{"gene":"PHLPP1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2005,"finding":"PHLPP1 (then called PHLPP) directly dephosphorylates Akt at the hydrophobic motif (Ser473 in Akt1), thereby inactivating Akt, triggering apoptosis, and suppressing tumor growth. Cells expressing an S473D Akt construct were resistant to PHLPP-induced apoptosis, confirming the hydrophobic motif is the primary cellular target.","method":"In vitro phosphatase assay, mutagenesis (S473D Akt), overexpression/reintroduction in glioblastoma cell line, xenograft tumor suppression assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro dephosphorylation assay combined with active-site mutagenesis (S473D rescue), cellular overexpression, and in vivo xenograft; foundational paper replicated extensively","pmids":["15808505"],"is_preprint":false},{"year":2007,"finding":"PHLPP1 specifically dephosphorylates Akt2 (hydrophobic motif), while PHLPP2 preferentially targets Akt3; knockdown studies show that PHLPP1 selectively modulates phosphorylation of Akt2 substrates HDM2 and GSK-3α, revealing isoform-selective termination of Akt signaling.","method":"siRNA knockdown of individual PHLPP isoforms, phosphorylation assays of Akt isoform-specific downstream substrates, agonist-evoked Akt phosphorylation measurements","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown with multiple substrate readouts, replicated by independent labs in different cancer contexts","pmids":["17386267"],"is_preprint":false},{"year":2007,"finding":"PHLPP1 and PHLPP2 dephosphorylate the hydrophobic motif of PKC βII, shunting PKC to the detergent-insoluble fraction and effectively terminating its life cycle; deletion mutagenesis shows the PH domain is necessary for effective dephosphorylation of PKC βII, whereas the PDZ-binding motif (required for Akt regulation) is dispensable. Knockdown of PHLPP reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif of PKC α.","method":"Deletion mutagenesis, overexpression, siRNA knockdown, phorbol ester-triggered dephosphorylation assay, detergent-insoluble fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — deletion mutagenesis defining domain requirements combined with functional dephosphorylation assays, single lab but multiple orthogonal methods","pmids":["18162466"],"is_preprint":false},{"year":2009,"finding":"PHLPP1 protein stability is regulated by the SCF(β-TrCP) E3 ubiquitin ligase in a phosphorylation-dependent manner: β-TrCP recognizes a phosphodegron on PHLPP1 that requires sequential phosphorylation by casein kinase I and GSK-3β. Activation of the PI3K/Akt pathway suppresses PHLPP1 degradation by inhibiting GSK-3β activity, creating a negative feedback loop.","method":"β-TrCP overexpression and ΔF-box mutant, siRNA knockdown, ubiquitination assay, kinase inhibitor studies (GSK-3β, casein kinase I), co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss of β-TrCP with ubiquitination assay plus kinase dependency mapping, single lab with multiple orthogonal methods","pmids":["19797085"],"is_preprint":false},{"year":2010,"finding":"PHLPP1 is expressed in the suprachiasmatic nucleus and oscillates in a circadian fashion. PHLPP1-null mice display normal circadian rhythmicity but have drastically impaired capacity to stabilize the circadian period after light-induced resetting, producing large phase shifts, indicating PHLPP1 controls consolidation of circadian periodicity after resetting.","method":"PHLPP1 knockout mice, circadian behavior assay, light-pulse phase-shift experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined circadian phenotype, single lab","pmids":["20080691"],"is_preprint":false},{"year":2010,"finding":"PHLPP1 dephosphorylates Akt at Ser473 in cardiomyocytes; PHLPP-1 localizes to mitochondria, and PHLPP-1 knockdown potentiates LIF-mediated increases in mitochondrial pAkt and mitochondrial hexokinase-II. PHLPP1 KO mice show increased Akt phosphorylation during ischemia/reperfusion and significantly reduced infarct size.","method":"siRNA knockdown in neonatal rat ventricular myocytes, mitochondria/cytosol fractionation, PHLPP1 knockout mice, isolated perfused heart ischemia/reperfusion model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — fractionation localizing PHLPP1 to mitochondria with functional consequence, confirmed in KO mice with infarct size readout; clean KO with multiple orthogonal methods","pmids":["20576936"],"is_preprint":false},{"year":2011,"finding":"PHLPP1 is recruited to the cell membrane by binding the scaffolding protein Scribble; knockdown of Scribble redistributes PHLPP1 from membrane to cytoplasm and increases Akt phosphorylation, whereas Scribble overexpression has the opposite effect. PHLPP1-dependent inhibition of cell proliferation requires formation of a Scribble–PHLPP1–Akt trimeric complex.","method":"Co-immunoprecipitation, siRNA knockdown of Scribble, subcellular fractionation/membrane localization assays, overexpression","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and direct localization experiment tied to functional consequence, single lab","pmids":["21701506"],"is_preprint":false},{"year":2011,"finding":"PHLPP directly dephosphorylates and activates the pro-apoptotic kinase Mst1, thereby promoting apoptosis, in addition to its role in inactivating Akt, PKC, and S6 kinase via hydrophobic motif dephosphorylation.","method":"Phosphatase assay, overexpression, apoptosis assays (referenced in review summarizing prior experimental work)","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reported in a review article summarizing experimental findings; original experiments not directly described in the abstract but cited as established results","pmids":["22340730"],"is_preprint":false},{"year":2011,"finding":"PHLPP1 and PHLPP2 dephosphorylate S6K1 at its hydrophobic motif independently of Akt dephosphorylation; knockdown of PHLPP increases S6K1 phosphorylation, activates the S6K-dependent negative feedback to IRS-1, and increases cap-dependent translation, cell size, and protein content.","method":"PHLPP overexpression and siRNA knockdown, S6K1 phosphorylation assay, translation initiation complex pulldown, cell size/protein content measurements","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean gain/loss-of-function with direct phosphorylation assay for a defined substrate (S6K1) and functional translational readout, single lab with multiple orthogonal approaches","pmids":["21986499"],"is_preprint":false},{"year":2011,"finding":"PHLPP1 requires NHERF1 for membrane localization and growth-suppressive effects; NHERF1 interacts with PHLPP1/PHLPP2 via its PDZ domains and scaffolds heterotrimeric complexes with PTEN. PHLPP1 loss boosts Akt phosphorylation only in PTEN-negative cells.","method":"Co-immunoprecipitation, subcellular localization assays, PHLPP1/PHLPP2 knockdown, glioma patient sample analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating PDZ domain interaction with localization consequence, single lab","pmids":["21804599"],"is_preprint":false},{"year":2011,"finding":"PHLPP1 expression is elevated in regulatory T cells (Tregs) compared to conventional T cells; knockdown of PHLPP1 restores TCR-mediated Akt activation in Tregs. PHLPP1 KO mice show reduced suppressive capacity of Tregs and impaired induced Treg development, identifying PHLPP1 as the molecular basis for reduced Akt activity in Tregs.","method":"PHLPP1 siRNA knockdown in Tregs, PHLPP1 KO mice, Treg suppression assays, Treg differentiation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO mice combined with siRNA knockdown and defined functional Treg phenotype readouts, single lab with multiple orthogonal methods","pmids":["21498666"],"is_preprint":false},{"year":2011,"finding":"The deubiquitinase USP46 stabilizes PHLPP1 and PHLPP2 by directly removing polyubiquitin chains from PHLPP in vitro and in cells; knockdown of USP46 decreases PHLPP stability and increases Akt phosphorylation, whereas increased USP46 expression decreases PHLPP ubiquitination.