{"gene":"PHLPP2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2007,"finding":"PHLPP2 dephosphorylates the hydrophobic motif (Ser-473) of Akt, thereby inactivating it; PHLPP2 specifically regulates Akt3, modulating phosphorylation of p27, while PHLPP1 regulates Akt2; knockdown of PHLPP2 increases agonist-evoked Akt phosphorylation by nearly two orders of magnitude and inhibits apoptosis/cell-cycle progression.","method":"siRNA knockdown, in-cell phosphorylation assays, isoform-specific substrate readouts (p27, HDM2, GSK-3α)","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown studies with multiple isoform-specific substrates, replicated across conditions, founding paper with orthogonal readouts","pmids":["17386267"],"is_preprint":false},{"year":2009,"finding":"A naturally occurring L1016S polymorphism in the phosphatase domain of PHLPP2 reduces its catalytic activity toward both Akt and PKC in vitro and in cells, resulting in elevated Akt phosphorylation and reduced apoptosis; depletion of the Ser-1016 variant in breast cancer cells confirmed reduced function toward Akt and PKC.","method":"In vitro phosphatase assay with polymorphic variants, siRNA depletion of endogenous PHLPP2 variants in breast cancer cells, pair-matched tumor/normal samples","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase assay plus cell-based validation with natural variant and allele retention in tumors, single lab but multiple orthogonal methods","pmids":["19324870"],"is_preprint":false},{"year":2009,"finding":"In neonatal rat cardiac myocytes, adenylyl cyclase type 6 (AC6) physically associates with PHLPP2 and inhibits its activity under basal conditions, preventing Akt dephosphorylation; however, isoproterenol or forskolin stimulation acutely activates PHLPP2 in a cAMP-independent manner requiring an intact cytoplasmic domain of AC6, leading to rapid Akt dephosphorylation at Ser473.","method":"Co-immunoprecipitation, PHLPP2 phosphatase activity assays, AC6 cytoplasmic-domain mutants, isoproterenol/forskolin stimulation in primary cardiomyocytes","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional phosphatase activity assay with domain-mutant controls, single lab","pmids":["19450723"],"is_preprint":false},{"year":2010,"finding":"In the retina, both PHLPP (PHLPP1) and PHLPPL (PHLPP2) phosphatase activities are significantly decreased in the presence of insulin ex vivo, and this inhibition is PI3K-dependent (reversed by LY294002), demonstrating that the IR-activated PI3K/Akt pathway negatively feeds back to regulate PHLPP2 activity.","method":"Ex vivo retinal culture phosphatase activity assays, PI3K inhibitor (LY294002) pre-treatment, insulin stimulation","journal":"Journal of Neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic activity measurement in ex vivo tissue with pharmacological inhibitor controls, single lab","pmids":["20089132"],"is_preprint":false},{"year":2012,"finding":"DGKδ deficiency leads to excessive PKCα activity, which promotes PHLPP2-mediated dephosphorylation of Akt; β-arrestin 1 acts as a scaffold bringing PHLPP2 and Akt1 together, conferring specificity for Akt dephosphorylation. Depletion of PHLPP2 (but not PHLPP1) rescues Akt phosphorylation in DGKδ-deficient cells.","method":"siRNA knockdown of DGKδ, PKCα, PHLPP2, PHLPP1; co-immunoprecipitation of β-arrestin 1 with PHLPP2 and Akt1; Akt phosphorylation assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal knockdowns with isoform specificity (PHLPP2 vs PHLPP1), scaffolding interaction via co-IP, multiple orthogonal methods in single lab","pmids":["23184957"],"is_preprint":false},{"year":2014,"finding":"PHLPP2 interacts with IKKβ kinase and decreases IKKβ phosphorylation, thereby suppressing NF-κB activation; mechanistically, PHLPP2 competes with MALT1 for binding to Bcl10, preventing Bcl10-MALT1 complex formation, NEMO ubiquitination, and downstream IKKβ phosphorylation. PHLPP2 loss enhances these interactions and increases NF-κB-dependent transcription.","method":"Co-immunoprecipitation of PHLPP2 with IKKβ and Bcl10, competitive displacement assays, NF-κB reporter assays, PHLPP2 knockdown/overexpression","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with multiple binding partners, competitive displacement, functional reporter assay, single lab","pmids":["24553260"],"is_preprint":false},{"year":2014,"finding":"In a rat cerebral ischemia/reperfusion model, FKBP51, PHLPP2, and AKT assemble into a trimeric signaling complex; I/R injury enhances interactions among these components, leading to Akt dephosphorylation and neuronal death. Antisense oligonucleotide inhibition of PHLPP2 disrupts complex assembly, reverses p-AKT decrease, and reduces caspase-3 cleavage and CA1 neuron loss.","method":"Co-immunoprecipitation in vivo rat I/R model, antisense oligonucleotide knockdown of PHLPP2, western blot for p-AKT, caspase-3, histological neuron counts","journal":"Brain Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo co-IP of trimeric complex, antisense knockdown with functional cellular outcome, single lab","pmids":["24746496"],"is_preprint":false},{"year":2015,"finding":"MYC strongly activates PHLPP2 transcription in primary prostate cells and prostate cancer metastasis; in Pten/Trp53 mutant cells, IL6-driven STAT3 activation induces MYC which upregulates PHLPP2, suppressing AKT. Genetic loss of Phlpp2 in the RapidCaP mouse model is essential for dictating the proliferation driven by MYC-mediated AKT suppression.","method":"Genetic mouse models (RapidCaP), Phlpp2 loss-of-function, IL6/STAT3/MYC pathway dissection, cell proliferation assays, tissue analysis","journal":"Cancer Discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetically engineered mouse model with epistasis, pathway dissection, single lab","pmids":["25829425"],"is_preprint":false},{"year":2015,"finding":"miR-205 induction following B[a]P/B[a]PDE exposure inhibits PHLPP2 protein translation by targeting PHLPP2-3'-UTR; reduced PHLPP2 contributes to lung inflammation and carcinogenesis. PHLPP2 ectopic expression represses inflammatory TNFα transcription, providing an antitumorigenic mechanism.","method":"Luciferase reporter assay for 3'-UTR targeting, ectopic PHLPP2 expression in cell transformation models, B[a]P mouse lung cancer model, TNFα transcription assays","journal":"Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'-UTR reporter, in vitro transformation model and in vivo mouse model, functional rescue with PHLPP2 overexpression","pmids":["25977341"],"is_preprint":false},{"year":2015,"finding":"p27 stabilizes PHLPP2 protein by inhibiting Hsp90 degradation; Hsp90 directly binds PHLPP2 and protects it from degradation. p27 stabilizes Hsp90 by inhibiting calpain1 gene transcription through attenuation of the Jak1/Stat1 cascade. PHLPP2 in turn inhibits bladder cancer invasion by promoting MMP2 degradation via p62-mediated autophagy.","method":"Co-immunoprecipitation of Hsp90-PHLPP2, calpain1 transcription assays, Jak1/Stat1 pathway inhibition, autophagy flux assays, invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of Hsp90-PHLPP2, pathway dissection with multiple readouts, single lab","pmids":["29930380"],"is_preprint":false},{"year":2015,"finding":"Pull-down assay with morin-conjugated beads demonstrated direct binding of morin to PHLPP2 protein; molecular docking revealed morin occupies the active site of PHLPP2, and morin treatment inhibits PHLPP2 activity and its association with Akt1, thereby preventing oxidant-induced Nrf2 suppression via the Akt/GSK3β/Fyn kinase axis.","method":"Morin-conjugated bead pull-down assay, molecular docking, PHLPP2 activity assay (ex vivo), Akt/GSK3β/Fyn pathway western blotting","journal":"Redox Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by affinity pull-down and molecular docking, functional phosphatase activity assay, single lab","pmids":["26513344"],"is_preprint":false},{"year":2016,"finding":"Free (mTORC1-independent) Raptor stabilizes PHLPP2 protein by reducing β-TrCP-mediated proteasomal degradation of PHLPP2; this leads to suppression of hepatic Akt activity and lipogenesis. Forced PHLPP2 expression in diet-induced obese mice ameliorates hepatic steatosis.","method":"Raptor overexpression/knockdown, β-TrCP interaction studies, PHLPP2 protein stability assays, liver-specific mouse models, triglyceride measurements","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection of Raptor-β-TrCP-PHLPP2 degradation pathway with multiple orthogonal approaches and in vivo validation in obese mice","pmids":["26743335"],"is_preprint":false},{"year":2016,"finding":"In AML cells, microRNAs from the miR-17-92 cluster (oncomir-1) target PHLPP2 mRNA and suppress PHLPP2 protein expression; ATRA treatment suppresses miR-17-92 expression and increases PHLPP2 protein and phosphatase activity. This regulation is mediated by transcription factor C/EBPβ, which binds the intronic promoter of the miR-17-92 gene to inhibit its transactivation.","method":"miRNA overexpression/knockdown, PHLPP2 phosphatase activity assay, chromatin immunoprecipitation (C/EBPβ on miR-17-92 promoter), ATRA treatment, western blotting","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct phosphatase activity assay, ChIP for transcriptional regulation, miRNA functional studies with multiple orthogonal methods","pmids":["26868909"],"is_preprint":false},{"year":2017,"finding":"In obese mice, glucagon/PKA-dependent phosphorylation of PHLPP2 at Ser1119 and Ser1210 promotes PHLPP2 binding to KCTD17 (a substrate-adaptor for Cul3-RING ubiquitin ligases), leading to PHLPP2 ubiquitin-mediated proteasomal degradation. Loss of PHLPP2 prolongs insulin action and increases lipogenic gene expression, causing hepatic steatosis.","method":"Mass spectrometry identification of PHLPP2 phosphorylation sites and interactors, KCTD17 co-IP/binding assay, KCTD17 shRNA knockdown in primary hepatocytes and obese mice, CRISPR/Cas9 PHLPP2-knockout hepatoma cells, liver-specific PHLPP2-knockout mice","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mass spectrometry identification of phosphorylation sites, in vivo genetic models, co-IP binding, multiple orthogonal methods, replicated in multiple model systems","pmids":["28859855"],"is_preprint":false},{"year":2018,"finding":"PHLPP2 physically interacts with GRK5 in neonatal rat ventricular myocytes (NRVMs); PHLPP2 overexpression (in a phosphatase-activity-dependent manner) blocks phenylephrine-induced nuclear accumulation of GRK5 and hypertrophic gene re-expression. Knockdown of PHLPP2 potentiates GRK5-dependent hypertrophic growth, and GRK5 is required for the hypertrophic response induced by PHLPP2 knockdown.","method":"Co-immunoprecipitation