{"gene":"PTEN","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1998,"finding":"PTEN/MMAC1 acts as a negative regulator of the PI3K/Akt pathway: it impairs activation of endogenous Akt, inhibits phosphorylation of 4E-BP1, and a catalytically inactive dominant-negative PTEN mutant enhances 4E-BP1 phosphorylation, placing PTEN upstream of Akt in the PI3K pathway.","method":"Biochemical assays in cells; catalytically inactive dominant-negative mutant; Akt activity measurement; 4E-BP1 phosphorylation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments with dominant-negative mutant and downstream readouts, replicated across multiple cell lines and xenograft models","pmids":["9861013"],"is_preprint":false},{"year":1998,"finding":"PTEN/MMAC1 expression induces G1 cell cycle arrest in human glioblastoma cells, correlating with increased p27(KIP1) and decreased G1 cyclin-dependent kinase activities; this effect is mimicked by the PI3K inhibitor LY294002 and is accompanied by inhibition of Akt, placing PTEN upstream of PI3K/Akt→p27(KIP1) in G1 control.","method":"PTEN re-expression in U87MG cells; cell cycle analysis; Western blotting for p27(KIP1), CDK activity assays; PI3K inhibitor LY294002 comparison","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell cycle, CDK assay, Akt inhibition, pharmacological comparison) in a single focused study","pmids":["9860981"],"is_preprint":false},{"year":2001,"finding":"PTEN's physiological substrate is phosphatidylinositol 3,4,5-trisphosphate (PIP3); PTEN specifically dephosphorylates the D3 position of PIP3, thereby negatively regulating PDK1/Akt survival signaling. Mutations impairing PTEN function markedly increase cellular PIP3 levels and constitutively activate Akt.","method":"Biochemical phosphatase assays; substrate specificity experiments; lipid phosphatase activity measurement","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical substrate identification replicated across multiple studies; reviewed and consolidated from primary biochemical data","pmids":["11395408"],"is_preprint":false},{"year":2006,"finding":"PCAF histone acetyltransferase physically interacts with PTEN and acetylates lysine residues K125 and K128 within PTEN's catalytic cleft in a growth-factor-dependent manner. Acetylation of PTEN inhibits its lipid phosphatase activity toward PIP3, reducing its ability to block PI3K signaling and G1 arrest. Acetylation-resistant K125R/K128R PTEN mutants retain phosphatase activity in the presence of enforced PCAF.","method":"Co-immunoprecipitation; shRNA knockdown of PCAF; site-directed mutagenesis (K125R, K128R); phosphatase activity assays; cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP, mutagenesis, shRNA knockdown, and functional phosphatase/cell cycle readouts in single study","pmids":["16829519"],"is_preprint":false},{"year":2000,"finding":"PTEN PDZ-binding domain (C-terminal) interacts with PDZ domains of hDLG and hMAST205; threonine phosphorylation of this domain inhibits binding to hDLG and hMAST205 PDZ domains but promotes binding to other proteins (~90 and ~120 kDa) from cell lysate, demonstrating phosphorylation-dependent modulation of PTEN protein-protein interactions.","method":"Yeast two-hybrid; microtiter plate binding assays; synthetic peptide co-precipitation from A431 cell lysate; anti-hDLG Western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid confirmed by peptide pulldown and binding assay, single lab with two orthogonal methods","pmids":["10646847"],"is_preprint":false},{"year":2008,"finding":"In PTEN-deficient cancers, growth and PI3K pathway signaling depend on PIK3CB (p110β) rather than PIK3CA (p110α); shRNA-mediated depletion of PIK3CB (but not PIK3CA) inhibits downstream PI3K signaling and cell growth in PTEN-null cancer cells, both in vitro and in vivo, and this function requires p110β lipid kinase activity.","method":"Lentiviral inducible shRNA knockdown of PI3K isoforms; PI3K signaling readouts (pAKT); cell growth assays; in vivo xenograft models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-selective shRNA with in vitro and in vivo validation; kinase-dead rescue experiment; replicated across multiple PTEN-deficient lines","pmids":["18755892"],"is_preprint":false},{"year":2009,"finding":"PTEN physically associates with the regulatory subunit p85 of PI3K; this association involves the unphosphorylated form of PTEN residing in a >600-kDa PTEN-associated complex (PAC) that also includes the p110β isoform of PI3K. The PTEN-p85 association is enhanced by trastuzumab and linked to decreased AKT phosphorylation in ERBB2-amplified breast cancer cells.","method":"Co-immunoprecipitation with newly generated antibodies; sucrose gradient fractionation to identify PAC; Western blotting for pAKT","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, biochemical fractionation, single lab with two orthogonal methods","pmids":["19635806"],"is_preprint":false},{"year":2013,"finding":"USP13 is a deubiquitylase that directly binds PTEN, removes its polyubiquitin chains, and stabilizes PTEN protein. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, and tumor growth through PTEN downregulation; this effect is PTEN-dependent.","method":"DUB screen (30 enzymes); co-immunoprecipitation; in vitro deubiquitylation assay; USP13 knockdown/overexpression; AKT phosphorylation; tumor growth assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical deubiquitylation assay combined with cellular knockdown/overexpression and in vivo tumor growth, multiple orthogonal methods","pmids":["24270891"],"is_preprint":false},{"year":2014,"finding":"PTEN functions as a protein tyrosine phosphatase that selectively dephosphorylates IRS1 (insulin receptor substrate-1). Loss of NEDD4 (a PTEN ubiquitin ligase that promotes PTEN degradation) causes defective IGF signaling including IRS1 and AKT phosphorylation, which is rescued by PTEN ablation. Direct biochemical and cellular reconstitution confirmed PTEN as the IRS1 phosphatase.","method":"Direct biochemical dephosphorylation assay; cellular reconstitution; NEDD4 and PTEN knockouts/knockdowns; IRS1 phosphorylation Western blot","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical reconstitution plus cellular validation with genetic rescue, single lab with multiple orthogonal methods","pmids":["24814346"],"is_preprint":false},{"year":2019,"finding":"PTEN protein phosphatase activity directly dephosphorylates autophosphorylated PGK1 at Y324, thereby inhibiting PGK1 kinase activity, glycolysis, and ATP production. PTEN physically interacts with PGK1. Knockin expression of PGK1 Y324F (phospho-resistant) inhibits brain tumor formation, and PGK1 Y324 phosphorylation inversely correlates with PTEN expression in glioblastoma specimens.","method":"Co-immunoprecipitation; in vitro dephosphorylation assay; PGK1 Y324F knockin mouse model; glycolysis/ATP assays; human tumor specimen analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assay plus knockin mouse model plus human specimen correlation, multiple orthogonal methods","pmids":["31492635"],"is_preprint":false},{"year":2019,"finding":"DNA double-strand breaks (DSBs) promote ATM-dependent phosphorylation of PTEN at T/S398, which enhances PTEN interaction with MDC1. DSBs also induce NSD2-mediated dimethylation of PTEN at K349; this methylation mark is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, where PTEN's protein phosphatase activity governs