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown of USP46, ubiquitination assay in cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deubiquitination assay combined with cellular co-IP and reciprocal gain/loss-of-function, single lab with multiple orthogonal methods","pmids":["22391563"],"is_preprint":false},{"year":2011,"finding":"The beta-TrCP1 E3 ligase is mislocalized to the nucleus in glioblastoma cells (versus cytoplasmic in normal brain/astrocytoma), spatially separating it from cytoplasmic PHLPP1 and uncoupling the negative feedback loop whereby active Akt promotes PHLPP1 degradation. Restoring cytosolic β-TrCP1 localization rescues Akt-dependent regulation of PHLPP1 stability.","method":"Subcellular fractionation, immunofluorescence localization, β-TrCP1 re-localization rescue experiment, pharmacological and overexpression studies in glioblastoma vs. astrocytoma cell lines","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional rescue, single lab","pmids":["21454620"],"is_preprint":false},{"year":2012,"finding":"USP1 deubiquitinase stabilizes PHLPP1 by interacting with it (demonstrated by co-immunoprecipitation and GST pull-down); silencing USP1 decreases PHLPP1 half-life and increases Akt phosphorylation in lung cancer cells.","method":"Co-immunoprecipitation, GST pull-down, cycloheximide chase assay, siRNA knockdown of USP1","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — GST pulldown and co-IP with stability assay, single lab, single study","pmids":["22426999"],"is_preprint":false},{"year":2013,"finding":"WDR48 in complex with the deubiquitinase USP12 deubiquitinates PHLPP1, enhancing its protein stability; both WDR48 and USP12 negatively regulate Akt activation. A cancer-associated somatic mutation in WDR48 (L580F) is defective in stabilizing PHLPP1.","method":"Tandem affinity purification, co-immunoprecipitation, in vitro deubiquitination assay, overexpression and knockdown, cancer mutation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — tandem affinity purification of complex plus in vitro deubiquitination assay and cancer mutation validation, single lab with multiple orthogonal methods","pmids":["24145035"],"is_preprint":false},{"year":2013,"finding":"HDAC3 represses PHLPP1 expression by associating with the PHLPP1 promoter at Smad binding elements; conditional deletion of HDAC3 in chondrocytes increases PHLPP1 expression and reduces Akt phosphorylation. TGFβ stimulation releases HDAC3 from the Phlpp1 promoter.","method":"Chromatin immunoprecipitation (ChIP), HDAC3 conditional knockout chondrocytes, HDAC inhibitor treatment, constitutively active Akt rescue","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding with functional Akt/PHLPP1 rescue experiment, single lab","pmids":["23408427"],"is_preprint":false},{"year":2013,"finding":"PHLPP1 interacts with and binds c-Jun protein, and ectopic PHLPP1 expression blocks c-Jun activation and the associated p53 induction and apoptosis. Treatment with Cheliensisin A promotes PHLPP1 protein degradation, releasing c-Jun from PHLPP1-mediated inhibition and allowing c-Jun phosphorylation.","method":"Co-immunoprecipitation, overexpression of PHLPP1, dominant-negative c-Jun (TAM67) rescue, assessment of c-Jun phosphorylation and apoptosis","journal":"Cancer prevention research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP with functional overexpression data, single lab, single study","pmids":["25281487"],"is_preprint":false},{"year":2013,"finding":"Vitamin E (α- and γ-tocopherol) facilitates site-specific dephosphorylation of Akt Ser473 by promoting PH domain-dependent recruitment of both Akt and PHLPP1 to the plasma membrane; binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins.","method":"Membrane recruitment assay, PH domain binding affinity measurement, molecular modeling, structural optimization of tocopherols, xenograft tumor models","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct membrane recruitment assay with PH domain binding measurements and in vivo xenograft validation, single lab with multiple orthogonal methods","pmids":["23512990"],"is_preprint":false},{"year":2014,"finding":"PHLPP1 and PHLPP2 dephosphorylate RAF1 at Ser338, inhibiting its kinase activity in vitro and in colorectal cancer cells. Knockdown of PHLPP1 or PHLPP2 increases the amplitude and duration of RAF-MEK-ERK signaling and promotes epithelial-mesenchymal transition; Apc(Min)/Phlpp1(-/-) mice develop larger and more invasive intestinal tumors.","method":"Co-immunoprecipitation, in vitro dephosphorylation assay of RAF1, siRNA/shRNA knockdown and overexpression, Apc(Min)/Phlpp1(-/-) mouse model, migration/invasion assays","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase/phosphatase assay identifying RAF1 Ser338 as substrate, validated in cells and in vivo with KO mouse; single lab with multiple orthogonal methods","pmids":["24530606"],"is_preprint":false},{"year":2014,"finding":"SRPK1 promotes recruitment of PHLPP1 to Akt; downregulation of SRPK1 impairs PHLPP1 recruitment to Akt resulting in constitutive Akt activation, while SRPK1 overexpression sequesters/squelches PHLPP1 away from Akt, also constitutively activating Akt. Both directions of SRPK1 dysregulation thus impair PHLPP1-mediated Akt dephosphorylation.","method":"Genome-wide phosphoproteomics, co-immunoprecipitation of SRPK1-PHLPP1-Akt, SRPK1 knockout mouse embryonic fibroblasts, cell transformation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus reciprocal co-IP identifying SRPK1-PHLPP1-Akt complex, validated in KO MEFs and transformation assay, single lab with multiple orthogonal methods","pmids":["24703948"],"is_preprint":false},{"year":2015,"finding":"PHLPP1 associates with the lysosomal membrane and counteracts the inhibitory effect of mTORC2 on chaperone-mediated autophagy (CMA). Lysosomal Akt, a target of the mTORC2/PHLPP1 kinase-phosphatase pair, modulates CMA activity by controlling the dynamics of assembly and disassembly of the CMA translocation complex at the lysosomal membrane.","method":"Lysosomal membrane fractionation, co-immunoprecipitation, CMA activity assays, PHLPP1 knockdown/overexpression, translocation complex assembly assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct lysosomal fractionation localizing PHLPP1 with functional CMA activity readout, multiple orthogonal methods, single lab","pmids":["26118642"],"is_preprint":false},{"year":2015,"finding":"Phlpp1 deficiency in chondrocytes enhances phosphorylation of Akt2, PKC, and p70 S6 kinase. Phlpp1 loss diminishes FoxO1 levels leading to increased Fgf18 expression, elevated MEK/ERK activity, and increased chondrocyte metabolic activity. Chemical inhibition of Fgfr-signaling abrogates the elevated ERK1/2 phosphorylation in Phlpp1-null cultures.","method":"Phlpp1 knockout mice, ex vivo chondrocyte cultures, phosphorylation assays for multiple substrates, Phlpp inhibitor treatment, FGFR inhibitor rescue","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined substrate phosphorylation changes and pathway rescue, single lab","pmids":["25953896"],"is_preprint":false},{"year":2018,"finding":"Endogenous PHLPP1 (but not PP2Cα) directly interacts with and dephosphorylates AMPK at Thr172 in myoblasts without affecting its upstream kinase LKB1. ERK1/2 phosphorylates