of PHLPP2 and GRK5, siRNA knockdown, PHLPP2 overexpression with phosphatase-dead mutant controls, cell size measurements, fetal gene expression (ANF, BNP), PE stimulation","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, phosphatase-dead mutant controls, genetic epistasis via double knockdown, single lab","pmids":["29628444"],"is_preprint":false},{"year":2018,"finding":"PHLPP2 interacts with and dephosphorylates MST1 (Mst1) in berberine-treated hepatoma cells; elevated PHLPP2 inactivates Akt by dephosphorylating Ser473, which releases Akt-mediated repression of Mst1, leading to heightened Mst1 phosphorylation at Thr183 and downstream JNK/Bim/Bak pro-apoptotic signaling. PHLPP2 and Mst1 form an autoinhibitory triangle with Akt.","method":"Co-immunoprecipitation of PHLPP2-Mst1, western blot for Akt(Ser473) and Mst1(Thr183), PHLPP2/Mst1 knockdown, berberine treatment in HepG2 cells","journal":"Toxicology and Applied Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating PHLPP2-Mst1 interaction, knockdown rescue experiments, single lab","pmids":["29626488"],"is_preprint":false},{"year":2019,"finding":"PHLPP2 dephosphorylates threonine-58 (T58) of MYC, a phosphorylation site linked to MYC degradation; this renders PHLPP2 a limiting positive regulator of MYC stability. In the RapidCaP mouse model, complete loss of Phlpp2 paradoxically blocks tumor growth by destabilizing MYC. Small-molecule PHLPP2 inhibitors suppress MYC and kill PTEN-mutant cells.","method":"RapidCaP genetically engineered mouse model, Phlpp2 knockout, MYC phospho-T58 assays, small-molecule PHLPP2 inhibitor treatment, cell viability assays","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic mouse model with Phlpp2 knockout, direct phosphorylation site (MYC T58) identified, pharmacological validation with small-molecule inhibitors, multiple orthogonal methods","pmids":["31092557"],"is_preprint":false},{"year":2019,"finding":"PHLPP2 promotes BECN1 (Beclin1) stabilization, thereby promoting BECN1-dependent macroautophagy, which inhibits bladder cancer tumor cell growth. The mechanism involves PHLPP2 indirectly preventing CUL4A-mediated BECN1 protein degradation.","method":"PHLPP2 overexpression/knockdown, autophagy flux assays, xenograft tumor growth, CUL4A interaction studies","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional autophagy assays, in vivo xenograft, mechanistic link to CUL4A-BECN1 axis, single lab","pmids":["32116109"],"is_preprint":false},{"year":2019,"finding":"Hepatic exosome-derived miR-130a-3p directly targets PHLPP2 mRNA and suppresses its expression in adipocytes, thereby activating AKT-AS160-GLUT4 signaling to improve glucose uptake and attenuate glucose intolerance in high-fat diet mice.","method":"miR-130a-3p knockout and overexpression mice, hepatic exosome injection, 3T3-L1 cell transfection, luciferase 3'-UTR reporter for PHLPP2, PHLPP2 siRNA, AKT/AS160/GLUT4 western blotting","journal":"Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic models, 3'-UTR reporter validation, functional rescue with PHLPP2 siRNA, single lab","pmids":["31715176"],"is_preprint":false},{"year":2020,"finding":"PHLPP2 dephosphorylates and inactivates AMPK (pAMPK); the PH domain of PHLPP2 is required for its interaction with pAMPK, for dephosphorylating and inactivating AMPK, and for the apoptotic response to glucose limitation in leukemia cells. PHLPP2 silencing prolongs leukemia cell survival under glucose limitation by promoting AMPK-mediated fatty acid oxidation.","method":"Co-immunoprecipitation of PHLPP2-AMPK, PH domain deletion mutants, PHLPP2 siRNA knockdown, metabolic stress (glucose limitation), cell survival/apoptosis assays","journal":"Cell Death & Disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating direct interaction, domain deletion mapping (PH domain required), functional metabolic assays, identification of novel substrate AMPK","pmids":["34608126"],"is_preprint":false},{"year":2021,"finding":"In adipocytes, PHLPP2 dephosphorylates Akt (Ser473); adipocyte-specific PHLPP2 knockout increases HSL phosphorylation, leading to enhanced lipolysis and increased PPARα-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to prevent obesity-induced fatty liver.","method":"Adipocyte-specific PHLPP2 knockout mice (A-PHLPP2), high-fat diet feeding, HSL phosphorylation assays, in vitro and in vivo lipolysis assays, adiponectin secretion measurement, hepatic FAO assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout mouse model, multiple orthogonal metabolic readouts, in vitro and in vivo validation, identifies PHLPP2-HSL-PPARα-adiponectin axis","pmids":["33758172"],"is_preprint":false},{"year":2021,"finding":"mettl3 knockout/knockdown increases PHLPP2 expression and reduces AKT phosphorylation (S473) with decreased mTOR phosphorylation (S2481), demonstrating that m6A RNA methylation by METTL3 regulates PHLPP2 levels to control vascular development via PHLPP2/mTOR-AKT signaling.","method":"CRISPR-Cas9 mettl3 knockout zebrafish, morpholino knockdown, constitutively active AKT1 rescue, METTL3 knockdown in human endothelial cells, PHLPP2/AKT/mTOR western blotting","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout and morpholino in two systems, AKT rescue, western blot mechanistic readouts, single lab","pmids":["33788967"],"is_preprint":false},{"year":2022,"finding":"TRIM46 acts as an E3 ubiquitin ligase that directly ubiquitinates PHLPP2 and promotes its proteasomal degradation; this requires the RING domain E3 ligase activity of TRIM46. PHLPP2 degradation activates AKT/HK2 signaling, driving glycolysis and chemoresistance in lung adenocarcinoma. PHLPP2 overexpression reverses these effects.","method":"TRIM46 wild-type vs. RING-mutant overexpression, ubiquitination assays, PHLPP2 protein level measurement, co-immunoprecipitation, glycolysis assays, PDX mouse model, cisplatin resistance assays","journal":"Cell Death & Disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — E3 ligase-dependent ubiquitination assay, RING-mutant controls, co-IP, in vivo PDX model, multiple orthogonal methods","pmids":["35354796"],"is_preprint":false},{"year":2022,"finding":"circANAPC7 acts as a sponge for miR-373, preventing miR-373-mediated suppression of PHLPP2; PHLPP2 then dephosphorylates AKT, suppresses cyclin D1, and inhibits TGF-β secretion via STAT5. Additionally, PHLPP2 induces dephosphorylation of CREB, forming a CREB-miR-373-PHLPP2 feed-forward loop.","method":"Biotinylated miRNA pulldown, RNA immunoprecipitation, luciferase reporter assays, PHLPP2 western blot, AKT phosphorylation, 3D organoids, mouse models","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA interaction assays, pathway western blots, in vitro and in vivo models, single lab","pmids":["35176309"],"is_preprint":false},{"year":2022,"finding":"TRIM22, whose expression is transcriptionally upregulated by p53 during IR-induced senescence, directly associates (via its SPRY domain) with the C-terminal domain of PHLPP2 at IKKβ-mediated phosphorylation sites; TRIM22-mediated ubiquitination and proteasomal degradation of PHLPP2 activates AKT-p53-p21 signaling, causing cellular senescence in HCC cells.","method":"Co-immunoprecipitation (TRIM22 SPRY domain with PHLPP2 C-terminal domain), ubiquitination assay, TRIM22 overexpression/knockdown, p-AKT/p53/p21 western blot, senescence assays (SA-β-gal), IR treatment","journal":"Cell Death & Disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-mapping co-IP, ubiquitination assay, functional senescence readouts, IKKβ phosphorylation site identification, multiple orthogonal methods","pmids":["38199981"],"is_preprint":false},{"year":2022,"finding":"Mutant p53 (hotspot mutations) directly binds to the PHLPP2 promoter and transcriptionally inhibits PHLPP2 expression, releasing AKT from PHLPP2-mediated suppression; activated AKT then promotes tumor proliferation/metastasis and via 4EBP1/eIF4E enhances PD-L1 translation, facilitating immune escape.","method":"Chromatin immunoprecipitation (mutant p53 on PHLPP2 promoter), PHLPP2 expression analysis in mutant p53 colorectal cancer samples, AKT pathway western blotting, PD-L1 expression assays","journal":"International Journal of Biological Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, cell line and patient sample validation, downstream pathway readouts, single lab","pmids":["35414774"],"is_preprint":false},{"year":2022,"finding":"SNAI2 binds to the PHLPP2 promoter region (as detected by chromatin immunoprecipitation) and transcriptionally represses PHLPP2, activating the Akt pathway and promoting glioma stem cell proliferation.","method":"Chromatin immunoprecipitation, RT-qPCR, SNAI2/PHLPP2 overexpression and knockdown, Akt phosphorylation assays, GSC proliferation/apoptosis assays, nude mouse xenografts","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, functional rescue experiments, in vivo xenograft, single lab","pmids":["35654777"],"is_preprint":false},{"year":2023,"finding":"The E3 ubiquitin ligase RNF149 physically interacts with PHLPP2 and promotes its E3 ligase-dependent proteasomal degradation, activating PI3K/AKT signaling and conferring cisplatin resistance in esophageal squamous cell carcinoma.","method":"Co-immunoprecipitation of RNF149-PHLPP2, ubiquitination assay, RNF149 overexpression/knockdown, PHLPP2 protein stability assays, AKT pathway western blotting, cisplatin resistance assays in vitro and in vivo","journal":"Medical Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, E3-ligase-dependent ubiquitination demonstrated, functional rescue, single lab","pmids":["37658961"],"is_preprint":false},{"year":2023,"finding":"Newcastle disease virus (NDV) V protein directly interacts with PHLPP2 (co-IP and indirect immunofluorescence) and targets PHLPP2 for ubiquitin-proteasome degradation (inhibited by MG132), thereby activating PI3K/AKT signaling, inhibiting cell apoptosis, and promoting viral replication.","method":"Co-immunoprecipitation (NDV V protein with PHLPP2), indirect immunofluorescence, MG132 proteasome inhibition, flow cytometry apoptosis assay, caspase-3 activity assay","journal":"Veterinary Microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and indirect IF demonstrate V protein-PHLPP2 interaction, proteasome inhibitor rescue, functional apoptosis readouts, single lab","pmids":["38128444"],"is_preprint":false},{"year":2024,"finding":"The E3 ubiquitin ligase MARCH1 physically interacts with PHLPP2 (by co-immunoprecipitation) and promotes PHLPP2 ubiquitination and degradation in oral squamous cell carcinoma, thereby activating AKT signaling and promoting tumor cell proliferation and suppressing apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, MARCH1 knockdown/overexpression, PHLPP2 protein levels, in vivo xenograft","journal":"Clinical & Translational Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay, in vivo xenograft, functional rescue, single lab","pmids":["35122633"],"is_preprint":false},{"year":2025,"finding":"PHLPP2 is a pseudophosphatase that lost catalytic activity in the metazoan ancestor; it contains a single zinc ion in its catalytic center and has no detectable phosphatase activity in vitro. Despite loss of catalytic activity, surface conservation suggests PHLPP2 may have retained substrate-binding capacity and likely functions as a scaffold on membranes, as supported by phylogenomic coevolution analyses.","method":"In vitro phosphatase activity assays, metalloprotein analysis (zinc binding), crystal/structural analysis implied, phylogenetic and phylogenomic analyses, cancer genomics analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical phosphatase activity assays with metal ion characterization, phylogenetic analyses, directly challenges prior model, single study with multiple orthogonal approaches","pmids":["40168118"],"is_preprint":false},{"year":2025,"finding":"FBXO32 (F-box protein) interacts with PHLPP2 and promotes K48-linked polyubiquitination of PHLPP2 at K592 and K942 sites, leading to PHLPP2 proteasomal degradation and activation of the PI3K-AKT pathway in hepatocellular carcinoma.","method":"Proteomics-based interactome, co-immunoprecipitation, ubiquitination assays identifying K48-linked polyubiquitination at K592/K942, FBXO32 overexpression/knockdown, orthotopic HCC mouse model, HCC patient-derived organoids","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified interaction confirmed by co-IP, site-specific ubiquitination mapping, in vivo orthotopic model, single lab","pmids":["41000374"],"is_preprint":false},{"year":2025,"finding":"ATP6V0D2 enhances lysosomal function to promote lysosomal degradation of PHLPP2, thereby sustaining AKT phosphorylation in triple-negative breast cancer; pharmacological inhibition of V-ATPase with bafilomycin A1 blocks PHLPP2 lysosomal degradation, restores PHLPP2 levels, and sensitizes TNBC cells to cisplatin.","method":"ATP6V0D2 knockdown, bafilomycin A1 (V-ATPase inhibitor) treatment, PHLPP2 protein stability assays, AKT phosphorylation western blot, in vitro and in vivo cisplatin sensitivity assays, patient-derived organoids","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pharmacological rescue with V-ATPase inhibitor, in vitro and in vivo functional assays, patient-derived organoids, single lab","pmids":["41312388"],"is_preprint":false},{"year":2020,"finding":"ENH (Enigma Homolog Protein) forms a scaffold complex with AKT1 and PHLPP2 in arterial endothelial cells; this complex facilitates PHLPP2-mediated dephosphorylation of AKT1 and eNOS, reducing nitric oxide production. Endothelium-specific knockout of either ENH or PHLPP2 in mice reduces ligation-induced neointima formation.","method":"Co-immunoprecipitation of ENH-AKT1-PHLPP2 complex, endothelium-specific ENH knockout and PHLPP2 knockout mice, carotid artery ligation model, AKT/eNOS phosphorylation assays, nitric oxide measurement","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — trimeric complex co-IP, tissue-specific knockout mouse models for both ENH and PHLPP2, in vivo neointima readout, multiple orthogonal methods","pmids":["32268790"],"is_preprint":false}],"current_model":"PHLPP2 is a member of the metal-dependent protein phosphatase family that dephosphorylates Akt (primarily Akt3, at the hydrophobic motif Ser473) and other AGC kinases (PKC, GRK5), as well as non-AGC substrates including MST1, AMPK, and MYC-T58, thereby broadly suppressing pro-survival and pro-growth signaling; however, a 2025 biochemical study found PHLPP2 has no detectable catalytic phosphatase activity in vitro (containing only a single zinc ion and acting as a pseudophosphatase), suggesting its roles may depend on substrate binding and scaffolding rather than direct catalysis. Its protein stability is regulated by multiple E3 ubiquitin ligases (TRIM46, TRIM22, MARCH1, KCTD17/Cul3, RNF149, FBXO32) that target it for proteasomal or lysosomal degradation downstream of diverse signals (glucagon/PKA phosphorylation, IKKβ phosphorylation, viral V proteins), while free Raptor stabilizes it by antagonizing β-TrCP-mediated degradation; PHLPP2 transcription is repressed by mutant p53 and SNAI2 at its promoter and is post-transcriptionally suppressed by numerous oncomiRs (miR-205, miR-141, miR-224, miR-181a/d, miR-135a, miR-372, miR-32, miR-760 and others) that target its 3'-UTR. Beyond Akt, PHLPP2 suppresses NF-κB signaling by binding Bcl10 and blocking Bcl10-MALT1 complex formation, promotes BECN1-dependent autophagy, regulates MYC stability (T58 dephosphorylation), and controls energy metabolism via AMPK dephosphorylation."},"narrative":{"mechanistic_narrative":"PHLPP2 is a negative regulator of the PI3K/Akt pro-survival pathway, originally defined as a phosphatase that dephosphorylates the Akt hydrophobic motif (Ser473), preferentially acting on Akt3 to control downstream effectors such as p27 and thereby restraining cell survival and cell-cycle progression [PMID:17386267]. Substrate specificity is conferred by scaffolds that assemble PHLPP2 with its targets: β-arrestin 1 brings PHLPP2 and Akt1 together [PMID:23184957], FKBP51 nucleates a PHLPP2–Akt trimeric complex driving Akt dephosphorylation and neuronal death in ischemia/reperfusion [PMID:24746496], and ENH organizes a PHLPP2–AKT1 complex that dephosphorylates AKT1 and eNOS in endothelium [PMID:32268790]. Beyond Akt, PHLPP2 acts on a broader set of signaling proteins—it dephosphorylates AMPK through its PH domain to govern metabolic stress responses [PMID:34608126], dephosphorylates MST1 to release pro-apoptotic JNK/Bim signaling [PMID:29626488], dephosphorylates MYC at Thr58 to stabilize it [PMID:31092557], and binds GRK5 to limit cardiac hypertrophic gene expression [PMID:29628444]; it also suppresses NF-κB by competing with MALT1 for Bcl10 binding [PMID:24553260] and promotes BECN1-dependent autophagy [PMID:32116109]. A 2025 biochemical and phylogenetic study redefined PHLPP2 as a pseudophosphatase that lost catalytic activity in the metazoan ancestor, retaining only a single zinc ion and no detectable in vitro phosphatase activity, indicating its functions rest on substrate binding and membrane scaffolding rather than direct catalysis [PMID:40168118]. PHLPP2 abundance is the principal control point of its activity: it is destabilized by numerous E3 ubiquitin ligases (TRIM46, TRIM22, MARCH1, KCTD17/Cul3, RNF149, FBXO32) downstream of signals including glucagon/PKA phosphorylation and IKKβ phosphorylation [PMID:28859855, PMID:35354796, PMID:38199981, PMID:37658961, PMID:35122633, PMID:41000374], degraded via the lysosome through ATP6V0D2/V-ATPase activity [PMID:41312388], and stabilized by free Raptor antagonizing β-TrCP-mediated degradation [PMID:26743335] and by Hsp90 [PMID:29930380]; its expression is transcriptionally repressed by mutant p53 and SNAI2 [PMID:35414774, PMID:35654777] and post-transcriptionally suppressed by multiple oncomiRs targeting its 3'-UTR [PMID:25977341, PMID:26868909, PMID:31715176, PMID:35176309]. Through these mechanisms PHLPP2 functions as a context-dependent tumor and metabolic regulator, suppressing Akt-driven growth and lipogenesis in liver and adipose tissue [PMID:26743335, PMID:28859855, PMID:33758172] yet acting as a pro-tumorigenic MYC stabilizer in PTEN-mutant prostate cancer [PMID:31092557].","teleology":[{"year":2007,"claim":"Established PHLPP2 as an isoform-selective Akt phosphatase, answering how the hydrophobic-motif phosphorylation of Akt is reversed and assigning PHLPP2 to Akt3-specific control of survival/cell-cycle outputs.","evidence":"siRNA knockdown with isoform-specific substrate readouts (p27, HDM2, GSK-3α) in cells","pmids":["17386267"],"confidence":"High","gaps":["Did not resolve how PHLPP2 is recruited to specific Akt isoforms","In-cell dephosphorylation does not prove direct catalysis"]},{"year":2009,"claim":"A natural L1016S variant linked PHLPP2 phosphatase-domain integrity to Akt/PKC suppression and tumor biology, reinforcing a catalytic model of PHLPP2 function.","evidence":"In vitro phosphatase assays with polymorphic variants plus siRNA depletion in breast cancer cells and tumor/normal pairs","pmids":["19324870"],"confidence":"High","gaps":["A single-residue activity change is consistent with but does not formally prove direct catalysis","Mechanism of allele retention in tumors not established"]},{"year":2009,"claim":"Showed PHLPP2 activity is acutely controlled by upstream regulators (AC6) in cardiomyocytes, introducing the idea that PHLPP2 is gated by physical partners rather than constitutively active.","evidence":"Co-IP, phosphatase activity assays, and AC6 cytoplasmic-domain mutants in primary cardiomyocytes","pmids":["19450723"],"confidence":"Medium","gaps":["cAMP-independent activation mechanism left undefined","Single lab, single tissue context"]},{"year":2010,"claim":"Demonstrated negative feedback from PI3K/Akt onto PHLPP2 activity, positioning PHLPP2 within a self-limiting insulin-signaling loop.","evidence":"Ex vivo retinal phosphatase activity assays with PI3K inhibitor (LY294002) and insulin stimulation","pmids":["20089132"],"confidence":"Medium","gaps":["Molecular mediator of PI3K-dependent inhibition not identified","Tissue-specific ex vivo result"]},{"year":2012,"claim":"Identified β-arrestin 1 as a scaffold conferring Akt1-isoform specificity, explaining how PHLPP2 substrate choice is spatially dictated.","evidence":"Reciprocal siRNA knockdowns (DGKδ, PKCα, PHLPP2, PHLPP1) and co-IP of β-arrestin 1 with PHLPP2/Akt1","pmids":["23184957"],"confidence":"High","gaps":["Structural basis of scaffolding not resolved","Generality beyond DGKδ-deficient context untested"]},{"year":2014,"claim":"Extended PHLPP2 function beyond Akt by showing it suppresses NF-κB through competing with MALT1 for Bcl10 binding, defining a catalysis-independent scaffolding role.","evidence":"Co-IP with IKKβ and Bcl10, competitive displacement, and NF-κB reporter assays","pmids":["24553260"],"confidence":"Medium","gaps":["Whether IKKβ dephosphorylation is direct vs. via Bcl10-MALT1 blockade unclear","Single lab"]},{"year":2014,"claim":"Defined a FKBP51–PHLPP2–Akt trimeric complex as a driver of neuronal death, showing PHLPP2 acts within multiprotein assemblies in vivo.","evidence":"In vivo co-IP in rat ischemia/reperfusion, antisense PHLPP2 knockdown, p-AKT/caspase-3/histology readouts","pmids":["24746496"],"confidence":"Medium","gaps":["Direct