efficient DSB repair partly through dephosphorylation of γH2AX.","method":"Co-immunoprecipitation; phosphoproteomics; site-directed mutagenesis of K349; in vitro methylation assay; γH2AX dephosphorylation assay; in vivo xenograft models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple biochemical assays (methylation, phosphorylation, co-IP, γH2AX dephosphorylation), mutagenesis, and in vivo validation in a single study","pmids":["31217297"],"is_preprint":false},{"year":2015,"finding":"PTEN controls the phosphorylation state of Dishevelled (DVL) and thereby regulates multicilia formation and cilia disassembly. PTEN is required for convergent extension movements. DVL is identified as a protein substrate of PTEN, coupling PTEN to regulation of cilia dynamics and WNT signaling.","method":"Loss-of-function studies (PTEN knockout/knockdown); phosphorylation assays on DVL; cilia formation and disassembly assays; convergent extension assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cellular loss-of-function with specific phosphorylation readout on identified substrate, single lab","pmids":["26399523"],"is_preprint":false},{"year":2015,"finding":"PTEN is physically associated with RPA1 (replication protein A 1) via the RPA1 C-terminal domain; PTEN localizes at replication forks (confirmed by iPOND) and promotes RPA1 accumulation there. PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination. Loss of PTEN leads to replication fork collapse and chromosomal instability under replication stress.","method":"Co-immunoprecipitation; STORM super-resolution microscopy; iPOND (isolation of proteins on nascent DNA); RPA1 deubiquitination assay; chromosomal instability assays in PTEN-KO cells","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical interaction, iPOND localization, deubiquitination assay, and functional chromosomal stability readout, multiple orthogonal methods","pmids":["26403191"],"is_preprint":false},{"year":2008,"finding":"PTEN enters the nucleus by monoubiquitylation-dependent import (as well as by simple diffusion and active shuttling). Nuclear PTEN plays roles in chromosome stability and DNA repair distinct from cytoplasmic PTEN's role as a PI3K/AKT pathway negative regulator. Cytoplasmic localization signal-dependent export also regulates PTEN compartmentalization.","method":"Ubiquitination assays; nuclear/cytoplasmic fractionation; chromosomal stability assays; genetic studies (referenced primary papers: Wang et al. 2007, Trotman et al. 2007, Shen et al. 2007)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review citing primary mechanistic papers on monoubiquitylation-dependent nuclear import; mechanistic basis established in referenced primary studies","pmids":["18216329"],"is_preprint":false},{"year":2020,"finding":"FBXO22 ubiquitylates nuclear PTEN specifically at lysine 221, leading to its proteasomal degradation. FBXO22 acts on nuclear but not cytoplasmic PTEN, identifying a compartment-specific E3 ubiquitin ligase for PTEN.","method":"Co-immunoprecipitation; ubiquitination assays; site-directed mutagenesis (K221R); nuclear/cytoplasmic fractionation; FBXO22 knockdown/overexpression in colorectal cancer cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ubiquitination assay with mutagenesis of target lysine, fractionation experiments, and cellular functional readout","pmids":["32249768"],"is_preprint":false},{"year":2008,"finding":"PTEN active-site cysteine is oxidized by reactive oxygen species forming an intramolecular disulfide bond between Cys124 and Cys71, which inactivates PTEN. Peroxiredoxin I (Prx I) protects PTEN from oxidation under moderate oxidative stress through direct interaction, preserving PTEN tumor-suppressive function. Prx II deficiency increases PTEN oxidation and insulin sensitivity.","method":"PTEN oxidation assays; Prx knockout/knockdown cell systems; direct binding assays; insulin signaling readouts","journal":"Antioxidants (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical oxidation assays and Prx knockout cell models; reviewed findings from multiple primary studies, single oxidation mechanism replicated","pmids":["33669370"],"is_preprint":false},{"year":2021,"finding":"PI3K/mTOR-dependent signaling controls PTEN protein expression through mTOR/4E-BP1-mediated translational regulation. Deletion of 4E-BP1 abolishes translational upregulation of PTEN by PI3K, establishing a homeostatic feedback loop: PI3K activation increases PTEN translation to limit pathway duration.","method":"4E-BP1 deletion; mTOR inhibitor treatment; polysome profiling/translational assays; PI3K inhibitor treatment; signaling readouts (pAKT, pS6K)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genetic deletion of 4E-BP1 combined with polysome/translational assays and pharmacological inhibition in multiple cell systems","pmids":["33606974"],"is_preprint":false},{"year":2008,"finding":"PTEN activity is regulated by C-terminal tail (CTT) phosphorylation at serine/threonine residues: phosphorylation of the unstructured CTT promotes interaction with the phosphatase-C2 superdomain and inactivates PTEN by preventing membrane association. Unphosphorylated PTEN is the active, membrane-associated form.","method":"Structural analysis; phosphorylation site mutagenesis; membrane-binding and activity assays (referenced in review of structural mechanisms)","journal":"Cold Spring Harbor perspectives in medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structural and biochemical data from multiple studies consolidated; primary mechanistic finding from structure/mutagenesis work","pmids":["31636093"],"is_preprint":false},{"year":2001,"finding":"PTEN and androgen receptor (AR) mutually repress each other in prostate cancer cells: PTEN (and PI3K inhibition) represses AR transcriptional activity and androgen-induced proliferation likely via AKT downregulation, while androgens protect from PTEN-induced apoptosis in an AR-dependent but AKT-independent manner.","method":"PTEN re-expression; PI3K inhibitor; reporter assays for AR transcriptional activity; PSA production assay; apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in prostate cancer cells with PTEN re-expression and pharmacological inhibition, single lab","pmids":["11278645"],"is_preprint":false},{"year":2008,"finding":"PTEN promotes EGR1 sumoylation via the Akt-EGR1-ARF-PTEN axis: Akt phosphorylates EGR1 at S350 and T309, promoting EGR1 interaction with ARF and sumoylation by the ARF/Ubc9/SUMO system. EGR1 sumoylation is required for PTEN transcriptional induction. ARF-deficient mice show reduced EGR1 sumoylation and reduced PTEN levels, establishing a feedback loop.","method":"Kinase assay; sumoylation assay; co-immunoprecipitation; ARF knockout mice; site-directed mutagenesis of EGR1 phosphorylation sites","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic (ARF-KO mice) combined with biochemical sumoylation/kinase assays, single lab","pmids":["19057511"],"is_preprint":false},{"year":2020,"finding":"PTEN promotes nuclear translocation of FOXO1 in cholangiocarcinoma cells. Nuclear FOXO1 increases expression of BACH1 and MAFF, which directly repress transcription of proteasome subunit genes. Loss of PTEN thus upregulates proteasome expression and activity, creating a dependency on proteasome function in PTEN-deficient cancers.","method":"PTEN knockdown/overexpression; nuclear fractionation; ChIP; reporter assays for proteasome gene promoters; PDX