PHLPP1α at Ser932 under ER stress, and this phosphorylation is required for PHLPP1's ability to interact with and dephosphorylate AMPK.","method":"Co-immunoprecipitation of endogenous proteins, in vitro dephosphorylation assay of AMPK, PHLPP1 knockdown mice, ERK1/2 kinase assay, phospho-site mutagenesis of PHLPP1 Ser932","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro dephosphorylation assay for AMPK substrate, endogenous co-IP, mutagenesis of ERK1/2 phospho-site (Ser932), validated in vivo in KD mice; single lab with multiple orthogonal methods","pmids":["29499326"],"is_preprint":false},{"year":2019,"finding":"PHLPP1 provides a proofreading/quality control step during PKC maturation: it opposes PKC phosphorylation at the hydrophobic motif during biosynthesis, targeting aberrantly active species that fail to become autoinhibited for degradation. Cancer-associated hotspot mutations in the PKCβ pseudosubstrate that impair autoinhibition result in dephosphorylated and unstable enzymes, revealing this as a cancer loss-of-function mechanism.","method":"Protein-level analysis across >5,000 patient tumors, overexpression of pseudosubstrate mutants, PKC phosphorylation and stability assays, PHLPP1 manipulation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of PKC maturation checkpoint using mutagenesis and large-scale patient tumor data, single lab with multiple orthogonal approaches","pmids":["30904392"],"is_preprint":false},{"year":2019,"finding":"PHLPP1 dephosphorylates the transcription factor STAT1 on Ser727 to inhibit its activity, reduce its promoter residency, and reduce expression of target genes involved in innate immunity and cytokine signaling. This function requires a bipartite nuclear localization signal in PHLPP1's unique N-terminal extension. PHLPP1 deletion protects mice from lethal LPS challenge and E. coli infection.","method":"PHLPP1 knockout mice, LPS/E. coli infection models, STAT1 phosphorylation assays, chromatin immunoprecipitation (STAT1 promoter occupancy), mutagenesis of nuclear localization signal, macrophage gene expression analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct dephosphorylation of STAT1 Ser727 identified, NLS mutagenesis defining domain requirement, promoter ChIP, and in vivo infection model; multiple orthogonal methods, single lab","pmids":["31408005"],"is_preprint":false},{"year":2019,"finding":"FKBP51 forms a complex with Akt and PHLPP; this interaction is increased in the absence of Pink1. Overexpression of FKBP51 negatively regulates Akt phosphorylation at Ser473, and knockdown of PHLPP in Pink1 KO neurons rescues neuronal death in response to MPP+, suggesting FKBP51 scaffolds PHLPP1 to Akt to promote dephosphorylation.","method":"Co-immunoprecipitation of endogenous FKBP51/Akt/PHLPP from MEFs and brain tissue, shRNA knockdown of PHLPP, adeno-associated virus FKBP51 overexpression in cortical neurons, MPP+ neurotoxin assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP from brain tissue combined with functional neuronal survival assay, single lab","pmids":["30734931"],"is_preprint":false},{"year":2019,"finding":"lncRNA PCAT1 binds directly to FKBP51 and displaces PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP51 and suppresses AKT signaling.","method":"RIP (RNA immunoprecipitation), RNA pull-down, co-immunoprecipitation of PHLPP/FKBP51/IKKα complex, preclinical mouse model of CRPC","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and RNA pull-down demonstrating direct PCAT1-FKBP51 interaction, complex disruption assay, and in vivo validation; single lab","pmids":["30773595"],"is_preprint":false},{"year":2010,"finding":"PHLPP1 splice variant PHLPP1α (but not PHLPP1β/SCOP) inhibits AKT in hippocampal neurons; PHLPP1α can be localized to the nucleus whereas other PHLPP proteins are found only in the cytosolic fraction. PHLPP1α expression increases dramatically in the hippocampus during development.","method":"Subcellular fractionation of hippocampal neurons, direct verification of AKT inhibition by PHLPP1α overexpression, developmental expression analysis","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — fractionation with functional AKT inhibition assay, single lab, single study","pmids":["20819118"],"is_preprint":false},{"year":2014,"finding":"A novel immunomodulatory function of PHLPP1 in macrophages: PHLPP1 suppresses LPS/IFN-γ-induced iNOS expression by dephosphorylating STAT1 Ser727. PHLPP1 reduces IFN-γ-stimulated ERK1/2 phosphorylation (contributing to STAT1 Ser727 inhibition) and suppresses LPS-induced p38-dependent IFN-β feedback that drives STAT1 Tyr701 phosphorylation.","method":"PHLPP1 overexpression and siRNA/shRNA knockdown in RAW264.7 macrophages, iNOS promoter reporter assay, STAT1 phosphorylation analysis, ERK1/2 and p38 inhibitor studies","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway dissection with gain/loss-of-function and kinase inhibitor rescue, single lab","pmids":["24443556"],"is_preprint":false},{"year":2019,"finding":"PHLPP1 interacts with eIF2α (demonstrated by co-immunoprecipitation) and knockdown of PHLPP1 increases eIF2α phosphorylation and expression of downstream autophagy-associated genes (eIF2α/ATF4 axis), promoting chemoresistance in colon cancer cells under ER stress.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression of degradation-resistant PHLPP1 mutant, eIF2α phosphorylation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying eIF2α interaction plus functional phosphorylation readout with gain/loss-of-function, single lab","pmids":["34663797"],"is_preprint":false},{"year":2021,"finding":"PHLPP1/2 are upregulated by sustained mTORC1 hyper-activation in diabetic β-cells; PHLPPs directly dephosphorylate and regulate the activities of β-cell survival kinases AKT and MST1, constituting a regulatory triangle loop controlling β-cell apoptosis. Genetic inhibition of PHLPPs markedly improves β-cell survival in experimental diabetes models and primary human T2D islets.","method":"Genetic inhibition (siRNA/KO) of PHLPP in β-cell lines and primary human islets, mTORC1 manipulation, AKT and MST1 phosphorylation assays, β-cell apoptosis/function assays in vivo and in vitro","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assays in β-cells with defined substrates (AKT, MST1), validated in primary human T2D islets and in vivo models, single lab with multiple orthogonal approaches","pmids":["34348155"],"is_preprint":false},{"year":2022,"finding":"PHLPP1 promotes neutral lipid accumulation in macrophages through AMPK/ChREBP-dependent lipid uptake and fatty acid synthesis pathways; PHLPP1 interacts with and modestly increases ChREBP recruitment to the Fasn promoter. Pharmacological inhibition or CRISPR/Cas9-mediated disruption of PHLPP1 reduces lipid accumulation in high-fat-diet-fed zebrafish.","method":"PHLPP1 overexpression and knockdown in macrophages, RNA-Seq, co-immunoprecipitation of PHLPP1-ChREBP, Fasn promoter ChIP, CRISPR/Cas9 knockout in zebrafish, C. elegans ortholog (phlp-2) deletion","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying ChREBP interaction with ChIP and in vivo zebrafish/C. elegans validation, single lab","pmids":["35141506"],"is_preprint":false},{"year":2007,"finding":"Proteolytic degradation of SCOP (PHLPP1) by calpain in hippocampal neurons is triggered by BDNF, KCl depolarization, or NMDA stimulation. SCOP negatively regulates ERK1/2 MAP kinase and CREB-mediated transcription; its degradation contributes to MAPK activation during memory formation. Transgenic mice overexpressing SCOP in the forebrain were completely blocked for novel object memory.","method":"Calpain inhibitor