signaling, cell proliferation, and tumor growth. Co-immunoprecipitation, ADP-ribosylation assay, ubiquitination assay, tankyrase knockdown, AKT phosphorylation assay, in vivo tumor model Genes & development High 25547115
2015 PTEN is physically associated with replication protein A 1 (RPA1) via the RPA1 C-terminal domain; PTEN localizes at replication sites (shown by iPOND) and promotes RPA1 accumulation on replication forks; PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination; PTEN deletion leads to replication fork collapse under hydroxyurea-induced stress. Co-immunoprecipitation, iPOND, STORM super-resolution imaging, deubiquitylation assay, replication fork analysis Cell research High 26403191
2015 AIF (apoptosis-inducing factor) physically interacts with PTEN and protects it from oxidation-mediated inactivation; PTEN is identified as a mitochondrial protein; AIF knockdown causes PTEN lipid phosphatase inactivation, AKT activation, and promotes epithelial-mesenchymal transition through β-catenin signaling. Co-immunoprecipitation, lipid phosphatase activity assay, oxidation assay, mitochondrial fractionation, in vitro and in vivo tumor metastasis models EMBO reports Medium 26415504
2015 PTEN physically associates with TOP2A (DNA topoisomerase IIα) and stabilizes it through OTUD3 deubiquitinase; PTEN deficiency leads to TOP2A downregulation, dysfunction of the decatenation G2 checkpoint, and incomplete DNA decatenation causing ultra-fine anaphase bridges. Co-immunoprecipitation, ubiquitination assay, ultra-fine bridge (UFB) analysis, decatenation checkpoint assay, PTEN-null cell analysis Scientific reports Medium 26657567
2016 PTEN physically associates with PLK1 (polo-like kinase 1) and reduces PLK1 phosphorylation in a protein phosphatase-dependent manner; PTEN deficiency leads to PLK1 hyperphosphorylation and polyploidy; a phospho-mimicking PLK1 mutant causes polyploidy, and a non-phosphorylatable PLK1 mutant rescues the polyploid phenotype. Co-immunoprecipitation, phosphatase assay, cell cycle analysis (polyploidy), site-directed mutagenesis of PLK1 Cell cycle Medium 27398835
2017 PARK2 depletion leads to AMPK-mediated activation of eNOS, increased reactive oxygen species and oxidized nitric oxide, resulting in PTEN inhibition by S-nitrosylation and subsequent ubiquitination; AMPK activation alone is sufficient to induce PTEN S-nitrosylation, linking energy stress to PTEN suppression. S-nitrosylation assay, AMPK activation, eNOS inhibition, ubiquitination assay, PI3K/Akt signaling measurement, in vivo cooperativity in Park2/Pten mouse model Molecular cell High 28306514
2019 PTEN directly interacts with and dephosphorylates autophosphorylated PGK1 (at Y324) via its protein phosphatase activity, thereby inhibiting PGK1 kinase activity, glycolysis, and ATP production in brain tumor cells; PGK1-Y324F knockin mice show reduced brain tumor formation. Co-immunoprecipitation, in vitro phosphatase assay, PGK1 Y324 phosphorylation analysis, glycolysis measurement, knockin mouse model, human GBM specimen analysis Molecular cell High 31492635
2019 PTEN inhibits ARID4B expression, while ARID4B is a transcriptional activator of PI3K subunit genes PIK3CA and PIK3R2; reciprocal binding of ARID4B and histone H1 to PIK3CA and PIK3R2 promoters modulates chromatin condensation; ARID4B is required for prostate tumorigenesis when PTEN is deficient. ChIP, promoter analysis, gene expression assays, functional tumorigenesis assays, patient cohort correlation Nature communications Medium 31551414
2020 FBXO22 induces ubiquitylation specifically of nuclear (not cytoplasmic) PTEN at lysine 221, targeting it for proteasomal degradation; FBXO22 acts as a tumor promoter by degrading nuclear PTEN, and is overexpressed in various cancer types. Co-immunoprecipitation, ubiquitylation assay, site-directed mutagenesis (K221), nuclear/cytoplasmic fractionation, functional tumor assays Nature communications High 32249768
2020 The carboxy-terminal tail (CTT) of PTEN, when phosphorylated, interacts with the phosphatase-C2 superdomain to prevent membrane association and inactivate the enzyme; alternate translation-initiation generates extended PTEN isoforms (e.g., PTEN-L) with a signal sequence, polyarginine motif, and membrane-binding helix that activates the enzyme and facilitates mitochondrial and nucleolar localization. Structural analysis, biochemical membrane association assays, isoform characterization, mutagenesis Cold Spring Harbor perspectives in medicine Medium 31636093
2021 Physiological and oncogenic PI3K pathway activation increases PTEN expression via mTOR/4E-BP1-dependent translational control; deletion of 4E-BP1 abolishes this translational regulation; this constitutes a homeostatic feedback loop limiting pathway duration and contributing to rebound activation upon PI3K inhibitor treatment. PI3K inhibitor treatment, 4E-BP1 deletion, translational rate measurement, in vitro and in vivo PI3K signaling assays Molecular cell High 33606974