models; autochthonous mouse models","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway defined by ChIP, nuclear fractionation, reporter assays, and validated in PDX and in vivo mouse models","pmids":["32967970"],"is_preprint":false},{"year":1999,"finding":"PTEN directly dephosphorylates tyrosine-phosphorylated focal adhesion kinase (FAK), thereby inhibiting integrin-triggered signaling, focal adhesion formation, cell spreading, and cell migration.","method":"Protein phosphatase assay on FAK substrate; cell migration/invasion assays with PTEN expression","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct dephosphorylation assay on FAK combined with cell biological readouts, findings reviewed and consolidated from primary studies","pmids":["10547389"],"is_preprint":false},{"year":2014,"finding":"PTEN localizes to the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), where it interacts with inositol 1,4,5-trisphosphate receptors (IP3Rs) and regulates Ca2+ release from the ER, thereby controlling sensitivity to apoptosis via its protein phosphatase activity.","method":"Subcellular fractionation; co-immunoprecipitation with IP3R; Ca2+ release measurements; apoptosis assays","journal":"Methods (San Diego, Calif.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — fractionation and co-IP with functional Ca2+ and apoptosis readouts; reviewed from primary mechanistic data","pmids":["25312582"],"is_preprint":false}],"current_model":"PTEN is a dual-specificity lipid and protein phosphatase whose primary tumor-suppressive function is dephosphorylation of PIP3 at the D3 position, thereby antagonizing PI3K/AKT/mTOR signaling to suppress proliferation, promote apoptosis, and induce G1 arrest via p27(KIP1); it additionally functions as a protein phosphatase that dephosphorylates substrates including FAK (inhibiting cell migration), IRS1 (modulating insulin/IGF signaling), PGK1 (suppressing glycolysis), DVL (regulating ciliogenesis), and γH2AX (facilitating DNA DSB repair after NSD2-mediated K349 methylation recruits PTEN to damage sites via 53BP1); its activity and stability are regulated post-translationally by PCAF-mediated acetylation (K125/K128, inhibitory), USP13-mediated deubiquitylation (stabilizing), FBXO22-mediated nuclear-specific ubiquitylation (destabilizing), C-terminal tail phosphorylation (inhibits membrane binding), Prx I-dependent protection from active-site Cys124/Cys71 oxidation, and mTOR/4E-BP1-dependent translational feedback, while its nuclear import is controlled by monoubiquitylation and its interactions with p85/PI3K complex and PDZ-domain proteins are phosphorylation-regulated."},"narrative":{"mechanistic_narrative":"PTEN is a dual-specificity phosphatase that functions as a tumor suppressor primarily by antagonizing PI3K/Akt signaling [PMID:9861013, PMID:11395408]. Its physiological substrate is the lipid second messenger PIP3, which it dephosphorylates at the D3 position to impair PDK1/Akt survival signaling; loss-of-function mutations elevate cellular PIP3 and constitutively activate Akt [PMID:11395408]. Through this activity PTEN induces G1 cell cycle arrest, correlating with increased p27(KIP1) and decreased G1 CDK activity [PMID:9860981], and in PTEN-deficient cancers the residual pathway signaling becomes selectively dependent on the p110β (PIK3CB) PI3K isoform [PMID:18755892]. Beyond its lipid phosphatase role, PTEN acts as a protein phosphatase on multiple substrates: it dephosphorylates FAK to inhibit cell spreading and migration [PMID:10547389], IRS1 to modulate insulin/IGF signaling [PMID:24814346], autophosphorylated PGK1 at Y324 to suppress glycolysis and tumor growth [PMID:31492635], Dishevelled to control cilia dynamics and WNT signaling [PMID:26399523], and γH2AX at DNA double-strand breaks to promote repair, where ATM-dependent phosphorylation and NSD2-mediated K349 methylation recognized by 53BP1 recruit PTEN to damage sites [PMID:31217297]. Nuclear PTEN additionally supports genome stability at replication forks by stabilizing RPA1 and recruiting the deubiquitinase OTUB1 [PMID:26403191]. PTEN activity and abundance are tightly regulated post-translationally—inhibited by PCAF-mediated acetylation of catalytic-cleft residues K125/K128 [PMID:16829519], inactivated by C-terminal tail phosphorylation that blocks membrane binding [PMID:31636093] and by ROS-driven Cys71–Cys124 disulfide oxidation (protected by peroxiredoxin) [PMID:33669370], stabilized by USP13-mediated deubiquitylation [PMID:24270891], and destabilized in the nucleus by FBXO22-mediated ubiquitylation [PMID:32249768], with nuclear import controlled by monoubiquitylation [PMID:18216329]. A homeostatic mTOR/4E-BP1 translational feedback loop further tunes PTEN expression to limit pathway duration [PMID:33606974].","teleology":[{"year":1998,"claim":"Establishing that PTEN negatively regulates the PI3K/Akt axis defined its core signaling function and placed it upstream of Akt.","evidence":"Dominant-negative catalytically inactive mutant with Akt and 4E-BP1 phosphorylation readouts in cells","pmids":["9861013","9860981"],"confidence":"High","gaps":["Did not identify the direct molecular substrate","Mechanism of growth suppression linked correlatively to p27(KIP1)"]},{"year":2001,"claim":"Identifying PIP3 as the physiological substrate revealed the biochemical basis of PTEN tumor suppression, showing it dephosphorylates the D3 position to antagonize PDK1/Akt.","evidence":"In vitro biochemical phosphatase and substrate-specificity assays; PIP3 measurement in mutant cells","pmids":["11395408"],"confidence":"High","gaps":["Did not address PTEN protein-substrate (non-lipid) activities","Membrane-recruitment dynamics not resolved here"]},{"year":1999,"claim":"Demonstrating direct dephosphorylation of FAK extended PTEN function to a protein phosphatase controlling adhesion and migration.","evidence":"Protein phosphatase assay on FAK plus migration/invasion assays with PTEN expression","pmids":["10547389"],"confidence":"Medium","gaps":["Consolidated review evidence rather than single definitive study","Cellular context dependence of FAK targeting unresolved"]},{"year":2000,"claim":"Showing that C-terminal PDZ-binding interactions are phosphorylation-regulated revealed how PTEN scaffolding and partner choice are dynamically controlled.","evidence":"Yeast two-hybrid, peptide pulldown, and binding assays with hDLG/hMAST205 PDZ domains","pmids":["10646847"],"confidence":"Medium","gaps":["Identity of the ~90/120 kDa phospho-promoted partners not established","Functional consequence of PDZ binding not defined"]},{"year":2001,"claim":"Defining mutual PTEN–androgen receptor repression connected PTEN signaling to hormone-driven prostate cancer proliferation.","evidence":"PTEN re-expression, PI3K inhibition, AR reporter and apoptosis assays in prostate cells","pmids":["11278645"],"confidence":"Medium","gaps":["AKT-independent protective arm mechanistically undefined","Single cell-type context"]},{"year":2006,"claim":"PCAF-mediated acetylation of catalytic-cleft lysines established a growth-factor-responsive switch that inhibits PTEN lipid phosphatase activity.","evidence":"Co-IP, PCAF knockdown, K125R/K128R mutagenesis, phosphatase and cell cycle assays","pmids":["16829519"],"confidence":"High","gaps":["Deacetylase reversing the mark not identified here","In vivo relevance not tested"]},{"year":2008,"claim":"Multiple regulatory mechanisms were