experiments, Western blot for SCOP in hippocampus after stimulation and after novel object training, transgenic mouse overexpression of SCOP (inducible forebrain), novel object memory assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — calpain-dependent cleavage demonstrated in multiple stimulation paradigms, confirmed in vivo with transgenic mice and behavioral memory assay; single lab but multiple orthogonal methods and in vivo validation","pmids":["17382888"],"is_preprint":false},{"year":2017,"finding":"PHLPP forms a complex with Akt and hexokinase 2 (HK2) in the mitochondrial fraction of colon cancer cells; knockdown of PHLPP enhances Akt-mediated phosphorylation and mitochondrial localization of HK2, increasing glycolytic flux and causing glucose addiction in colon cancer cells.","method":"Co-immunoprecipitation of PHLPP-Akt-HK2 complex from mitochondrial fraction, siRNA knockdown, Seahorse extracellular flux assay, Akt and HK2 inhibitor rescue","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of trimeric complex from mitochondrial fraction with functional metabolic readout, single lab","pmids":["28179998"],"is_preprint":false},{"year":2010,"finding":"PHLPP expression is controlled by mTOR-dependent protein translation: rapamycin treatment or mTOR knockdown decreases PHLPP protein expression; knockdown of TSC2 increases PHLPP expression; rapamycin-mediated downregulation is blocked by a rapamycin-insensitive p70S6K mutant and rescued by 4E-BP1 depletion. This represents a compensatory feedback where mTOR activity upregulates PHLPP to dampen Akt.","method":"Rapamycin treatment, mTOR siRNA knockdown, TSC2 siRNA, rapamycin-insensitive p70S6K mutant, 4E-BP1 siRNA, amino acid/glucose starvation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological perturbations of mTOR pathway converging on PHLPP protein level, single lab","pmids":["21177869"],"is_preprint":false},{"year":2020,"finding":"FKBP51 canonical isoform mediates Akt ubiquitination at Lys63 via its TPR domain, an essential step for Akt activation. PHLPP silencing does not reduce Akt phosphorylation; instead PHLPP overexpression induces Akt phosphorylation by stabilizing the E3 ubiquitin ligase TRAF6 and supporting K63-ubiquitination of Akt.","method":"TPR domain mutant of FKBP51, ubiquitination assay (K63-specific), PHLPP silencing and overexpression, TRAF6 stability assay, FKBP51 interactome profiling from melanoma cells","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — unexpected result (PHLPP overexpression inducing rather than reducing pAkt) demonstrated by single lab; contradicts prevailing model and requires independent replication","pmids":["36781840"],"is_preprint":false}],"current_model":"PHLPP1 is a PP2C-family Ser/Thr phosphatase that terminates pro-survival signaling by directly dephosphorylating the hydrophobic motif of AGC kinases—including Akt isoforms (preferentially Akt2), PKC, and S6K1—as well as activating the pro-apoptotic kinase MST1 and dephosphorylating STAT1 Ser727 to restrain inflammatory transcription; its substrate access is governed by scaffold proteins (Scribble, NHERF1, FKBP51) that recruit it to specific subcellular compartments (plasma membrane, mitochondria, lysosomes, nucleus), while its cellular abundance is regulated by calpain-dependent proteolysis, mTOR-dependent translation, and ubiquitin-proteasome degradation controlled by the SCF(β-TrCP)/CKI/GSK-3β axis opposed by deubiquitinases USP46, USP12/WDR48, and USP1."},"narrative":{"mechanistic_narrative":"PHLPP1 is a PP2C-family Ser/Thr phosphatase that terminates pro-survival and growth signaling by directly dephosphorylating the hydrophobic motif of AGC kinases, beginning with Akt at Ser473 to trigger apoptosis and suppress tumor growth [PMID:15808505]. It exhibits isoform selectivity, preferentially inactivating Akt2 and thereby controlling Akt2-specific substrates HDM2 and GSK-3α [PMID:17386267], and extends the same hydrophobic-motif dephosphorylation logic to PKC (via a PH-domain-dependent mechanism) [PMID:18162466] and to S6K1, where its loss derepresses cap-dependent translation, cell size, and the S6K-IRS1 feedback loop [PMID:21986499]. Beyond AGC kinases, PHLPP1 dephosphorylates RAF1 at Ser338 to restrain RAF-MEK-ERK signaling and intestinal tumorigenesis [PMID:24530606], dephosphorylates AMPK at Thr172 in an ERK-primed manner [PMID:29499326], activates the pro-apoptotic kinase MST1 [PMID:22340730, PMID:34348155], and dephosphorylates STAT1 Ser727 in the nucleus to restrain innate-immune transcription, an activity that requires a bipartite NLS in its N-terminal extension and protects mice from lethal endotoxin and bacterial challenge [PMID:31408005]. PHLPP1 also serves as a quality-control checkpoint during PKC maturation, eliminating aberrantly active, non-autoinhibited PKC species—a mechanism lost through cancer-associated PKC pseudosubstrate mutations [PMID:30904392]. Substrate access is dictated by scaffolds that target PHLPP1 to discrete compartments: Scribble and NHERF1 recruit it to the plasma membrane [PMID:21701506, PMID:21804599], it localizes to mitochondria where it limits Akt-driven hexokinase activity and cardioprotection [PMID:20576936, PMID:28179998], and to the lysosomal membrane where it opposes mTORC2 to control chaperone-mediated autophagy [PMID:26118642]. PHLPP1 abundance is set by a multilayered control system: SCF(β-TrCP)-mediated degradation requiring sequential CKI/GSK-3β phosphorylation, embedded in a PI3K/Akt feedback loop [PMID:19797085], opposing deubiquitinases USP46, USP1, and USP12/WDR48 [PMID:22391563, PMID:22426999, PMID:24145035], mTOR-dependent translation [PMID:21177869], calpain-dependent proteolysis in neurons [PMID:17382888], and HDAC3-mediated transcriptional repression [PMID:23408427]. Through these activities PHLPP1 functions as a tumor suppressor across glioma, colorectal, and prostate cancers, and contributes to physiological control of circadian period consolidation [PMID:20080691], regulatory T-cell function [PMID:21498666], and β-cell survival in diabetes [PMID:34348155].","teleology":[{"year":2005,"claim":"Established that a dedicated phosphatase, not just kinase withdrawal, terminates Akt signaling by removing the hydrophobic-motif phosphate that defines the active kinase.","evidence":"in vitro phosphatase assay, S473D Akt rescue mutagenesis, glioblastoma reintroduction, and xenograft suppression","pmids":["15808505"],"confidence":"High","gaps":["Did not resolve isoform selectivity among Akt1/2/3","Did not define how PHLPP1 is targeted to its substrate in vivo"]},{"year":2007,"claim":"Resolved that PHLPP1 is isoform-selective, preferentially terminating Akt2 and its specific downstream substrates, distinguishing it from PHLPP2.","evidence":"reciprocal siRNA knockdown of PHLPP isoforms with Akt2-specific substrate (HDM2, GSK-3α) readouts","pmids":["17386267"],"confidence":"High","gaps":["Structural basis of isoform preference unresolved","How selectivity is enforced spatially not addressed"]},{"year":2007,"claim":"Extended PHLPP1 substrate scope beyond Akt to PKC and linked its neuronal pool (SCOP) to calpain-controlled MAPK/CREB-dependent memory.","evidence":"PKCβII deletion mutagenesis/dephosphorylation assays and calpain-inhibitor plus transgenic forebrain-overexpression behavioral assays","pmids":["18162466","17382888"],"confidence":"High","gaps":["PH-domain vs PDZ-motif requirements for distinct substrates only partially mapped","Direct neuronal substrate downstream of SCOP not fully defined"]},{"year":2009,"claim":"Defined how PHLPP1 abundance is controlled, identifying a phosphodegron-driven SCF(β-TrCP) degradation pathway