vs. indirect interactions within the complex not dissected","Single in vivo model"]},{"year":2015,"claim":"Revealed a MYC–PHLPP2 transcriptional axis that suppresses Akt, establishing context-dependent control of PHLPP2 expression in prostate cancer.","evidence":"RapidCaP mouse model with Phlpp2 loss and IL6/STAT3/MYC pathway dissection","pmids":["25829425"],"confidence":"Medium","gaps":["Direct MYC binding at the PHLPP2 promoter not shown here","Single lab"]},{"year":2015,"claim":"Showed oncomiR (miR-205) and Hsp90/p27 control of PHLPP2 protein/translation, opening the layer of post-transcriptional and stability regulation that governs PHLPP2 abundance.","evidence":"3'-UTR luciferase reporters, Hsp90-PHLPP2 co-IP, autophagy/invasion and TNFα transcription assays in carcinogenesis models","pmids":["25977341","29930380"],"confidence":"Medium","gaps":["Relative contribution of each layer to net PHLPP2 levels unquantified","Mechanism connecting PHLPP2 to MMP2 autophagic degradation indirect"]},{"year":2016,"claim":"Defined the Raptor–β-TrCP stability axis and oncomiR cluster regulation, establishing proteasomal turnover and miRNA suppression as dominant determinants of PHLPP2-controlled Akt activity and hepatic lipogenesis.","evidence":"Raptor/β-TrCP interaction and stability assays with liver mouse models; miR-17-92/C/EBPβ ChIP and phosphatase activity assays in AML","pmids":["26743335","26868909"],"confidence":"High","gaps":["How free Raptor competes with β-TrCP mechanistically not fully resolved","Cross-tissue generality of the stability axis untested"]},{"year":2017,"claim":"Identified glucagon/PKA-driven phosphorylation (Ser1119/Ser1210) coupling PHLPP2 to KCTD17/Cul3 degradation, linking hormonal signaling to PHLPP2 turnover and hepatic steatosis.","evidence":"Mass spectrometry phospho-site/interactor mapping, KCTD17 co-IP, CRISPR-KO hepatoma and liver-specific KO mice","pmids":["28859855"],"confidence":"High","gaps":["Whether phospho-degron creation is the sole trigger unclear","Other kinases feeding this degron not enumerated"]},{"year":2018,"claim":"Expanded the PHLPP2 substrate/partner repertoire to GRK5 and MST1, connecting PHLPP2 to cardiac hypertrophy control and pro-apoptotic Hippo-axis signaling.","evidence":"Co-IP, phosphatase-dead mutant controls and epistasis (GRK5); PHLPP2-MST1 co-IP and knockdown rescue (MST1) in cellular models","pmids":["29628444","29626488"],"confidence":"Medium","gaps":["Direct dephosphorylation of GRK5 vs. indirect effect not isolated","Single-lab biochemistry"]},{"year":2019,"claim":"Established PHLPP2 as a MYC-T58 dephosphorylating MYC stabilizer and a druggable dependency in PTEN-mutant cancer, revealing a pro-tumorigenic role opposite to its Akt-suppressive function.","evidence":"RapidCaP Phlpp2 knockout, MYC phospho-T58 assays, small-molecule PHLPP2 inhibitor cell-killing","pmids":["31092557"],"confidence":"High","gaps":["Reconciliation of Akt-suppressive vs. MYC-stabilizing roles incomplete","Inhibitor target specificity not exhaustively defined"]},{"year":2019,"claim":"Demonstrated PHLPP2 promotion of BECN1-dependent autophagy and additional oncomiR (miR-130a-3p) control, broadening its tumor-suppressive and metabolic outputs.","evidence":"Autophagy flux/CUL4A-BECN1 studies with xenografts; miR-130a-3p KO/overexpression mice, 3'-UTR reporters and AKT-AS160-GLUT4 readouts","pmids":["32116109","31715176"],"confidence":"Medium","gaps":["Mechanism by which PHLPP2 blocks CUL4A-mediated BECN1 degradation indirect","Single-lab models"]},{"year":2020,"claim":"Defined AMPK as a PH-domain-dependent PHLPP2 target and ENH as a vascular scaffold, integrating PHLPP2 into metabolic-stress survival and endothelial NO signaling.","evidence":"Co-IP and PH-domain deletion with glucose-limitation survival assays (AMPK); ENH-AKT1-PHLPP2 co-IP with endothelium-specific knockouts and neointima model (ENH)","pmids":["34608126","32268790"],"confidence":"High","gaps":["Direct AMPK dephosphorylation vs. complex-mediated effect not fully separated","Tissue-restricted scaffolding contexts"]},{"year":2021,"claim":"Showed adipocyte PHLPP2 governs systemic lipid handling and that m6A methylation (METTL3) controls PHLPP2 levels, embedding PHLPP2 in inter-organ metabolic crosstalk and developmental signaling.","evidence":"Adipocyte-specific PHLPP2 knockout mice with lipolysis/adiponectin/hepatic FAO readouts; mettl3 knockout zebrafish/endothelial cells with AKT rescue","pmids":["33758172","33788967"],"confidence":"High","gaps":["Direct m6A site on PHLPP2 transcript not mapped in detail","Cross-species generality of vascular phenotype untested"]},{"year":2022,"claim":"Mapped a network of E3 ligases (TRIM46, TRIM22) and transcriptional repressors (mutant p53, SNAI2) plus circRNA/miRNA sponging that converge on PHLPP2 abundance to dictate Akt activation, glycolysis, senescence, and chemoresistance.","evidence":"RING-mutant ubiquitination assays, domain-mapping co-IP, ChIP for promoter binding, circANAPC7/miR-373 RNA interaction assays with in vivo tumor models","pmids":["35354796","38199981","35414774","35654777","35176309"],"confidence":"High","gaps":["Hierarchy and dominance among the many regulators in a given tissue unclear","Whether transcriptional and degradative controls act redundantly or sequentially unknown"]},{"year":2023,"claim":"Added RNF149 and viral V-protein-driven degradation of PHLPP2, showing diverse pathologic stimuli converge on PHLPP2 destabilization to activate PI3K/AKT.","evidence":"Co-IP and E3-ligase-dependent ubiquitination (RNF149) with cisplatin-resistance assays; NDV V-protein co-IP, IF, and MG132 rescue with apoptosis readouts","pmids":["37658961","38128444"],"confidence":"Medium","gaps":["Ubiquitination site specificity not mapped","Single-lab, model-restricted findings"]},{"year":2024,"claim":"Added MARCH1 as a further E3 ligase degrading PHLPP2 in oral cancer, consolidating ubiquitin-mediated turnover as a recurrent oncogenic mechanism.","evidence":"Co-IP, ubiquitination assay, MARCH1 knockdown/overexpression with xenograft","pmids":["35122633"],"confidence":"Medium","gaps":["Degradation site and linkage type not defined","Single lab"]},{"year":2025,"claim":"Reframed PHLPP2 as a catalytically dead pseudophosphatase, fundamentally challenging the long-standing direct-phosphatase model and implying its functions arise from substrate binding and membrane scaffolding; concurrently mapped FBXO32 and lysosomal (ATP6V0D2/V-ATPase) routes of PHLPP2 destruction.","evidence":"In vitro phosphatase assays with zinc characterization and phylogenomic coevolution analyses (pseudophosphatase); proteomics/co-IP with site-specific K592/K942 ubiquitination (FBXO32) and bafilomycin A1 rescue (ATP6V0D2)","pmids":["40168118","41000374","41312388"],"confidence":"High","gaps":["The retained substrate-binding/scaffolding partners under physiological conditions not directly demonstrated","Reconciliation of pseudophosphatase model with prior cell-based dephosphorylation data unresolved","Whether any residual or conditional catalysis exists in vivo unknown"]},{"year":null,"claim":"How a catalytically inactive PHLPP2 produces the dephosphorylation events attributed to it across so many substrates—and which scaffold/adaptor interactions reconstitute that function biochemically—remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted system reconciles pseudophosphatase status with observed substrate dephosphorylation","Direct vs. recruited-catalyst mechanism for each substrate undefined","No structural model of PHLPP2 bound to a substrate on membranes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,15,16,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,6,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,17,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,33]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,13,19,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,22,25,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,6,15,28]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]}],"complexes":["β-arrestin 1–PHLPP2–Akt1 complex","FKBP51–PHLPP2–AKT complex","ENH–AKT1–PHLPP2 complex"],"partners":["AKT1","AC6","BCL10","IKKB","GRK5","MST1","AMPK","RAPTOR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZVD8","full_name":"PH domain leucine-rich repeat-containing protein phosphatase 2","aliases":["PH domain leucine-rich repeat-containing protein phosphatase-like","PHLPP-like"],"length_aa":1323,"mass_kda":146.8,"function":"Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on 'Ser-473' of AKT1, 'Ser-660' of PRKCB isoform beta-II and 'Ser-657' of PRKCA. Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and decreases cell proliferation. Also controls the phosphorylation of AKT3. Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis (PubMed:20513427). Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation (PubMed:21986499). Inhibits cancer cell proliferation and may act as a tumor suppressor. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Dephosphorylates RAF1 inhibiting its kinase activity (PubMed:24530606)","subcellular_location":"Cytoplasm; Membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6ZVD8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHLPP2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PHLPP2","total_profiled":1310},"omim":[{"mim_id":"611066","title":"PH DOMAIN AND LEUCINE-RICH REPEAT PROTEIN PHOSPHATASE-LIKE; PHLPPL","url":"https://www.omim.org/entry/611066"},{"mim_id":"609396","title":"PH DOMAIN AND LEUCINE-RICH REPEAT PROTEIN PHOSPHATASE 1; PHLPP1","url":"https://www.omim.org/entry/609396"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytokinetic bridge","reliability":"Supported"},{"location":"Mitotic spindle","reliability":"Supported"},{"location":"Primary cilium","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":20.7},{"tissue":"retina","ntpm":29.8}],"url":"https://www.proteinatlas.org/search/PHLPP2"},"hgnc":{"alias_symbol":["KIAA0931","PPM3B"],"prev_symbol":["PHLPPL"]},"alphafold":{"accession":"Q6ZVD8","domains":[{"cath_id":"3.10.20.90","chopping":"19-39_60-139","consensus_level":"high","plddt":88.6902,"start":19,"end":139},{"cath_id":"2.30.29.30","chopping":"146-251","consensus_level":"high","plddt":84.6481,"start":146,"end":251},{"cath_id":"-","chopping":"274-312","consensus_level":"medium","plddt":87.2946,"start":274,"end":312},{"cath_id":"3.80.10.10","chopping":"329-394","consensus_level":"medium","plddt":95.0977,"start":329,"end":394},{"cath_id":"3.80.10.10","chopping":"396-537","consensus_level":"medium","plddt":94.4596,"start":396,"end":537},{"cath_id":"3.60.40.10","chopping":"785-1034","consensus_level":"high","plddt":92.0307,"start":785,"end":1034}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZVD8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZVD8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZVD8-F1-predicted_aligned_error_v6.png","plddt_mean":74.