resolved—isoform-selective PI3K dependency, redox inactivation, C-terminal tail autoinhibition, and monoubiquitylation-driven nuclear import—mapping how PTEN function is spatially and biochemically controlled.","evidence":"Isoform shRNA with xenografts; oxidation/Prx assays; structural/mutagenesis review; ubiquitination and fractionation assays","pmids":["18755892","33669370","31636093","18216329"],"confidence":"Medium","gaps":["Some mechanisms derived from consolidated review evidence","Coordination between tail phosphorylation, oxidation, and localization not integrated"]},{"year":2008,"claim":"Discovery of the Akt-EGR1-ARF-PTEN feedback loop showed how PTEN transcription is induced downstream of its own pathway.","evidence":"Kinase and sumoylation assays, ARF-knockout mice, EGR1 phospho-site mutagenesis","pmids":["19057511"],"confidence":"Medium","gaps":["Quantitative contribution to PTEN homeostasis unclear","Tissue specificity of the loop not defined"]},{"year":2009,"claim":"Identifying a >600-kDa PTEN-associated complex containing p85 and p110β revealed direct physical engagement with the PI3K machinery.","evidence":"Reciprocal Co-IP and sucrose-gradient fractionation; trastuzumab-modulated association in ERBB2 cells","pmids":["19635806"],"confidence":"Medium","gaps":["Structural architecture of the complex unknown","Functional consequence of p85 binding for phosphatase activity unresolved"]},{"year":2013,"claim":"USP13 was identified as a deubiquitylase that directly stabilizes PTEN, defining a stability control node whose loss drives AKT-dependent tumor growth.","evidence":"DUB screen, Co-IP, in vitro deubiquitylation, knockdown/overexpression, tumor growth assays","pmids":["24270891"],"confidence":"High","gaps":["Opposing E3 ligase context not fully mapped here","Compartment specificity of USP13 action unexplored"]},{"year":2014,"claim":"PTEN was established as the direct IRS1 phosphatase and as an ER/MAM-localized regulator of IP3R-dependent Ca2+ release, broadening its protein-substrate repertoire and apoptotic control.","evidence":"Biochemical dephosphorylation and reconstitution with NEDD4/PTEN genetics; fractionation and IP3R Co-IP with Ca2+/apoptosis assays","pmids":["24814346","25312582"],"confidence":"Medium","gaps":["MAM findings partly from consolidated review evidence","Structural basis of IP3R interaction unknown"]},{"year":2015,"claim":"Identification of DVL and RPA1 engagement linked PTEN protein-phosphatase and scaffolding activity to ciliogenesis/WNT signaling and to replication-fork protection.","evidence":"Loss-of-function phosphorylation assays on DVL; Co-IP, iPOND, STORM, and OTUB1-mediated RPA1 deubiquitination assays","pmids":["26399523","26403191"],"confidence":"Medium","gaps":["Direct vs indirect DVL dephosphorylation not fully resolved","How PTEN recruits OTUB1 mechanistically undefined"]},{"year":2019,"claim":"Defining PTEN dephosphorylation of PGK1 Y324 and recruitment to DSBs via NSD2/53BP1 established its roles in suppressing glycolysis and promoting DNA repair through protein-phosphatase activity.","evidence":"Co-IP, in vitro dephosphorylation, PGK1 Y324F knockin mice, tumor specimens; methylation, γH2AX dephosphorylation assays and xenografts","pmids":["31492635","31217297"],"confidence":"High","gaps":["Interplay between metabolic and DNA-repair functions not integrated","Relative contributions of lipid vs protein phosphatase activity in tumors unresolved"]},{"year":2020,"claim":"Compartment-specific nuclear degradation by FBXO22 and the PTEN-FOXO1-BACH1/MAFF proteasome-repression axis revealed how nuclear PTEN levels and a targetable proteasome dependency are controlled.","evidence":"Ubiquitination assays with K221R mutagenesis and fractionation; ChIP, reporter, PDX and autochthonous mouse models","pmids":["32249768","32967970"],"confidence":"High","gaps":["Signals triggering nuclear FBXO22 activity unknown","Generality of proteasome dependency across PTEN-null cancers untested"]},{"year":2021,"claim":"Demonstrating mTOR/4E-BP1-dependent translational upregulation of PTEN defined a homeostatic feedback loop limiting PI3K pathway duration.","evidence":"4E-BP1 deletion, mTOR/PI3K inhibition, polysome profiling, signaling readouts","pmids":["33606974"],"confidence":"High","gaps":["Quantitative dynamics of the feedback loop in vivo unclear","Tissue-specific dependence not addressed"]},{"year":null,"claim":"How PTEN's many regulatory layers and substrate choices are integrated into a single coordinated tumor-suppressive program across compartments remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating acetylation, oxidation, tail phosphorylation, and localization","Relative in vivo importance of lipid vs protein phosphatase substrates undefined","Mechanisms directing PTEN to specific compartmental substrates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,8,9,21]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,9,10,11,21]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,12,13,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[22]}],"complexes":["PTEN-associated complex (PAC; with p85/p110β)"],"partners":["PIK3R1","PIK3CB","USP13","FBXO22","RPA1","PCAF","MDC1","ITPR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60484","full_name":"Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN","aliases":["Inositol polyphosphate 3-phosphatase","Mutated in multiple advanced cancers 1","Phosphatase and tensin homolog"],"length_aa":403,"mass_kda":47.2,"function":"Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (PubMed:9187108, PubMed:9256433, PubMed:9616126). Also functions as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring of PtdIns(3,4,5)P3/phosphatidylinositol 3,4,5-trisphosphate, PtdIns(3,4)P2/phosphatidylinositol 3,4-diphosphate and PtdIns3P/phosphatidylinositol 3-phosphate with a preference for PtdIns(3,4,5)P3 (PubMed:16824732, PubMed:26504226, PubMed:9593664, PubMed:9811831). Furthermore, this enzyme can also act as a cytosolic inositol 3-phosphatase acting on Ins(1,3,4,5,6)P5/inositol 1,3,4,5,6 pentakisphosphate and possibly Ins(1,3,4,5)P4/1D-myo-inositol 1,3,4,5-tetrakisphosphate (PubMed:11418101, PubMed:15979280). Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (PubMed:31492966, PubMed:37279284). The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation (PubMed:11707428). In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement (PubMed:22279049). Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation (PubMed:22279049). Required for growth factor-induced epithelial cell migration; growth factor stimulation induces PTEN phosphorylation which changes its binding preference from the p85 regulatory subunit of the PI3K kinase complex to DLC1 and results in translocation of the PTEN-DLC1 complex to the posterior of migrating cells to promote RHOA activation (PubMed:26166433). Meanwhile, TNS3 switches binding preference from DLC1 to p85 and the TNS3-p85 complex translocates to the leading edge of migrating cells to activate RAC1 activation (PubMed:26166433). 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 (By similarity). Involved in the regulation of synaptic function in excitatory hippocampal synapses. Recruited to the postsynaptic membrane upon NMDA receptor activation, is required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression (LTD) (By similarity). 