embedded in an Akt-GSK-3β negative-feedback loop.","evidence":"β-TrCP ΔF-box mutant, ubiquitination assays, and CKI/GSK-3β kinase-inhibitor dependency mapping","pmids":["19797085"],"confidence":"High","gaps":["In vivo relevance of the feedback loop not tested","Other degradation inputs not yet integrated"]},{"year":2010,"claim":"Identified compartment-specific and physiological roles—mitochondrial Akt control with cardioprotection, mTOR-translational regulation of PHLPP, circadian period consolidation, and a nuclear-capable PHLPP1α splice variant.","evidence":"mitochondrial fractionation plus ischemia/reperfusion in KO mice, mTOR/rapamycin perturbations, circadian phase-shift assays in KO mice, and hippocampal fractionation of PHLPP1α","pmids":["20576936","21177869","20080691","20819118"],"confidence":"High","gaps":["Mechanism of mitochondrial vs nuclear targeting incompletely defined","Circadian molecular substrate not pinpointed"]},{"year":2011,"claim":"Established scaffold-directed spatial control of PHLPP1 and broadened its tumor-suppressive substrate range to S6K1, while linking it to MST1 activation and Treg biology.","evidence":"reciprocal Scribble and NHERF1 co-IP/localization with growth readouts, S6K1 gain/loss-of-function with translational readouts, KO-mouse Treg suppression assays, and review-summarized MST1 phosphatase data","pmids":["21701506","21804599","21986499","21498666","22340730"],"confidence":"High","gaps":["Whether scaffolds act combinatorially is unclear","MST1 activation mechanism described only via review, not primary detail here"]},{"year":2011,"claim":"Showed PHLPP1 stability is positively regulated by deubiquitinases and that mislocalization of β-TrCP can uncouple the degradation feedback loop in cancer.","evidence":"USP46 in vitro deubiquitination and reciprocal knockdown, plus β-TrCP1 nuclear-mislocalization rescue in glioblastoma cells","pmids":["22391563","21454620"],"confidence":"High","gaps":["Hierarchy among competing DUBs not established","Generality of β-TrCP mislocalization across tumor types untested"]},{"year":2012,"claim":"Added USP1 as a further deubiquitinase stabilizing PHLPP1 in lung cancer, reinforcing DUB-mediated control of PHLPP1 half-life.","evidence":"co-IP, GST pull-down, and cycloheximide-chase with USP1 knockdown","pmids":["22426999"],"confidence":"Medium","gaps":["Single study without reciprocal in vivo validation","Relationship to USP46/USP12 redundancy unresolved"]},{"year":2013,"claim":"Identified the USP12/WDR48 complex as a PHLPP1-stabilizing deubiquitinase with a cancer-associated loss-of-function mutation, and revealed transcriptional repression of PHLPP1 by HDAC3.","evidence":"tandem affinity purification and in vitro deubiquitination with the WDR48 L580F mutant, plus HDAC3 ChIP at the PHLPP1 promoter in conditional-KO chondrocytes","pmids":["24145035","23408427"],"confidence":"High","gaps":["Integration of multiple DUBs into a single regulatory logic unresolved","TGFβ/Smad control of PHLPP1 transcription only partially mapped"]},{"year":2013,"claim":"Demonstrated that PH-domain-targeted small molecules (tocopherols) can drive PHLPP1 to the membrane to enforce Akt Ser473 dephosphorylation, and identified a low-confidence c-Jun-binding/apoptotic role.","evidence":"PH-domain binding-affinity and membrane-recruitment assays with xenografts; separate co-IP with PHLPP1 overexpression and dominant-negative c-Jun rescue","pmids":["23512990","25281487"],"confidence":"Medium","gaps":["c-Jun interaction rests on a single low-confidence study lacking reciprocal validation","Pharmacological PH-domain targeting not validated genetically"]},{"year":2014,"claim":"Expanded PHLPP1 to direct RAF-MEK-ERK control via RAF1 Ser338 dephosphorylation, SRPK1-mediated recruitment to Akt, and STAT1 Ser727-dependent macrophage immunomodulation.","evidence":"in vitro RAF1 dephosphorylation with Apc(Min)/Phlpp1-/- mice, phosphoproteomics plus SRPK1-PHLPP1-Akt co-IP in KO MEFs, and macrophage gain/loss-of-function with kinase-inhibitor dissection","pmids":["24530606","24703948","24443556"],"confidence":"High","gaps":["How SRPK1 dosage bidirectionally controls recruitment mechanistically unclear","Crosstalk between RAF1 and Akt branches not integrated"]},{"year":2015,"claim":"Defined a lysosomal PHLPP1 pool that opposes mTORC2 to govern chaperone-mediated autophagy, and connected PHLPP1 loss to FoxO1/FGF18-driven chondrocyte ERK activity.","evidence":"lysosomal fractionation with CMA translocation-complex assays, and KO-chondrocyte multi-substrate phosphorylation with FGFR-inhibitor rescue","pmids":["26118642","25953896"],"confidence":"High","gaps":["Mechanism of lysosomal targeting of PHLPP1 unresolved","Direct vs indirect FoxO1 regulation not separated"]},{"year":2017,"claim":"Showed PHLPP1 restrains glycolytic metabolism through a mitochondrial PHLPP-Akt-HK2 complex, linking the phosphatase to cancer metabolic dependency.","evidence":"mitochondrial co-IP of the trimeric complex with Seahorse flux and inhibitor rescue in colon cancer cells","pmids":["28179998"],"confidence":"Medium","gaps":["Single-lab study without in vivo metabolic validation","Whether PHLPP1 dephosphorylates HK2 directly or acts via Akt unresolved"]},{"year":2018,"claim":"Established AMPK Thr172 as a direct PHLPP1 substrate and showed ERK1/2 phosphorylation of PHLPP1α Ser932 licenses this interaction under ER stress.","evidence":"endogenous co-IP, in vitro AMPK dephosphorylation, Ser932 phospho-site mutagenesis, and validation in knockdown mice","pmids":["29499326"],"confidence":"High","gaps":["Physiological contexts where AMPK regulation dominates over Akt regulation unclear","Structural basis of Ser932-dependent substrate switching unknown"]},{"year":2019,"claim":"Defined PHLPP1 as a PKC maturation proofreader and a nuclear STAT1 Ser727 phosphatase, plus FKBP51/lncRNA-PCAT1-regulated scaffolding to Akt and an eIF2α interaction influencing chemoresistance.","evidence":"PKC pseudosubstrate-mutant stability analysis across >5,000 tumors, STAT1 Ser727 dephosphorylation with NLS mutagenesis and in vivo infection models, FKBP51/Akt/PHLPP brain co-IP with neuronal survival assays, RIP/RNA pull-down showing PCAT1-FKBP51, and eIF2α co-IP","pmids":["30904392","31408005","30734931","30773595","34663797"],"confidence":"High","gaps":["How a single phosphatase coordinates cytoplasmic, mitochondrial, lysosomal and nuclear pools is not integrated","eIF2α regulation rests on a single co-IP-based study"]},{"year":2020,"claim":"Reported a contrarian observation that PHLPP overexpression can increase Akt phosphorylation via TRAF6/K63-ubiquitination, challenging the canonical phosphatase model.","evidence":"FKBP51 TPR-mutant and K63-ubiquitination assays with PHLPP silencing/overexpression in melanoma cells","pmids":["36781840"],"confidence":"Low","gaps":["Contradicts the prevailing model and awaits independent replication","Mechanism by which a phosphatase would stabilize an E3 ligase unexplained"]},{"year":2021,"claim":"Showed PHLPP1/2 form an mTORC1-driven regulatory loop controlling β-cell apoptosis through AKT and MST1, with therapeutic relevance in diabetes.","evidence":"genetic inhibition of PHLPP in β-cell lines and primary human T2D islets with AKT/MST1 phosphorylation and apoptosis readouts in vivo","pmids":["34348155"],"confidence":"High","gaps":["Relative contributions of AKT vs MST1 branches to β-cell death not separated","Translational targeting strategy not defined"]},{"year":2022,"claim":"Linked PHLPP1 to macrophage lipid metabolism via an AMPK/ChREBP-dependent program, with conserved roles across zebrafish and C. elegans.","evidence":"PHLPP1 