2021 Peroxiredoxin I (Prx I) directly interacts with PTEN and protects it from oxidation under mild oxidative stress, preserving PTEN tumor-suppressive function; Prx II-deficient cells show increased PTEN oxidation and insulin sensitivity; Prx III protects PTEN from oxidation by pro-oxidant lipid mediators. Co-immunoprecipitation, PTEN oxidation assay, Prx-deficient cell lines, insulin signaling measurement Antioxidants Medium 33669370
1999 PTEN overexpression in glioblastoma cells blocks G0/G1 to S phase progression by recruiting the CDK inhibitor p27Kip1 into cyclin E/CDK2 complexes, resulting in reduced CDK2 kinase activity and decreased phosphorylated retinoblastoma protein; CDK4 activity and p21Cip1 levels are unaffected. Adenoviral gene transfer, cell cycle analysis, CDK2 kinase assay, co-immunoprecipitation of p27Kip1 with cyclin E Cancer research Medium 10344736
2000 PTEN expression in glioma cells inhibits phospholipase C signaling (reducing intracellular IP3 and extracellular Ca2+ influx) and inhibits integrin-linked kinase (ILK) activity through its catalytic activity; AKT3 (highly expressed in brain) is identified as a target for PTEN repression. IP3 measurement, Ca2+ influx assay, ILK activity assay, PTEN overexpression, catalytic mutant control Oncogene Medium 10644997

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science (New York, N.Y.) 4169 9072974
1998 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. The Journal of biological chemistry 2594 9593664
1997 Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature genetics 2442 9090379
2007 MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2291 17681183
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
1997 Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature genetics 1644 9140396
2012 The functions and regulation of the PTEN tumour suppressor. Nature reviews. Molecular cell biology 1642 22473468
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science (New York, N.Y.) 1392 21252315
2007 A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer cell 1328 17936563
1998 Pten is essential for embryonic development and tumour suppression. Nature genetics 1280 9697695
2015 Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer discovery 1264 26645196
1998 Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science (New York, N.Y.) 1049 9616126
2011 Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer cell 1018 21575859
1998 The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proceedings of the National Academy of Sciences of the United States of America 1007 9811831
2015 Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 976 26479035
2008 MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer research 931 18199536
1999 Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 894 10555148
2002 Reversible inactivation of the tumor suppressor PTEN by H2O2. The Journal of biological chemistry 867 11916965
2008 An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer research 855 18676830
2011 Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 842 22000013
2014 Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature genetics 834 24509480
2006 Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 816 16762633
1999 Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proceedings of the National Academy of Sciences of the United States of America 805 9990064
2007 Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 797 17218262
2020 Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proceedings of the National Academy of Sciences of the United States of America 792 33229547
1997 TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer research 791 9187108
2006 Pten regulates neuronal arborization and social interaction in mice. Neuron 775 16675393
2001 Regulation of PTEN transcription by p53. Molecular cell 771 11545734
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nature medicine 734 17873882
2010 STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Molecular cell 724 20797623
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1998 Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proceedings of the National Academy of Sciences of the United States of America 543 9560261
2014 PTEN. Annual review of biochemistry 478 24905788
2009 PI3K/PTEN signaling in angiogenesis and tumorigenesis. Advances in cancer research 461 19595306
1999 Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. Journal of the National Cancer Institute 415 10564676
1997 Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Human molecular genetics 397 9259288
1998 Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer research 374 9443392
2002 Protean PTEN: form and function. American journal of human genetics 349 11875759
2007 PTEN, more than the AKT pathway. Carcinogenesis 338 17341655
1998 PTEN mutations in gliomas and glioneuronal tumors. Oncogene 295 9619835
2007 PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochimica et biophysica acta 280 17964232
2000 Mutations of the human PTEN gene. Human mutation 266 10923032
2014 PTEN function: the long and the short of it. Trends in biochemical sciences 249 24656806
2008 The nuclear affairs of PTEN. Journal of cell science 242 18216329
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