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 (PubMed:10468583, PubMed:18716620) Functional kinase, like isoform 1 it antagonizes the PI3K-AKT/PKB signaling pathway. 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tumorigenesis.","date":"2007","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/17827710","citation_count":58,"is_preprint":false},{"pmid":"23379765","id":"PMC_23379765","title":"PTEN modulators: a patent review.","date":"2013","source":"Expert opinion on therapeutic patents","url":"https://pubmed.ncbi.nlm.nih.gov/23379765","citation_count":58,"is_preprint":false},{"pmid":"9467947","id":"PMC_9467947","title":"Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9467947","citation_count":57,"is_preprint":false},{"pmid":"31569439","id":"PMC_31569439","title":"PTEN and Gynecological Cancers.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31569439","citation_count":54,"is_preprint":false},{"pmid":"26399523","id":"PMC_26399523","title":"PTEN regulates cilia through 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pathway: it impairs activation of endogenous Akt, inhibits phosphorylation of 4E-BP1, and a catalytically inactive dominant-negative PTEN mutant enhances 4E-BP1 phosphorylation, placing PTEN upstream of Akt in the PI3K pathway.\",\n      \"method\": \"Biochemical assays in cells; catalytically inactive dominant-negative mutant; Akt activity measurement; 4E-BP1 phosphorylation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments with dominant-negative mutant and downstream readouts, replicated across multiple cell lines and xenograft models\",\n      \"pmids\": [\"9861013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PTEN/MMAC1 expression induces G1 cell cycle arrest in human glioblastoma cells, correlating with increased p27(KIP1) and decreased G1 cyclin-dependent kinase activities; this effect is mimicked by the PI3K inhibitor LY294002 and is accompanied by inhibition of Akt, placing PTEN upstream of PI3K/Akt→p27(KIP1) in G1 control.\",\n      \"method\": \"PTEN re-expression in U87MG cells; cell cycle analysis; Western blotting for p27(KIP1), CDK activity assays; PI3K inhibitor LY294002 comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell cycle, CDK assay, Akt inhibition, pharmacological comparison) in a single focused study\",\n      \"pmids\": [\"9860981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PTEN's physiological substrate is phosphatidylinositol 3,4,5-trisphosphate (PIP3); PTEN specifically dephosphorylates the D3 position of PIP3, thereby negatively regulating PDK1/Akt survival signaling. Mutations impairing PTEN function markedly increase cellular PIP3 levels and constitutively activate Akt.\",\n      \"method\": \"Biochemical phosphatase assays; substrate specificity experiments; lipid phosphatase activity measurement\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical substrate identification replicated across multiple studies; reviewed and consolidated from primary biochemical data\",\n      \"pmids\": [\"11395408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PCAF histone acetyltransferase physically interacts with PTEN and acetylates lysine residues K125 and K128 within PTEN's catalytic cleft in a growth-factor-dependent manner. Acetylation of PTEN inhibits its lipid phosphatase activity toward PIP3, reducing its ability to block PI3K signaling and G1 arrest. Acetylation-resistant K125R/K128R PTEN mutants retain phosphatase activity in the presence of enforced PCAF.\",\n      \"method\": \"Co-immunoprecipitation; shRNA knockdown of PCAF; site-directed mutagenesis (K125R, K128R); phosphatase activity assays; cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP, mutagenesis, shRNA knockdown, and functional phosphatase/cell cycle readouts in single study\",\n      \"pmids\": [\"16829519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTEN PDZ-binding domain (C-terminal) interacts with PDZ domains of hDLG and hMAST205; threonine phosphorylation of this domain inhibits binding to hDLG and hMAST205 PDZ domains but promotes binding to other proteins (~90 and ~120 kDa) from cell lysate, demonstrating phosphorylation-dependent modulation of PTEN protein-protein interactions.\",\n      \"method\": \"Yeast two-hybrid; microtiter plate binding assays; synthetic peptide co-precipitation from A431 cell lysate; anti-hDLG Western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid confirmed by peptide pulldown and binding assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"10646847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In PTEN-deficient cancers, growth and PI3K pathway signaling depend on PIK3CB (p110β) rather than PIK3CA (p110α); shRNA-mediated depletion of PIK3CB (but not PIK3CA) inhibits downstream PI3K signaling and cell growth in PTEN-null cancer cells, both in vitro and in vivo, and this function requires p110β lipid kinase activity.\",\n      \"method\": \"Lentiviral inducible shRNA knockdown of PI3K isoforms; PI3K signaling readouts (pAKT); cell growth assays; in vivo xenograft models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-selective shRNA with in vitro and in vivo validation; kinase-dead rescue experiment; replicated across multiple PTEN-deficient lines\",\n      \"pmids\": [\"18755892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTEN physically associates with the regulatory subunit p85 of PI3K; this association involves the unphosphorylated form of PTEN residing in a >600-kDa PTEN-associated complex (PAC) that also includes the p110β isoform of PI3K. The PTEN-p85 association is enhanced by trastuzumab and linked to decreased AKT phosphorylation in ERBB2-amplified breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation with newly generated antibodies; sucrose gradient fractionation to identify PAC; Western blotting for pAKT\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, biochemical fractionation, single lab with two orthogonal methods\",\n      \"pmids\": [\"19635806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP13 is a deubiquitylase that directly binds PTEN, removes its polyubiquitin chains, and stabilizes PTEN protein. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, and tumor growth through PTEN downregulation; this effect is PTEN-dependent.\",\n      \"method\": \"DUB screen (30 enzymes); co-immunoprecipitation; in vitro deubiquitylation assay; USP13 knockdown/overexpression; AKT phosphorylation; tumor growth assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical deubiquitylation assay combined with cellular knockdown/overexpression and in vivo tumor growth, multiple orthogonal methods\",\n      \"pmids\": [\"24270891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTEN functions as a protein tyrosine phosphatase that selectively dephosphorylates IRS1 (insulin receptor substrate-1). Loss of NEDD4 (a PTEN ubiquitin ligase that promotes PTEN degradation) causes defective IGF signaling including IRS1 and AKT phosphorylation, which is rescued by PTEN ablation. Direct biochemical and cellular reconstitution confirmed PTEN as the IRS1 phosphatase.\",\n      \"method\": \"Direct biochemical dephosphorylation assay; cellular reconstitution; NEDD4 and PTEN knockouts/knockdowns; IRS1 phosphorylation Western blot\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical reconstitution plus cellular validation with genetic rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24814346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTEN protein phosphatase activity directly dephosphorylates autophosphorylated PGK1 at Y324, thereby inhibiting PGK1 kinase activity, glycolysis, and ATP production. PTEN physically interacts with PGK1. Knockin expression of PGK1 Y324F (phospho-resistant) inhibits brain tumor formation, and PGK1 Y324 phosphorylation inversely correlates with PTEN expression in glioblastoma specimens.