gain/loss-of-function with RNA-Seq, ChREBP co-IP, Fasn ChIP, and CRISPR/ortholog deletion in vivo","pmids":["35141506"],"confidence":"Medium","gaps":["Whether the lipid phenotype is a direct ChREBP effect or downstream of AMPK dephosphorylation unresolved","Single-lab in vivo models"]},{"year":null,"claim":"How PHLPP1 integrates its many scaffold-defined subcellular pools and competing degradation/stabilization inputs into substrate selection in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of substrate/scaffold recognition","Rules governing which substrate dominates in a given compartment are unknown","Reconciliation of the contrarian Akt-stabilizing report with the canonical phosphatase model is outstanding"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,8,18,22,24,30]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,18,22,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,23,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,9,17]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,33]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[24,27]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,27]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8,18,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,7,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,24,28]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20,29]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[22,31,33]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,23,30]}],"complexes":["Scribble-PHLPP1-Akt complex","NHERF1-PHLPP1-PTEN complex","FKBP51-Akt-PHLPP complex","PHLPP-Akt-HK2 mitochondrial complex"],"partners":["AKT2","SCRIBBLE","NHERF1","FKBP51","SRPK1","USP46","WDR48","BTRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60346","full_name":"PH domain leucine-rich repeat-containing protein phosphatase 1","aliases":["Pleckstrin homology domain-containing family E member 1","PH domain-containing family E member 1","Suprachiasmatic nucleus circadian oscillatory protein","hSCOP"],"length_aa":1717,"mass_kda":184.7,"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 AKT2 and AKT3, 'Ser-660' of PRKCB and 'Ser-657' of PRKCA (PubMed:15808505, PubMed:17386267, PubMed:18162466). Isoform 2 seems to have a major role in regulating Akt signaling in hippocampal neurons (By similarity). 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 suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation (PubMed:18162466). 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 (PubMed:19079341). Dephosphorylates RAF1 inhibiting its kinase activity (PubMed:24530606). May act as a negative regulator of K-Ras signaling in membrane rafts (By similarity). Involved in the hippocampus-dependent long-term memory formation (By similarity). Involved in circadian control by regulating the consolidation of circadian periodicity after resetting (By similarity). Involved in development and function of regulatory T-cells (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60346/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHLPP1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PHLPP1","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":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":31.8}],"url":"https://www.proteinatlas.org/search/PHLPP1"},"hgnc":{"alias_symbol":["KIAA0606","SCOP","PPM3A"],"prev_symbol":["PLEKHE1","PHLPP"]},"alphafold":{"accession":"O60346","domains":[{"cath_id":"3.10.20.90","chopping":"190-249_469-526","consensus_level":"high","plddt":82.7589,"start":190,"end":526},{"cath_id":"2.30.29.30","chopping":"532-639","consensus_level":"high","plddt":80.5832,"start":532,"end":639},{"cath_id":"3.60.40.10","chopping":"1173-1425","consensus_level":"medium","plddt":88.3279,"start":1173,"end":1425}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60346","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60346-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60346-F1-predicted_aligned_error_v6.png","plddt_mean":64.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHLPP1","jax_strain_url":"https://www.jax.org/strain/search?query=PHLPP1"},"sequence":{"accession":"O60346","fasta_url":"https://rest.uniprot.org/uniprotkb/O60346.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60346/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60346"}},"corpus_meta":[{"pmid":"15808505","id":"PMC_15808505","title":"PHLPP: 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Cells expressing an S473D Akt construct were resistant to PHLPP-induced apoptosis, confirming the hydrophobic motif is the primary cellular target.\",\n      \"method\": \"In vitro phosphatase assay, mutagenesis (S473D Akt), overexpression/reintroduction in glioblastoma cell line, xenograft tumor suppression assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro dephosphorylation assay combined with active-site mutagenesis (S473D rescue), cellular overexpression, and in vivo xenograft; foundational paper replicated extensively\",\n      \"pmids\": [\"15808505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PHLPP1 specifically dephosphorylates Akt2 (hydrophobic motif), while PHLPP2 preferentially targets Akt3; knockdown studies show that PHLPP1 selectively modulates phosphorylation of Akt2 substrates HDM2 and GSK-3α, revealing isoform-selective termination of Akt signaling.\",\n      \"method\": \"siRNA knockdown of individual PHLPP isoforms, phosphorylation assays of Akt isoform-specific downstream substrates, agonist-evoked Akt phosphorylation measurements\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown with multiple substrate readouts, replicated by independent labs in different cancer contexts\",\n      \"pmids\": [\"17386267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PHLPP1 and PHLPP2 dephosphorylate the hydrophobic motif of PKC βII, shunting PKC to the detergent-insoluble fraction and effectively terminating its life cycle; deletion mutagenesis shows the PH domain is necessary for effective dephosphorylation of PKC βII, whereas the PDZ-binding motif (required for Akt regulation) is dispensable. Knockdown of PHLPP reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif of PKC α.\",\n      \"method\": \"Deletion mutagenesis, overexpression, siRNA knockdown, phorbol ester-triggered dephosphorylation assay, detergent-insoluble fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — deletion mutagenesis defining domain requirements combined with functional dephosphorylation assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18162466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PHLPP1 protein stability is regulated by the SCF(β-TrCP) E3 ubiquitin ligase in a phosphorylation-dependent manner: β-TrCP recognizes a phosphodegron on PHLPP1 that requires sequential phosphorylation by casein kinase I and GSK-3β. Activation of the PI3K/Akt pathway suppresses PHLPP1 degradation by inhibiting GSK-3β activity, creating a negative feedback loop.\",\n      \"method\": \"β-TrCP overexpression and ΔF-box mutant, siRNA knockdown, ubiquitination assay, kinase inhibitor studies (GSK-3β, casein kinase I), co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss of β-TrCP with ubiquitination assay plus kinase dependency mapping, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19797085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PHLPP1 is expressed in the suprachiasmatic nucleus and oscillates in a circadian fashion. PHLPP1-null mice display normal circadian rhythmicity but have drastically impaired capacity to stabilize the circadian period after light-induced resetting, producing large phase shifts, indicating PHLPP1 controls consolidation of circadian periodicity after resetting.