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHLPP2","jax_strain_url":"https://www.jax.org/strain/search?query=PHLPP2"},"sequence":{"accession":"Q6ZVD8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZVD8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZVD8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZVD8"}},"corpus_meta":[{"pmid":"17386267","id":"PMC_17386267","title":"PHLPP 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progression.\",\n      \"method\": \"siRNA knockdown, in-cell phosphorylation assays, isoform-specific substrate readouts (p27, HDM2, GSK-3α)\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown studies with multiple isoform-specific substrates, replicated across conditions, founding paper with orthogonal readouts\",\n      \"pmids\": [\"17386267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A naturally occurring L1016S polymorphism in the phosphatase domain of PHLPP2 reduces its catalytic activity toward both Akt and PKC in vitro and in cells, resulting in elevated Akt phosphorylation and reduced apoptosis; depletion of the Ser-1016 variant in breast cancer cells confirmed reduced function toward Akt and PKC.\",\n      \"method\": \"In vitro phosphatase assay with polymorphic variants, siRNA depletion of endogenous PHLPP2 variants in breast cancer cells, pair-matched tumor/normal samples\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase assay plus cell-based validation with natural variant and allele retention in tumors, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19324870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In neonatal rat cardiac myocytes, adenylyl cyclase type 6 (AC6) physically associates with PHLPP2 and inhibits its activity under basal conditions, preventing Akt dephosphorylation; however, isoproterenol or forskolin stimulation acutely activates PHLPP2 in a cAMP-independent manner requiring an intact cytoplasmic domain of AC6, leading to rapid Akt dephosphorylation at Ser473.\",\n      \"method\": \"Co-immunoprecipitation, PHLPP2 phosphatase activity assays, AC6 cytoplasmic-domain mutants, isoproterenol/forskolin stimulation in primary cardiomyocytes\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional phosphatase activity assay with domain-mutant controls, single lab\",\n      \"pmids\": [\"19450723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In the retina, both PHLPP (PHLPP1) and PHLPPL (PHLPP2) phosphatase activities are significantly decreased in the presence of insulin ex vivo, and this inhibition is PI3K-dependent (reversed by LY294002), demonstrating that the IR-activated PI3K/Akt pathway negatively feeds back to regulate PHLPP2 activity.\",\n      \"method\": \"Ex vivo retinal culture phosphatase activity assays, PI3K inhibitor (LY294002) pre-treatment, insulin stimulation\",\n      \"journal\": \"Journal of Neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic activity measurement in ex vivo tissue with pharmacological inhibitor controls, single lab\",\n      \"pmids\": [\"20089132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DGKδ deficiency leads to excessive PKCα activity, which promotes PHLPP2-mediated dephosphorylation of Akt; β-arrestin 1 acts as a scaffold bringing PHLPP2 and Akt1 together, conferring specificity for Akt dephosphorylation. Depletion of PHLPP2 (but not PHLPP1) rescues Akt phosphorylation in DGKδ-deficient cells.\",\n      \"method\": \"siRNA knockdown of DGKδ, PKCα, PHLPP2, PHLPP1; co-immunoprecipitation of β-arrestin 1 with PHLPP2 and Akt1; Akt phosphorylation assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal knockdowns with isoform specificity (PHLPP2 vs PHLPP1), scaffolding interaction via co-IP, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"23184957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PHLPP2 interacts with IKKβ kinase and decreases IKKβ phosphorylation, thereby suppressing NF-κB activation; mechanistically, PHLPP2 competes with MALT1 for binding to Bcl10, preventing Bcl10-MALT1 complex formation, NEMO ubiquitination, and downstream IKKβ phosphorylation. PHLPP2 loss enhances these interactions and increases NF-κB-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation of PHLPP2 with IKKβ and Bcl10, competitive displacement assays, NF-κB reporter assays, PHLPP2 knockdown/overexpression\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with multiple binding partners, competitive displacement, functional reporter assay, single lab\",\n      \"pmids\": [\"24553260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In a rat cerebral ischemia/reperfusion model, FKBP51, PHLPP2, and AKT assemble into a trimeric signaling complex; I/R injury enhances interactions among these components, leading to Akt dephosphorylation and neuronal death. Antisense oligonucleotide inhibition of PHLPP2 disrupts complex assembly, reverses p-AKT decrease, and reduces caspase-3 cleavage and CA1 neuron loss.\",\n      \"method\": \"Co-immunoprecipitation in vivo rat I/R model, antisense oligonucleotide knockdown of PHLPP2, western blot for p-AKT, caspase-3, histological neuron counts\",\n      \"journal\": \"Brain Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo co-IP of trimeric complex, antisense knockdown with functional cellular outcome, single lab\",\n      \"pmids\": [\"24746496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYC strongly activates PHLPP2 transcription in primary prostate cells and prostate cancer metastasis; in Pten/Trp53 mutant cells, IL6-driven STAT3 activation induces MYC which upregulates PHLPP2, suppressing AKT. Genetic loss of Phlpp2 in the RapidCaP mouse model is essential for dictating the proliferation driven by MYC-mediated AKT suppression.\",\n      \"method\": \"Genetic mouse models (RapidCaP), Phlpp2 loss-of-function, IL6/STAT3/MYC pathway dissection, cell proliferation assays, tissue analysis\",\n      \"journal\": \"Cancer Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetically engineered mouse model with epistasis, pathway dissection, single lab\",\n      \"pmids\": [\"25829425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-205 induction following B[a]P/B[a]PDE exposure inhibits PHLPP2 protein translation by targeting PHLPP2-3'-UTR; reduced PHLPP2 contributes to lung inflammation and carcinogenesis. PHLPP2 ectopic expression represses inflammatory TNFα transcription, providing an antitumorigenic mechanism.\",\n      \"method\": \"Luciferase reporter assay for 3'-UTR targeting, ectopic PHLPP2 expression in cell transformation models, B[a]P mouse lung cancer model, TNFα transcription assays\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'-UTR reporter, in vitro transformation model and in vivo mouse model, functional rescue with PHLPP2 overexpression\",\n      \"pmids\": [\"25977341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"p27 stabilizes PHLPP2 protein by inhibiting Hsp90 degradation; Hsp90 directly binds PHLPP2 and protects it from degradation. p27 stabilizes Hsp90 by inhibiting calpain1 gene transcription through attenuation of the Jak1/Stat1 cascade. PHLPP2 in turn inhibits bladder cancer invasion by promoting MMP2 degradation via p62-mediated autophagy.\",\n      \"method\": \"Co-immunoprecipitation of Hsp90-PHLPP2, calpain1 transcription assays, Jak1/Stat1 pathway inhibition, autophagy flux assays, invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of Hsp90-PHLPP2, pathway dissection with multiple readouts, single lab\",\n      \"pmids\": [\"29930380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pull-down assay with morin-conjugated beads demonstrated direct binding of morin to PHLPP2 protein; molecular docking revealed morin occupies the active site of PHLPP2, and morin treatment inhibits PHLPP2 activity and its association with Akt1, thereby preventing oxidant-induced Nrf2 suppression via the Akt/GSK3β/Fyn kinase axis.\",\n      \"method\": \"Morin-conjugated bead pull-down assay, molecular docking, PHLPP2 activity assay (ex vivo), Akt/GSK3β/Fyn pathway western blotting\",\n      \"journal\": \"Redox Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by affinity pull-down and molecular docking, functional phosphatase activity assay, single lab\",\n      \"pmids\": [\"26513344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Free (mTORC1-independent) Raptor stabilizes PHLPP2 protein by reducing β-TrCP-mediated proteasomal degradation of PHLPP2; this leads to suppression of hepatic Akt activity and lipogenesis. Forced PHLPP2 expression in diet-induced obese mice ameliorates hepatic steatosis.\",\n      \"method\": \"Raptor overexpression/knockdown, β-TrCP interaction studies, PHLPP2 protein stability assays, liver-specific mouse models, triglyceride measurements\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection of Raptor-β-TrCP-PHLPP2 degradation pathway with multiple orthogonal approaches and in vivo validation in obese mice\",\n      \"pmids\": [\"26743335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In AML cells, microRNAs from the miR-17-92 cluster (oncomir-1) target PHLPP2 mRNA and suppress PHLPP2 protein expression; ATRA treatment suppresses miR-17-92 expression and increases PHLPP2 protein and phosphatase activity. This regulation is mediated by transcription factor C/EBPβ, which binds the intronic promoter of the miR-17-92 gene to inhibit its transactivation.\",\n      \"method\": \"miRNA overexpression/knockdown, PHLPP2 phosphatase activity assay, chromatin immunoprecipitation (C/EBPβ on miR-17-92 promoter), ATRA treatment, western blotting\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct phosphatase activity assay, ChIP for transcriptional regulation, miRNA functional studies with multiple orthogonal methods\",\n      \"pmids\": [\"26868909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In obese mice, glucagon/PKA-dependent phosphorylation of PHLPP2 at Ser1119 and Ser1210 promotes PHLPP2 binding to KCTD17 (a substrate-adaptor for Cul3-RING ubiquitin ligases), leading to PHLPP2 ubiquitin-mediated proteasomal degradation. Loss of PHLPP2 prolongs insulin action and increases lipogenic gene expression, causing hepatic steatosis.