\",\n      \"method\": \"Co-immunoprecipitation; in vitro dephosphorylation assay; PGK1 Y324F knockin mouse model; glycolysis/ATP assays; human tumor specimen analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assay plus knockin mouse model plus human specimen correlation, multiple orthogonal methods\",\n      \"pmids\": [\"31492635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNA double-strand breaks (DSBs) promote ATM-dependent phosphorylation of PTEN at T/S398, which enhances PTEN interaction with MDC1. DSBs also induce NSD2-mediated dimethylation of PTEN at K349; this methylation mark is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, where PTEN's protein phosphatase activity governs efficient DSB repair partly through dephosphorylation of γH2AX.\",\n      \"method\": \"Co-immunoprecipitation; phosphoproteomics; site-directed mutagenesis of K349; in vitro methylation assay; γH2AX dephosphorylation assay; in vivo xenograft models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple biochemical assays (methylation, phosphorylation, co-IP, γH2AX dephosphorylation), mutagenesis, and in vivo validation in a single study\",\n      \"pmids\": [\"31217297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTEN controls the phosphorylation state of Dishevelled (DVL) and thereby regulates multicilia formation and cilia disassembly. PTEN is required for convergent extension movements. DVL is identified as a protein substrate of PTEN, coupling PTEN to regulation of cilia dynamics and WNT signaling.\",\n      \"method\": \"Loss-of-function studies (PTEN knockout/knockdown); phosphorylation assays on DVL; cilia formation and disassembly assays; convergent extension assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cellular loss-of-function with specific phosphorylation readout on identified substrate, single lab\",\n      \"pmids\": [\"26399523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTEN is physically associated with RPA1 (replication protein A 1) via the RPA1 C-terminal domain; PTEN localizes at replication forks (confirmed by iPOND) and promotes RPA1 accumulation there. PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination. Loss of PTEN leads to replication fork collapse and chromosomal instability under replication stress.\",\n      \"method\": \"Co-immunoprecipitation; STORM super-resolution microscopy; iPOND (isolation of proteins on nascent DNA); RPA1 deubiquitination assay; chromosomal instability assays in PTEN-KO cells\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical interaction, iPOND localization, deubiquitination assay, and functional chromosomal stability readout, multiple orthogonal methods\",\n      \"pmids\": [\"26403191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PTEN enters the nucleus by monoubiquitylation-dependent import (as well as by simple diffusion and active shuttling). Nuclear PTEN plays roles in chromosome stability and DNA repair distinct from cytoplasmic PTEN's role as a PI3K/AKT pathway negative regulator. Cytoplasmic localization signal-dependent export also regulates PTEN compartmentalization.\",\n      \"method\": \"Ubiquitination assays; nuclear/cytoplasmic fractionation; chromosomal stability assays; genetic studies (referenced primary papers: Wang et al. 2007, Trotman et al. 2007, Shen et al. 2007)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review citing primary mechanistic papers on monoubiquitylation-dependent nuclear import; mechanistic basis established in referenced primary studies\",\n      \"pmids\": [\"18216329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXO22 ubiquitylates nuclear PTEN specifically at lysine 221, leading to its proteasomal degradation. FBXO22 acts on nuclear but not cytoplasmic PTEN, identifying a compartment-specific E3 ubiquitin ligase for PTEN.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays; site-directed mutagenesis (K221R); nuclear/cytoplasmic fractionation; FBXO22 knockdown/overexpression in colorectal cancer cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ubiquitination assay with mutagenesis of target lysine, fractionation experiments, and cellular functional readout\",\n      \"pmids\": [\"32249768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PTEN active-site cysteine is oxidized by reactive oxygen species forming an intramolecular disulfide bond between Cys124 and Cys71, which inactivates PTEN. Peroxiredoxin I (Prx I) protects PTEN from oxidation under moderate oxidative stress through direct interaction, preserving PTEN tumor-suppressive function. Prx II deficiency increases PTEN oxidation and insulin sensitivity.\",\n      \"method\": \"PTEN oxidation assays; Prx knockout/knockdown cell systems; direct binding assays; insulin signaling readouts\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical oxidation assays and Prx knockout cell models; reviewed findings from multiple primary studies, single oxidation mechanism replicated\",\n      \"pmids\": [\"33669370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PI3K/mTOR-dependent signaling controls PTEN protein expression through mTOR/4E-BP1-mediated translational regulation. Deletion of 4E-BP1 abolishes translational upregulation of PTEN by PI3K, establishing a homeostatic feedback loop: PI3K activation increases PTEN translation to limit pathway duration.\",\n      \"method\": \"4E-BP1 deletion; mTOR inhibitor treatment; polysome profiling/translational assays; PI3K inhibitor treatment; signaling readouts (pAKT, pS6K)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genetic deletion of 4E-BP1 combined with polysome/translational assays and pharmacological inhibition in multiple cell systems\",\n      \"pmids\": [\"33606974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PTEN activity is regulated by C-terminal tail (CTT) phosphorylation at serine/threonine residues: phosphorylation of the unstructured CTT promotes interaction with the phosphatase-C2 superdomain and inactivates PTEN by preventing membrane association. Unphosphorylated PTEN is the active, membrane-associated form.\",\n      \"method\": \"Structural analysis; phosphorylation site mutagenesis; membrane-binding and activity assays (referenced in review of structural mechanisms)\",\n      \"journal\": \"Cold Spring Harbor perspectives in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural and biochemical data from multiple studies consolidated; primary mechanistic finding from structure/mutagenesis work\",\n      \"pmids\": [\"31636093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PTEN and androgen receptor (AR) mutually repress each other in prostate cancer cells: PTEN (and PI3K inhibition) represses AR transcriptional activity and androgen-induced proliferation likely via AKT downregulation, while androgens protect from PTEN-induced apoptosis in an AR-dependent but AKT-independent manner.