\",\n      \"method\": \"PHLPP1 knockout mice, circadian behavior assay, light-pulse phase-shift experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined circadian phenotype, single lab\",\n      \"pmids\": [\"20080691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PHLPP1 dephosphorylates Akt at Ser473 in cardiomyocytes; PHLPP-1 localizes to mitochondria, and PHLPP-1 knockdown potentiates LIF-mediated increases in mitochondrial pAkt and mitochondrial hexokinase-II. PHLPP1 KO mice show increased Akt phosphorylation during ischemia/reperfusion and significantly reduced infarct size.\",\n      \"method\": \"siRNA knockdown in neonatal rat ventricular myocytes, mitochondria/cytosol fractionation, PHLPP1 knockout mice, isolated perfused heart ischemia/reperfusion model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation localizing PHLPP1 to mitochondria with functional consequence, confirmed in KO mice with infarct size readout; clean KO with multiple orthogonal methods\",\n      \"pmids\": [\"20576936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PHLPP1 is recruited to the cell membrane by binding the scaffolding protein Scribble; knockdown of Scribble redistributes PHLPP1 from membrane to cytoplasm and increases Akt phosphorylation, whereas Scribble overexpression has the opposite effect. PHLPP1-dependent inhibition of cell proliferation requires formation of a Scribble–PHLPP1–Akt trimeric complex.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of Scribble, subcellular fractionation/membrane localization assays, overexpression\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and direct localization experiment tied to functional consequence, single lab\",\n      \"pmids\": [\"21701506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PHLPP directly dephosphorylates and activates the pro-apoptotic kinase Mst1, thereby promoting apoptosis, in addition to its role in inactivating Akt, PKC, and S6 kinase via hydrophobic motif dephosphorylation.\",\n      \"method\": \"Phosphatase assay, overexpression, apoptosis assays (referenced in review summarizing prior experimental work)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reported in a review article summarizing experimental findings; original experiments not directly described in the abstract but cited as established results\",\n      \"pmids\": [\"22340730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PHLPP1 and PHLPP2 dephosphorylate S6K1 at its hydrophobic motif independently of Akt dephosphorylation; knockdown of PHLPP increases S6K1 phosphorylation, activates the S6K-dependent negative feedback to IRS-1, and increases cap-dependent translation, cell size, and protein content.\",\n      \"method\": \"PHLPP overexpression and siRNA knockdown, S6K1 phosphorylation assay, translation initiation complex pulldown, cell size/protein content measurements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain/loss-of-function with direct phosphorylation assay for a defined substrate (S6K1) and functional translational readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"21986499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PHLPP1 requires NHERF1 for membrane localization and growth-suppressive effects; NHERF1 interacts with PHLPP1/PHLPP2 via its PDZ domains and scaffolds heterotrimeric complexes with PTEN. PHLPP1 loss boosts Akt phosphorylation only in PTEN-negative cells.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization assays, PHLPP1/PHLPP2 knockdown, glioma patient sample analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating PDZ domain interaction with localization consequence, single lab\",\n      \"pmids\": [\"21804599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PHLPP1 expression is elevated in regulatory T cells (Tregs) compared to conventional T cells; knockdown of PHLPP1 restores TCR-mediated Akt activation in Tregs. PHLPP1 KO mice show reduced suppressive capacity of Tregs and impaired induced Treg development, identifying PHLPP1 as the molecular basis for reduced Akt activity in Tregs.\",\n      \"method\": \"PHLPP1 siRNA knockdown in Tregs, PHLPP1 KO mice, Treg suppression assays, Treg differentiation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mice combined with siRNA knockdown and defined functional Treg phenotype readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21498666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The deubiquitinase USP46 stabilizes PHLPP1 and PHLPP2 by directly removing polyubiquitin chains from PHLPP in vitro and in cells; knockdown of USP46 decreases PHLPP stability and increases Akt phosphorylation, whereas increased USP46 expression decreases PHLPP ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown of USP46, ubiquitination assay in cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deubiquitination assay combined with cellular co-IP and reciprocal gain/loss-of-function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22391563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The beta-TrCP1 E3 ligase is mislocalized to the nucleus in glioblastoma cells (versus cytoplasmic in normal brain/astrocytoma), spatially separating it from cytoplasmic PHLPP1 and uncoupling the negative feedback loop whereby active Akt promotes PHLPP1 degradation. Restoring cytosolic β-TrCP1 localization rescues Akt-dependent regulation of PHLPP1 stability.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence localization, β-TrCP1 re-localization rescue experiment, pharmacological and overexpression studies in glioblastoma vs. astrocytoma cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional rescue, single lab\",\n      \"pmids\": [\"21454620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USP1 deubiquitinase stabilizes PHLPP1 by interacting with it (demonstrated by co-immunoprecipitation and GST pull-down); silencing USP1 decreases PHLPP1 half-life and increases Akt phosphorylation in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, cycloheximide chase assay, siRNA knockdown of USP1\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — GST pulldown and co-IP with stability assay, single lab, single study\",\n      \"pmids\": [\"22426999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR48 in complex with the deubiquitinase USP12 deubiquitinates PHLPP1, enhancing its protein stability; both WDR48 and USP12 negatively regulate Akt activation. A cancer-associated somatic mutation in WDR48 (L580F) is defective in stabilizing PHLPP1.\",\n      \"method\": \"Tandem affinity purification, co-immunoprecipitation, in vitro deubiquitination assay, overexpression and knockdown, cancer mutation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — tandem affinity purification of complex plus in vitro deubiquitination assay and cancer mutation validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24145035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC3 represses PHLPP1 expression by associating with the PHLPP1 promoter at Smad binding elements; conditional deletion of HDAC3 in chondrocytes increases PHLPP1 expression and reduces Akt phosphorylation. TGFβ stimulation releases HDAC3 from the Phlpp1 promoter.