\",\n      \"method\": \"Mass spectrometry identification of PHLPP2 phosphorylation sites and interactors, KCTD17 co-IP/binding assay, KCTD17 shRNA knockdown in primary hepatocytes and obese mice, CRISPR/Cas9 PHLPP2-knockout hepatoma cells, liver-specific PHLPP2-knockout mice\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mass spectrometry identification of phosphorylation sites, in vivo genetic models, co-IP binding, multiple orthogonal methods, replicated in multiple model systems\",\n      \"pmids\": [\"28859855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHLPP2 physically interacts with GRK5 in neonatal rat ventricular myocytes (NRVMs); PHLPP2 overexpression (in a phosphatase-activity-dependent manner) blocks phenylephrine-induced nuclear accumulation of GRK5 and hypertrophic gene re-expression. Knockdown of PHLPP2 potentiates GRK5-dependent hypertrophic growth, and GRK5 is required for the hypertrophic response induced by PHLPP2 knockdown.\",\n      \"method\": \"Co-immunoprecipitation of PHLPP2 and GRK5, siRNA knockdown, PHLPP2 overexpression with phosphatase-dead mutant controls, cell size measurements, fetal gene expression (ANF, BNP), PE stimulation\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, phosphatase-dead mutant controls, genetic epistasis via double knockdown, single lab\",\n      \"pmids\": [\"29628444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHLPP2 interacts with and dephosphorylates MST1 (Mst1) in berberine-treated hepatoma cells; elevated PHLPP2 inactivates Akt by dephosphorylating Ser473, which releases Akt-mediated repression of Mst1, leading to heightened Mst1 phosphorylation at Thr183 and downstream JNK/Bim/Bak pro-apoptotic signaling. PHLPP2 and Mst1 form an autoinhibitory triangle with Akt.\",\n      \"method\": \"Co-immunoprecipitation of PHLPP2-Mst1, western blot for Akt(Ser473) and Mst1(Thr183), PHLPP2/Mst1 knockdown, berberine treatment in HepG2 cells\",\n      \"journal\": \"Toxicology and Applied Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating PHLPP2-Mst1 interaction, knockdown rescue experiments, single lab\",\n      \"pmids\": [\"29626488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHLPP2 dephosphorylates threonine-58 (T58) of MYC, a phosphorylation site linked to MYC degradation; this renders PHLPP2 a limiting positive regulator of MYC stability. In the RapidCaP mouse model, complete loss of Phlpp2 paradoxically blocks tumor growth by destabilizing MYC. Small-molecule PHLPP2 inhibitors suppress MYC and kill PTEN-mutant cells.\",\n      \"method\": \"RapidCaP genetically engineered mouse model, Phlpp2 knockout, MYC phospho-T58 assays, small-molecule PHLPP2 inhibitor treatment, cell viability assays\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic mouse model with Phlpp2 knockout, direct phosphorylation site (MYC T58) identified, pharmacological validation with small-molecule inhibitors, multiple orthogonal methods\",\n      \"pmids\": [\"31092557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHLPP2 promotes BECN1 (Beclin1) stabilization, thereby promoting BECN1-dependent macroautophagy, which inhibits bladder cancer tumor cell growth. The mechanism involves PHLPP2 indirectly preventing CUL4A-mediated BECN1 protein degradation.\",\n      \"method\": \"PHLPP2 overexpression/knockdown, autophagy flux assays, xenograft tumor growth, CUL4A interaction studies\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional autophagy assays, in vivo xenograft, mechanistic link to CUL4A-BECN1 axis, single lab\",\n      \"pmids\": [\"32116109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hepatic exosome-derived miR-130a-3p directly targets PHLPP2 mRNA and suppresses its expression in adipocytes, thereby activating AKT-AS160-GLUT4 signaling to improve glucose uptake and attenuate glucose intolerance in high-fat diet mice.\",\n      \"method\": \"miR-130a-3p knockout and overexpression mice, hepatic exosome injection, 3T3-L1 cell transfection, luciferase 3'-UTR reporter for PHLPP2, PHLPP2 siRNA, AKT/AS160/GLUT4 western blotting\",\n      \"journal\": \"Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic models, 3'-UTR reporter validation, functional rescue with PHLPP2 siRNA, single lab\",\n      \"pmids\": [\"31715176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHLPP2 dephosphorylates and inactivates AMPK (pAMPK); the PH domain of PHLPP2 is required for its interaction with pAMPK, for dephosphorylating and inactivating AMPK, and for the apoptotic response to glucose limitation in leukemia cells. PHLPP2 silencing prolongs leukemia cell survival under glucose limitation by promoting AMPK-mediated fatty acid oxidation.\",\n      \"method\": \"Co-immunoprecipitation of PHLPP2-AMPK, PH domain deletion mutants, PHLPP2 siRNA knockdown, metabolic stress (glucose limitation), cell survival/apoptosis assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating direct interaction, domain deletion mapping (PH domain required), functional metabolic assays, identification of novel substrate AMPK\",\n      \"pmids\": [\"34608126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In adipocytes, PHLPP2 dephosphorylates Akt (Ser473); adipocyte-specific PHLPP2 knockout increases HSL phosphorylation, leading to enhanced lipolysis and increased PPARα-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to prevent obesity-induced fatty liver.\",\n      \"method\": \"Adipocyte-specific PHLPP2 knockout mice (A-PHLPP2), high-fat diet feeding, HSL phosphorylation assays, in vitro and in vivo lipolysis assays, adiponectin secretion measurement, hepatic FAO assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout mouse model, multiple orthogonal metabolic readouts, in vitro and in vivo validation, identifies PHLPP2-HSL-PPARα-adiponectin axis\",\n      \"pmids\": [\"33758172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"mettl3 knockout/knockdown increases PHLPP2 expression and reduces AKT phosphorylation (S473) with decreased mTOR phosphorylation (S2481), demonstrating that m6A RNA methylation by METTL3 regulates PHLPP2 levels to control vascular development via PHLPP2/mTOR-AKT signaling.\",\n      \"method\": \"CRISPR-Cas9 mettl3 knockout zebrafish, morpholino knockdown, constitutively active AKT1 rescue, METTL3 knockdown in human endothelial cells, PHLPP2/AKT/mTOR western blotting\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout and morpholino in two systems, AKT rescue, western blot mechanistic readouts, single lab\",\n      \"pmids\": [\"33788967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM46 acts as an E3 ubiquitin ligase that directly ubiquitinates PHLPP2 and promotes its proteasomal degradation; this requires the RING domain E3 ligase activity of TRIM46. PHLPP2 degradation activates AKT/HK2 signaling, driving glycolysis and chemoresistance in lung adenocarcinoma. PHLPP2 overexpression reverses these effects.\",\n      \"method\": \"TRIM46 wild-type vs. RING-mutant overexpression, ubiquitination assays, PHLPP2 protein level measurement, co-immunoprecipitation, glycolysis assays, PDX mouse model, cisplatin resistance assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — E3 ligase-dependent ubiquitination assay, RING-mutant controls, co-IP, in vivo PDX model, multiple orthogonal methods\",\n      \"pmids\": [\"35354796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circANAPC7 acts as a sponge for miR-373, preventing miR-373-mediated suppression of PHLPP2; PHLPP2 then dephosphorylates AKT, suppresses cyclin D1, and inhibits TGF-β secretion via STAT5. Additionally, PHLPP2 induces dephosphorylation of CREB, forming a CREB-miR-373-PHLPP2 feed-forward loop.\",\n      \"method\": \"Biotinylated miRNA pulldown, RNA immunoprecipitation, luciferase reporter assays, PHLPP2 western blot, AKT phosphorylation, 3D organoids, mouse models\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA interaction assays, pathway western blots, in vitro and in vivo models, single lab\",\n      \"pmids\": [\"35176309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM22, whose expression is transcriptionally upregulated by p53 during IR-induced senescence, directly associates (via its SPRY domain) with the C-terminal domain of PHLPP2 at IKKβ-mediated phosphorylation sites; TRIM22-mediated ubiquitination and proteasomal degradation of PHLPP2 activates AKT-p53-p21 signaling, causing cellular senescence in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation (TRIM22 SPRY domain with PHLPP2 C-terminal domain), ubiquitination assay, TRIM22 overexpression/knockdown, p-AKT/p53/p21 western blot, senescence assays (SA-β-gal), IR treatment\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping co-IP, ubiquitination assay, functional senescence readouts, IKKβ phosphorylation site identification, multiple orthogonal methods\",\n      \"pmids\": [\"38199981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mutant p53 (hotspot mutations) directly binds to the PHLPP2 promoter and transcriptionally inhibits PHLPP2 expression, releasing AKT from PHLPP2-mediated suppression; activated AKT then promotes tumor proliferation/metastasis and via 4EBP1/eIF4E enhances PD-L1 translation, facilitating immune escape.\",\n      \"method\": \"Chromatin immunoprecipitation (mutant p53 on PHLPP2 promoter), PHLPP2 expression analysis in mutant p53 colorectal cancer samples, AKT pathway western blotting, PD-L1 expression assays\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, cell line and patient sample validation, downstream pathway readouts, single lab\",\n      \"pmids\": [\"35414774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SNAI2 binds to the PHLPP2 promoter region (as detected by chromatin immunoprecipitation) and transcriptionally represses PHLPP2, activating the Akt pathway and promoting glioma stem cell proliferation.\",\n      \"method\": \"Chromatin immunoprecipitation, RT-qPCR, SNAI2/PHLPP2 overexpression and knockdown, Akt phosphorylation assays, GSC proliferation/apoptosis assays, nude mouse xenografts\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, functional rescue experiments, in vivo xenograft, single lab\",\n      \"pmids\": [\"35654777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The E3 ubiquitin ligase RNF149 physically interacts with PHLPP2 and promotes its E3 ligase-dependent proteasomal degradation, activating PI3K/AKT signaling and conferring cisplatin resistance in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation of RNF149-PHLPP2, ubiquitination assay, RNF149 overexpression/knockdown, PHLPP2 protein stability assays, AKT pathway western blotting, cisplatin resistance assays in vitro and in vivo\",\n      \"journal\": \"Medical Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, E3-ligase-dependent ubiquitination demonstrated, functional rescue, single lab\",\n      \"pmids\": [\"37658961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Newcastle disease virus (NDV) V protein directly interacts with PHLPP2 (co-IP and indirect immunofluorescence) and targets PHLPP2 for ubiquitin-proteasome degradation (inhibited by MG132), thereby activating PI3K/AKT signaling, inhibiting cell apoptosis, and promoting viral replication.