\",\n      \"method\": \"PTEN re-expression; PI3K inhibitor; reporter assays for AR transcriptional activity; PSA production assay; apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in prostate cancer cells with PTEN re-expression and pharmacological inhibition, single lab\",\n      \"pmids\": [\"11278645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PTEN promotes EGR1 sumoylation via the Akt-EGR1-ARF-PTEN axis: Akt phosphorylates EGR1 at S350 and T309, promoting EGR1 interaction with ARF and sumoylation by the ARF/Ubc9/SUMO system. EGR1 sumoylation is required for PTEN transcriptional induction. ARF-deficient mice show reduced EGR1 sumoylation and reduced PTEN levels, establishing a feedback loop.\",\n      \"method\": \"Kinase assay; sumoylation assay; co-immunoprecipitation; ARF knockout mice; site-directed mutagenesis of EGR1 phosphorylation sites\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic (ARF-KO mice) combined with biochemical sumoylation/kinase assays, single lab\",\n      \"pmids\": [\"19057511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTEN promotes nuclear translocation of FOXO1 in cholangiocarcinoma cells. Nuclear FOXO1 increases expression of BACH1 and MAFF, which directly repress transcription of proteasome subunit genes. Loss of PTEN thus upregulates proteasome expression and activity, creating a dependency on proteasome function in PTEN-deficient cancers.\",\n      \"method\": \"PTEN knockdown/overexpression; nuclear fractionation; ChIP; reporter assays for proteasome gene promoters; PDX models; autochthonous mouse models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway defined by ChIP, nuclear fractionation, reporter assays, and validated in PDX and in vivo mouse models\",\n      \"pmids\": [\"32967970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PTEN directly dephosphorylates tyrosine-phosphorylated focal adhesion kinase (FAK), thereby inhibiting integrin-triggered signaling, focal adhesion formation, cell spreading, and cell migration.\",\n      \"method\": \"Protein phosphatase assay on FAK substrate; cell migration/invasion assays with PTEN expression\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct dephosphorylation assay on FAK combined with cell biological readouts, findings reviewed and consolidated from primary studies\",\n      \"pmids\": [\"10547389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTEN localizes to the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), where it interacts with inositol 1,4,5-trisphosphate receptors (IP3Rs) and regulates Ca2+ release from the ER, thereby controlling sensitivity to apoptosis via its protein phosphatase activity.\",\n      \"method\": \"Subcellular fractionation; co-immunoprecipitation with IP3R; Ca2+ release measurements; apoptosis assays\",\n      \"journal\": \"Methods (San Diego, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — fractionation and co-IP with functional Ca2+ and apoptosis readouts; reviewed from primary mechanistic data\",\n      \"pmids\": [\"25312582\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTEN is a dual-specificity lipid and protein phosphatase whose primary tumor-suppressive function is dephosphorylation of PIP3 at the D3 position, thereby antagonizing PI3K/AKT/mTOR signaling to suppress proliferation, promote apoptosis, and induce G1 arrest via p27(KIP1); it additionally functions as a protein phosphatase that dephosphorylates substrates including FAK (inhibiting cell migration), IRS1 (modulating insulin/IGF signaling), PGK1 (suppressing glycolysis), DVL (regulating ciliogenesis), and γH2AX (facilitating DNA DSB repair after NSD2-mediated K349 methylation recruits PTEN to damage sites via 53BP1); its activity and stability are regulated post-translationally by PCAF-mediated acetylation (K125/K128, inhibitory), USP13-mediated deubiquitylation (stabilizing), FBXO22-mediated nuclear-specific ubiquitylation (destabilizing), C-terminal tail phosphorylation (inhibits membrane binding), Prx I-dependent protection from active-site Cys124/Cys71 oxidation, and mTOR/4E-BP1-dependent translational feedback, while its nuclear import is controlled by monoubiquitylation and its interactions with p85/PI3K complex and PDZ-domain proteins are phosphorylation-regulated.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTEN is a dual-specificity phosphatase that functions as a tumor suppressor primarily by antagonizing PI3K/Akt signaling [#0, #2]. Its physiological substrate is the lipid second messenger PIP3, which it dephosphorylates at the D3 position to impair PDK1/Akt survival signaling; loss-of-function mutations elevate cellular PIP3 and constitutively activate Akt [#2]. Through this activity PTEN induces G1 cell cycle arrest, correlating with increased p27(KIP1) and decreased G1 CDK activity [#1], and in PTEN-deficient cancers the residual pathway signaling becomes selectively dependent on the p110\\u03b2 (PIK3CB) PI3K isoform [#5]. Beyond its lipid phosphatase role, PTEN acts as a protein phosphatase on multiple substrates: it dephosphorylates FAK to inhibit cell spreading and migration [#21], IRS1 to modulate insulin/IGF signaling [#8], autophosphorylated PGK1 at Y324 to suppress glycolysis and tumor growth [#9], Dishevelled to control cilia dynamics and WNT signaling [#11], and \\u03b3H2AX at DNA double-strand breaks to promote repair, where ATM-dependent phosphorylation and NSD2-mediated K349 methylation recognized by 53BP1 recruit PTEN to damage sites [#10]. Nuclear PTEN additionally supports genome stability at replication forks by stabilizing RPA1 and recruiting the deubiquitinase OTUB1 [#12]. PTEN activity and abundance are tightly regulated post-translationally\\u2014inhibited by PCAF-mediated acetylation of catalytic-cleft residues K125/K128 [#3], inactivated by C-terminal tail phosphorylation that blocks membrane binding [#17] and by ROS-driven Cys71\\u2013Cys124 disulfide oxidation (protected by peroxiredoxin) [#15], stabilized by USP13-mediated deubiquitylation [#7], and destabilized in the nucleus by FBXO22-mediated ubiquitylation [#14], with nuclear import controlled by monoubiquitylation [#13]. A homeostatic mTOR/4E-BP1 translational feedback loop further tunes PTEN expression to limit pathway duration [#16].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that PTEN negatively regulates the PI3K/Akt axis defined its core signaling function and placed it upstream of Akt.\",\n      \"evidence\": \"Dominant-negative catalytically inactive mutant with Akt and 4E-BP1 phosphorylation readouts in cells\",\n      \"pmids\": [\"9861013\", \"9860981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the direct molecular substrate\", \"Mechanism of growth suppression linked correlatively to p27(KIP1)\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying PIP3 as the physiological substrate revealed the biochemical basis of PTEN tumor suppression, showing it dephosphorylates the D3 position to antagonize PDK1/Akt.\",\n      \"evidence\": \"In vitro biochemical phosphatase and substrate-specificity assays; PIP3 measurement in mutant cells\",\n      \"pmids\": [\"11395408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address PTEN protein-substrate (non-lipid) activities\", \"Membrane-recruitment dynamics not resolved here\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating direct dephosphorylation of FAK extended PTEN function to a protein phosphatase controlling adhesion and migration.