\",\n      \"method\": \"Co-immunoprecipitation (NDV V protein with PHLPP2), indirect immunofluorescence, MG132 proteasome inhibition, flow cytometry apoptosis assay, caspase-3 activity assay\",\n      \"journal\": \"Veterinary Microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and indirect IF demonstrate V protein-PHLPP2 interaction, proteasome inhibitor rescue, functional apoptosis readouts, single lab\",\n      \"pmids\": [\"38128444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The E3 ubiquitin ligase MARCH1 physically interacts with PHLPP2 (by co-immunoprecipitation) and promotes PHLPP2 ubiquitination and degradation in oral squamous cell carcinoma, thereby activating AKT signaling and promoting tumor cell proliferation and suppressing apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, MARCH1 knockdown/overexpression, PHLPP2 protein levels, in vivo xenograft\",\n      \"journal\": \"Clinical & Translational Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay, in vivo xenograft, functional rescue, single lab\",\n      \"pmids\": [\"35122633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PHLPP2 is a pseudophosphatase that lost catalytic activity in the metazoan ancestor; it contains a single zinc ion in its catalytic center and has no detectable phosphatase activity in vitro. Despite loss of catalytic activity, surface conservation suggests PHLPP2 may have retained substrate-binding capacity and likely functions as a scaffold on membranes, as supported by phylogenomic coevolution analyses.\",\n      \"method\": \"In vitro phosphatase activity assays, metalloprotein analysis (zinc binding), crystal/structural analysis implied, phylogenetic and phylogenomic analyses, cancer genomics analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical phosphatase activity assays with metal ion characterization, phylogenetic analyses, directly challenges prior model, single study with multiple orthogonal approaches\",\n      \"pmids\": [\"40168118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO32 (F-box protein) interacts with PHLPP2 and promotes K48-linked polyubiquitination of PHLPP2 at K592 and K942 sites, leading to PHLPP2 proteasomal degradation and activation of the PI3K-AKT pathway in hepatocellular carcinoma.\",\n      \"method\": \"Proteomics-based interactome, co-immunoprecipitation, ubiquitination assays identifying K48-linked polyubiquitination at K592/K942, FBXO32 overexpression/knockdown, orthotopic HCC mouse model, HCC patient-derived organoids\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified interaction confirmed by co-IP, site-specific ubiquitination mapping, in vivo orthotopic model, single lab\",\n      \"pmids\": [\"41000374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATP6V0D2 enhances lysosomal function to promote lysosomal degradation of PHLPP2, thereby sustaining AKT phosphorylation in triple-negative breast cancer; pharmacological inhibition of V-ATPase with bafilomycin A1 blocks PHLPP2 lysosomal degradation, restores PHLPP2 levels, and sensitizes TNBC cells to cisplatin.\",\n      \"method\": \"ATP6V0D2 knockdown, bafilomycin A1 (V-ATPase inhibitor) treatment, PHLPP2 protein stability assays, AKT phosphorylation western blot, in vitro and in vivo cisplatin sensitivity assays, patient-derived organoids\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pharmacological rescue with V-ATPase inhibitor, in vitro and in vivo functional assays, patient-derived organoids, single lab\",\n      \"pmids\": [\"41312388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ENH (Enigma Homolog Protein) forms a scaffold complex with AKT1 and PHLPP2 in arterial endothelial cells; this complex facilitates PHLPP2-mediated dephosphorylation of AKT1 and eNOS, reducing nitric oxide production. Endothelium-specific knockout of either ENH or PHLPP2 in mice reduces ligation-induced neointima formation.\",\n      \"method\": \"Co-immunoprecipitation of ENH-AKT1-PHLPP2 complex, endothelium-specific ENH knockout and PHLPP2 knockout mice, carotid artery ligation model, AKT/eNOS phosphorylation assays, nitric oxide measurement\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — trimeric complex co-IP, tissue-specific knockout mouse models for both ENH and PHLPP2, in vivo neointima readout, multiple orthogonal methods\",\n      \"pmids\": [\"32268790\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHLPP2 is a member of the metal-dependent protein phosphatase family that dephosphorylates Akt (primarily Akt3, at the hydrophobic motif Ser473) and other AGC kinases (PKC, GRK5), as well as non-AGC substrates including MST1, AMPK, and MYC-T58, thereby broadly suppressing pro-survival and pro-growth signaling; however, a 2025 biochemical study found PHLPP2 has no detectable catalytic phosphatase activity in vitro (containing only a single zinc ion and acting as a pseudophosphatase), suggesting its roles may depend on substrate binding and scaffolding rather than direct catalysis. Its protein stability is regulated by multiple E3 ubiquitin ligases (TRIM46, TRIM22, MARCH1, KCTD17/Cul3, RNF149, FBXO32) that target it for proteasomal or lysosomal degradation downstream of diverse signals (glucagon/PKA phosphorylation, IKKβ phosphorylation, viral V proteins), while free Raptor stabilizes it by antagonizing β-TrCP-mediated degradation; PHLPP2 transcription is repressed by mutant p53 and SNAI2 at its promoter and is post-transcriptionally suppressed by numerous oncomiRs (miR-205, miR-141, miR-224, miR-181a/d, miR-135a, miR-372, miR-32, miR-760 and others) that target its 3'-UTR. Beyond Akt, PHLPP2 suppresses NF-κB signaling by binding Bcl10 and blocking Bcl10-MALT1 complex formation, promotes BECN1-dependent autophagy, regulates MYC stability (T58 dephosphorylation), and controls energy metabolism via AMPK dephosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHLPP2 is a negative regulator of the PI3K/Akt pro-survival pathway, originally defined as a phosphatase that dephosphorylates the Akt hydrophobic motif (Ser473), preferentially acting on Akt3 to control downstream effectors such as p27 and thereby restraining cell survival and cell-cycle progression [#0]. Substrate specificity is conferred by scaffolds that assemble PHLPP2 with its targets: \\u03b2-arrestin 1 brings PHLPP2 and Akt1 together [#4], FKBP51 nucleates a PHLPP2\\u2013Akt trimeric complex driving Akt dephosphorylation and neuronal death in ischemia/reperfusion [#6], and ENH organizes a PHLPP2\\u2013AKT1 complex that dephosphorylates AKT1 and eNOS in endothelium [#33]. Beyond Akt, PHLPP2 acts on a broader set of signaling proteins\\u2014it dephosphorylates AMPK through its PH domain to govern metabolic stress responses [#19], dephosphorylates MST1 to release pro-apoptotic JNK/Bim signaling [#15], dephosphorylates MYC at Thr58 to stabilize it [#16], and binds GRK5 to limit cardiac hypertrophic gene expression [#14]; it also suppresses NF-\\u03baB by competing with MALT1 for Bcl10 binding [#5] and promotes BECN1-dependent autophagy [#17]. A 2025 biochemical and phylogenetic study redefined PHLPP2 as a pseudophosphatase that lost catalytic activity in the metazoan ancestor, retaining only a single zinc ion and no detectable in vitro phosphatase activity, indicating its functions rest on substrate binding and membrane scaffolding rather than direct catalysis [#30]. PHLPP2 abundance is the principal control point of its activity: it is destabilized by numerous E3 ubiquitin ligases (TRIM46, TRIM22, MARCH1, KCTD17/Cul3, RNF149, FBXO32) downstream of signals including glucagon/PKA phosphorylation and IKK\\u03b2 phosphorylation [#13, #22, #24, #27, #29, #31], degraded via the lysosome through ATP6V0D2/V-ATPase activity [#32], and stabilized by free Raptor antagonizing \\u03b2-TrCP-mediated degradation [#11] and by Hsp90 [#9]; its expression is transcriptionally repressed by mutant p53 and SNAI2 [#25, #26] and post-transcriptionally suppressed by multiple oncomiRs targeting its 3'-UTR [#8, #12, #18, #23]. Through these mechanisms PHLPP2 functions as a context-dependent tumor and metabolic regulator, suppressing Akt-driven growth and lipogenesis in liver and adipose tissue [#11, #13, #20] yet acting as a pro-tumorigenic MYC stabilizer in PTEN-mutant prostate cancer [#16].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established PHLPP2 as an isoform-selective Akt phosphatase, answering how the hydrophobic-motif phosphorylation of Akt is reversed and assigning PHLPP2 to Akt3-specific control of survival/cell-cycle outputs.\",\n      \"evidence\": \"siRNA knockdown with isoform-specific substrate readouts (p27, HDM2, GSK-3\\u03b1) in cells\",\n      \"pmids\": [\"17386267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how PHLPP2 is recruited to specific Akt isoforms\", \"In-cell dephosphorylation does not prove direct catalysis\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A natural L1016S variant linked PHLPP2 phosphatase-domain integrity to Akt/PKC suppression and tumor biology, reinforcing a catalytic model of PHLPP2 function.\",\n      \"evidence\": \"In vitro phosphatase assays with polymorphic variants plus siRNA depletion in breast cancer cells and tumor/normal pairs\",\n      \"pmids\": [\"19324870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"A single-residue activity change is consistent with but does not formally prove direct catalysis\", \"Mechanism of allele retention in tumors not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed PHLPP2 activity is acutely controlled by upstream regulators (AC6) in cardiomyocytes, introducing the idea that PHLPP2 is gated by physical partners rather than constitutively active.\",\n      \"evidence\": \"Co-IP, phosphatase activity assays, and AC6 cytoplasmic-domain mutants in primary cardiomyocytes\",\n      \"pmids\": [\"19450723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cAMP-independent activation mechanism left undefined\", \"Single lab, single tissue context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated negative feedback from PI3K/Akt onto PHLPP2 activity, positioning PHLPP2 within a self-limiting insulin-signaling loop.\",\n      \"evidence\": \"Ex vivo retinal phosphatase activity assays with PI3K inhibitor (LY294002) and insulin stimulation\",\n      \"pmids\": [\"20089132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mediator of PI3K-dependent inhibition not identified\", \"Tissue-specific ex vivo result\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified \\u03b2-arrestin 1 as a scaffold conferring Akt1-isoform specificity, explaining how PHLPP2 substrate choice is spatially dictated.\",\n      \"evidence\": \"Reciprocal siRNA knockdowns (DGK\\u03b4, PKC\\u03b1, PHLPP2, PHLPP1) and co-IP of \\u03b2-arrestin 1 with PHLPP2/Akt1\",\n      \"pmids\": [\"23184957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of scaffolding not resolved\", \"Generality beyond DGK\\u03b4-deficient context untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended PHLPP2 function beyond Akt by showing it suppresses NF-\\u03baB through competing with MALT1 for Bcl10 binding, defining a catalysis-independent scaffolding role.\",\n      \"evidence\": \"Co-IP with IKK\\u03b2 and Bcl10, competitive displacement, and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"24553260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IKK\\u03b2 dephosphorylation is direct vs. via Bcl10-MALT1 blockade unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a FKBP51\\u2013PHLPP2\\u2013Akt trimeric complex as a driver of neuronal death, showing PHLPP2 acts within multiprotein assemblies in vivo.\",\n      \"evidence\": \"In vivo co-IP in rat ischemia/reperfusion, antisense PHLPP2 knockdown, p-AKT/caspase-3/histology readouts\",\n      \"pmids\": [\"24746496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect interactions within the complex not dissected\", \"Single in vivo model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a MYC\\u2013PHLPP2 transcriptional axis that suppresses Akt, establishing context-dependent control of PHLPP2 expression in prostate cancer.\",\n      \"evidence\": \"RapidCaP mouse model with Phlpp2 loss and IL6/STAT3/MYC pathway dissection\",\n      \"pmids\": [\"25829425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MYC binding at the PHLPP2 promoter not shown here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed oncomiR (miR-205) and Hsp90/p27 control of PHLPP2 protein/translation, opening the layer of post-transcriptional and stability regulation that governs PHLPP2 abundance.\",\n      \"evidence\": \"3'-UTR luciferase reporters, Hsp90-PHLPP2 co-IP, autophagy/invasion and TNF\\u03b1 transcription assays in carcinogenesis models\",\n      \"pmids\": [\"25977341\", \"29930380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each layer to net PHLPP2 levels unquantified\", \"Mechanism connecting PHLPP2 to MMP2 autophagic degradation indirect\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the Raptor\\u2013\\u03b2-TrCP stability axis and oncomiR cluster regulation, establishing proteasomal turnover and miRNA suppression as dominant determinants of PHLPP2-controlled Akt activity and hepatic lipogenesis.\",\n      \"evidence\": \"Raptor/\\u03b2-TrCP interaction and stability assays with liver mouse models; miR-17-92/C/EBP\\u03b2 ChIP and phosphatase activity assays in AML\",\n      \"pmids\": [\"26743335\", \"26868909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How free Raptor competes with \\u03b2-TrCP mechanistically not fully resolved\", \"Cross-tissue generality of the stability axis untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified glucagon/PKA-driven phosphorylation (Ser1119/Ser1210) coupling PHLPP2 to KCTD17/Cul3 degradation, linking hormonal signaling to PHLPP2 turnover and hepatic steatosis.\",\n      \"evidence\": \"Mass spectrometry phospho-site/interactor mapping, KCTD17 co-IP, CRISPR-KO hepatoma and liver-specific KO mice\",\n      \"pmids\": [\"28859855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phospho-degron creation is the sole trigger unclear\", \"Other kinases feeding this degron not enumerated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the PHLPP2 substrate/partner repertoire to GRK5 and MST1, connecting PHLPP2 to cardiac hypertrophy control and pro-apoptotic Hippo-axis signaling.\",\n      \"evidence\": \"Co-IP, phosphatase-dead mutant controls and epistasis (GRK5); PHLPP2-MST1 co-IP and knockdown rescue (MST1) in cellular models\",\n      \"pmids\": [\"29628444\", \"29626488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of GRK5 vs. indirect effect not isolated\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established PHLPP2 as a MYC-T58 dephosphorylating MYC stabilizer and a druggable dependency in PTEN-mutant cancer, revealing a pro-tumorigenic role opposite to its Akt-suppressive function.\",\n      \"evidence\": \"RapidCaP Phlpp2 knockout, MYC phospho-T58 assays, small-molecule PHLPP2 inhibitor cell-killing\",\n      \"pmids\": [\"31092557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of Akt-suppressive vs. MYC-stabilizing roles incomplete\", \"Inhibitor target specificity not exhaustively defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated PHLPP2 promotion of BECN1-dependent autophagy and additional oncomiR (miR-130a-3p) control, broadening its tumor-suppressive and metabolic outputs.\",\n      \"evidence\": \"Autophagy flux/CUL4A-BECN1 studies with xenografts; miR-130a-3p KO/overexpression mice, 3'-UTR reporters and AKT-AS160-GLUT4 readouts\",\n      \"pmids\": [\"32116109\", \"31715176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PHLPP2 blocks CUL4A-mediated BECN1 degradation indirect\", \"Single-lab models\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined AMPK as a PH-domain-dependent PHLPP2 target and ENH as a vascular scaffold, integrating PHLPP2 into metabolic-stress survival and endothelial NO signaling.\",\n      \"evidence\": \"Co-IP and PH-domain deletion with glucose-limitation survival assays (AMPK); ENH-AKT1-PHLPP2 co-IP with endothelium-specific knockouts and neointima model (ENH)\",\n      \"pmids\": [\"34608126\", \"32268790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AMPK dephosphorylation vs. complex-mediated effect not fully separated\", \"Tissue-restricted scaffolding contexts\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed adipocyte PHLPP2 governs systemic lipid handling and that m6A methylation (METTL3) controls PHLPP2 levels, embedding PHLPP2 in inter-organ metabolic crosstalk and developmental signaling.\",\n      \"evidence\": \"Adipocyte-specific PHLPP2 knockout mice with lipolysis/adiponectin/hepatic FAO readouts; mettl3 knockout zebrafish/endothelial cells with AKT rescue\",\n      \"pmids\": [\"33758172\", \"33788967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct m6A site on PHLPP2 transcript not mapped in detail\", \"Cross-species generality of vascular phenotype untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped a network of E3 ligases (TRIM46, TRIM22) and transcriptional repressors (mutant p53, SNAI2) plus circRNA/miRNA sponging that converge on PHLPP2 abundance to dictate Akt activation, glycolysis, senescence, and chemoresistance.\",\n      \"evidence\": \"RING-mutant ubiquitination assays, domain-mapping co-IP, ChIP for promoter binding, circANAPC7/miR-373 RNA interaction assays with in vivo tumor models\",\n      \"pmids\": [\"35354796\", \"38199981\", \"35414774\", \"35654777\", \"35176309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy and dominance among the many regulators in a given tissue unclear\", \"Whether transcriptional and degradative controls act redundantly or sequentially unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added RNF149 and viral V-protein-driven degradation of PHLPP2, showing diverse pathologic stimuli converge on PHLPP2 destabilization to activate PI3K/AKT.\",\n      \"evidence\": \"Co-IP and E3-ligase-dependent ubiquitination (RNF149) with cisplatin-resistance assays; NDV V-protein co-IP, IF, and MG132 rescue with apoptosis readouts\",\n      \"pmids\": [\"37658961\", \"38128444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site specificity not mapped\", \"Single-lab, model-restricted findings\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added MARCH1 as a further E3 ligase degrading PHLPP2 in oral cancer, consolidating ubiquitin-mediated turnover as a recurrent oncogenic mechanism.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, MARCH1 knockdown/overexpression with xenograft\",\n      \"pmids\": [\"35122633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation site and linkage type not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reframed PHLPP2 as a catalytically dead pseudophosphatase, fundamentally challenging the long-standing direct-phosphatase model and implying its functions arise from substrate binding and membrane scaffolding; concurrently mapped FBXO32 and lysosomal (ATP6V0D2/V-ATPase) routes of PHLPP2 destruction.\",\n      \"evidence\": \"In vitro phosphatase assays with zinc characterization and phylogenomic coevolution analyses (pseudophosphatase); proteomics/co-IP with site-specific K592/K942 ubiquitination (FBXO32) and bafilomycin A1 rescue (ATP6V0D2)\",\n      \"pmids\": [\"40168118\", \"41000374\", \"41312388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The retained substrate-binding/scaffolding partners under physiological conditions not directly demonstrated\", \"Reconciliation of pseudophosphatase model with prior cell-based dephosphorylation data unresolved\", \"Whether any residual or conditional catalysis exists in vivo unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a catalytically inactive PHLPP2 produces the dephosphorylation events attributed to it across so many substrates\\u2014and which scaffold/adaptor interactions reconstitute that function biochemically\\u2014remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No reconstituted system reconciles pseudophosphatase status with observed substrate dephosphorylation\", \"Direct vs. recruited-catalyst mechanism for each substrate undefined\", \"No structural model of PHLPP2 bound to a substrate on membranes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 15, 16, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 6, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 17, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 33]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 13, 19, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 22, 25, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 6, 15, 28]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"\\u03b2-arrestin 1\\u2013PHLPP2\\u2013Akt1 complex\",\n      \"FKBP51\\u2013PHLPP2\\u2013AKT complex\",\n      \"ENH\\u2013AKT1\\u2013PHLPP2 complex\"\n    ],\n    \"partners\": [\n      \"AKT1\",\n      \"AC6\",\n      \"Bcl10\",\n      \"IKKB\",\n      \"GRK5\",\n      \"MST1\",\n      \"AMPK\",\n      \"Raptor\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}