\",\n      \"evidence\": \"Protein phosphatase assay on FAK plus migration/invasion assays with PTEN expression\",\n      \"pmids\": [\"10547389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Consolidated review evidence rather than single definitive study\", \"Cellular context dependence of FAK targeting unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showing that C-terminal PDZ-binding interactions are phosphorylation-regulated revealed how PTEN scaffolding and partner choice are dynamically controlled.\",\n      \"evidence\": \"Yeast two-hybrid, peptide pulldown, and binding assays with hDLG/hMAST205 PDZ domains\",\n      \"pmids\": [\"10646847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the ~90/120 kDa phospho-promoted partners not established\", \"Functional consequence of PDZ binding not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining mutual PTEN\\u2013androgen receptor repression connected PTEN signaling to hormone-driven prostate cancer proliferation.\",\n      \"evidence\": \"PTEN re-expression, PI3K inhibition, AR reporter and apoptosis assays in prostate cells\",\n      \"pmids\": [\"11278645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AKT-independent protective arm mechanistically undefined\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"PCAF-mediated acetylation of catalytic-cleft lysines established a growth-factor-responsive switch that inhibits PTEN lipid phosphatase activity.\",\n      \"evidence\": \"Co-IP, PCAF knockdown, K125R/K128R mutagenesis, phosphatase and cell cycle assays\",\n      \"pmids\": [\"16829519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deacetylase reversing the mark not identified here\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Multiple regulatory mechanisms were resolved—isoform-selective PI3K dependency, redox inactivation, C-terminal tail autoinhibition, and monoubiquitylation-driven nuclear import—mapping how PTEN function is spatially and biochemically controlled.\",\n      \"evidence\": \"Isoform shRNA with xenografts; oxidation/Prx assays; structural/mutagenesis review; ubiquitination and fractionation assays\",\n      \"pmids\": [\"18755892\", \"33669370\", \"31636093\", \"18216329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some mechanisms derived from consolidated review evidence\", \"Coordination between tail phosphorylation, oxidation, and localization not integrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of the Akt-EGR1-ARF-PTEN feedback loop showed how PTEN transcription is induced downstream of its own pathway.\",\n      \"evidence\": \"Kinase and sumoylation assays, ARF-knockout mice, EGR1 phospho-site mutagenesis\",\n      \"pmids\": [\"19057511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution to PTEN homeostasis unclear\", \"Tissue specificity of the loop not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying a >600-kDa PTEN-associated complex containing p85 and p110\\u03b2 revealed direct physical engagement with the PI3K machinery.\",\n      \"evidence\": \"Reciprocal Co-IP and sucrose-gradient fractionation; trastuzumab-modulated association in ERBB2 cells\",\n      \"pmids\": [\"19635806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural architecture of the complex unknown\", \"Functional consequence of p85 binding for phosphatase activity unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"USP13 was identified as a deubiquitylase that directly stabilizes PTEN, defining a stability control node whose loss drives AKT-dependent tumor growth.\",\n      \"evidence\": \"DUB screen, Co-IP, in vitro deubiquitylation, knockdown/overexpression, tumor growth assays\",\n      \"pmids\": [\"24270891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Opposing E3 ligase context not fully mapped here\", \"Compartment specificity of USP13 action unexplored\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PTEN was established as the direct IRS1 phosphatase and as an ER/MAM-localized regulator of IP3R-dependent Ca2+ release, broadening its protein-substrate repertoire and apoptotic control.\",\n      \"evidence\": \"Biochemical dephosphorylation and reconstitution with NEDD4/PTEN genetics; fractionation and IP3R Co-IP with Ca2+/apoptosis assays\",\n      \"pmids\": [\"24814346\", \"25312582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MAM findings partly from consolidated review evidence\", \"Structural basis of IP3R interaction unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of DVL and RPA1 engagement linked PTEN protein-phosphatase and scaffolding activity to ciliogenesis/WNT signaling and to replication-fork protection.\",\n      \"evidence\": \"Loss-of-function phosphorylation assays on DVL; Co-IP, iPOND, STORM, and OTUB1-mediated RPA1 deubiquitination assays\",\n      \"pmids\": [\"26399523\", \"26403191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect DVL dephosphorylation not fully resolved\", \"How PTEN recruits OTUB1 mechanistically undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining PTEN dephosphorylation of PGK1 Y324 and recruitment to DSBs via NSD2/53BP1 established its roles in suppressing glycolysis and promoting DNA repair through protein-phosphatase activity.\",\n      \"evidence\": \"Co-IP, in vitro dephosphorylation, PGK1 Y324F knockin mice, tumor specimens; methylation, \\u03b3H2AX dephosphorylation assays and xenografts\",\n      \"pmids\": [\"31492635\", \"31217297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between metabolic and DNA-repair functions not integrated\", \"Relative contributions of lipid vs protein phosphatase activity in tumors unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Compartment-specific nuclear degradation by FBXO22 and the PTEN-FOXO1-BACH1/MAFF proteasome-repression axis revealed how nuclear PTEN levels and a targetable proteasome dependency are controlled.\",\n      \"evidence\": \"Ubiquitination assays with K221R mutagenesis and fractionation; ChIP, reporter, PDX and autochthonous mouse models\",\n      \"pmids\": [\"32249768\", \"32967970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering nuclear FBXO22 activity unknown\", \"Generality of proteasome dependency across PTEN-null cancers untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating mTOR/4E-BP1-dependent translational upregulation of PTEN defined a homeostatic feedback loop limiting PI3K pathway duration.\",\n      \"evidence\": \"4E-BP1 deletion, mTOR/PI3K inhibition, polysome profiling, signaling readouts\",\n      \"pmids\": [\"33606974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative dynamics of the feedback loop in vivo unclear\", \"Tissue-specific dependence not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTEN's many regulatory layers and substrate choices are integrated into a single coordinated tumor-suppressive program across compartments remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating acetylation, oxidation, tail phosphorylation, and localization\", \"Relative in vivo importance of lipid vs protein phosphatase substrates undefined\", \"Mechanisms directing PTEN to specific compartmental substrates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 8, 9, 21]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 9, 10, 11, 21]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 12, 13, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [\"PTEN-associated complex (PAC; with p85/p110\\u03b2)\"],\n    \"partners\": [\"PIK3R1\", \"PIK3CB\", \"USP13\", \"FBXO22\", \"RPA1\", \"PCAF\", \"MDC1\", \"ITPR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}