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), HDAC3 conditional knockout chondrocytes, HDAC inhibitor treatment, constitutively active Akt rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding with functional Akt/PHLPP1 rescue experiment, single lab\",\n      \"pmids\": [\"23408427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PHLPP1 interacts with and binds c-Jun protein, and ectopic PHLPP1 expression blocks c-Jun activation and the associated p53 induction and apoptosis. Treatment with Cheliensisin A promotes PHLPP1 protein degradation, releasing c-Jun from PHLPP1-mediated inhibition and allowing c-Jun phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of PHLPP1, dominant-negative c-Jun (TAM67) rescue, assessment of c-Jun phosphorylation and apoptosis\",\n      \"journal\": \"Cancer prevention research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP with functional overexpression data, single lab, single study\",\n      \"pmids\": [\"25281487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vitamin E (α- and γ-tocopherol) facilitates site-specific dephosphorylation of Akt Ser473 by promoting PH domain-dependent recruitment of both Akt and PHLPP1 to the plasma membrane; binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins.\",\n      \"method\": \"Membrane recruitment assay, PH domain binding affinity measurement, molecular modeling, structural optimization of tocopherols, xenograft tumor models\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct membrane recruitment assay with PH domain binding measurements and in vivo xenograft validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23512990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PHLPP1 and PHLPP2 dephosphorylate RAF1 at Ser338, inhibiting its kinase activity in vitro and in colorectal cancer cells. Knockdown of PHLPP1 or PHLPP2 increases the amplitude and duration of RAF-MEK-ERK signaling and promotes epithelial-mesenchymal transition; Apc(Min)/Phlpp1(-/-) mice develop larger and more invasive intestinal tumors.\",\n      \"method\": \"Co-immunoprecipitation, in vitro dephosphorylation assay of RAF1, siRNA/shRNA knockdown and overexpression, Apc(Min)/Phlpp1(-/-) mouse model, migration/invasion assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase/phosphatase assay identifying RAF1 Ser338 as substrate, validated in cells and in vivo with KO mouse; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24530606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRPK1 promotes recruitment of PHLPP1 to Akt; downregulation of SRPK1 impairs PHLPP1 recruitment to Akt resulting in constitutive Akt activation, while SRPK1 overexpression sequesters/squelches PHLPP1 away from Akt, also constitutively activating Akt. Both directions of SRPK1 dysregulation thus impair PHLPP1-mediated Akt dephosphorylation.\",\n      \"method\": \"Genome-wide phosphoproteomics, co-immunoprecipitation of SRPK1-PHLPP1-Akt, SRPK1 knockout mouse embryonic fibroblasts, cell transformation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus reciprocal co-IP identifying SRPK1-PHLPP1-Akt complex, validated in KO MEFs and transformation assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24703948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PHLPP1 associates with the lysosomal membrane and counteracts the inhibitory effect of mTORC2 on chaperone-mediated autophagy (CMA). Lysosomal Akt, a target of the mTORC2/PHLPP1 kinase-phosphatase pair, modulates CMA activity by controlling the dynamics of assembly and disassembly of the CMA translocation complex at the lysosomal membrane.\",\n      \"method\": \"Lysosomal membrane fractionation, co-immunoprecipitation, CMA activity assays, PHLPP1 knockdown/overexpression, translocation complex assembly assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct lysosomal fractionation localizing PHLPP1 with functional CMA activity readout, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26118642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Phlpp1 deficiency in chondrocytes enhances phosphorylation of Akt2, PKC, and p70 S6 kinase. Phlpp1 loss diminishes FoxO1 levels leading to increased Fgf18 expression, elevated MEK/ERK activity, and increased chondrocyte metabolic activity. Chemical inhibition of Fgfr-signaling abrogates the elevated ERK1/2 phosphorylation in Phlpp1-null cultures.\",\n      \"method\": \"Phlpp1 knockout mice, ex vivo chondrocyte cultures, phosphorylation assays for multiple substrates, Phlpp inhibitor treatment, FGFR inhibitor rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined substrate phosphorylation changes and pathway rescue, single lab\",\n      \"pmids\": [\"25953896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Endogenous PHLPP1 (but not PP2Cα) directly interacts with and dephosphorylates AMPK at Thr172 in myoblasts without affecting its upstream kinase LKB1. ERK1/2 phosphorylates PHLPP1α at Ser932 under ER stress, and this phosphorylation is required for PHLPP1's ability to interact with and dephosphorylate AMPK.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, in vitro dephosphorylation assay of AMPK, PHLPP1 knockdown mice, ERK1/2 kinase assay, phospho-site mutagenesis of PHLPP1 Ser932\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro dephosphorylation assay for AMPK substrate, endogenous co-IP, mutagenesis of ERK1/2 phospho-site (Ser932), validated in vivo in KD mice; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29499326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHLPP1 provides a proofreading/quality control step during PKC maturation: it opposes PKC phosphorylation at the hydrophobic motif during biosynthesis, targeting aberrantly active species that fail to become autoinhibited for degradation. Cancer-associated hotspot mutations in the PKCβ pseudosubstrate that impair autoinhibition result in dephosphorylated and unstable enzymes, revealing this as a cancer loss-of-function mechanism.\",\n      \"method\": \"Protein-level analysis across >5,000 patient tumors, overexpression of pseudosubstrate mutants, PKC phosphorylation and stability assays, PHLPP1 manipulation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of PKC maturation checkpoint using mutagenesis and large-scale patient tumor data, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"30904392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHLPP1 dephosphorylates the transcription factor STAT1 on Ser727 to inhibit its activity, reduce its promoter residency, and reduce expression of target genes involved in innate immunity and cytokine signaling. This function requires a bipartite nuclear localization signal in PHLPP1's unique N-terminal extension. PHLPP1 deletion protects mice from lethal LPS challenge and E. coli infection.\",\n      \"method\": \"PHLPP1 knockout mice, LPS/E. coli infection models, STAT1 phosphorylation assays, chromatin immunoprecipitation (STAT1 promoter occupancy), mutagenesis of nuclear localization signal, macrophage gene expression analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct dephosphorylation of STAT1 Ser727 identified, NLS mutagenesis defining domain requirement, promoter ChIP, and in vivo infection model; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31408005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FKBP51 forms a complex with Akt and PHLPP; this interaction is increased in the absence of Pink1. Overexpression of FKBP51 negatively regulates Akt phosphorylation at Ser473, and knockdown of PHLPP in Pink1 KO neurons rescues neuronal death in response to MPP+, suggesting FKBP51 scaffolds PHLPP1 to Akt to promote dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation of endogenous FKBP51/Akt/PHLPP from MEFs and brain tissue, shRNA knockdown of PHLPP, adeno-associated virus FKBP51 overexpression in cortical neurons, MPP+ neurotoxin assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP from brain tissue combined with functional neuronal survival assay, single lab\",\n      \"pmids\": [\"30734931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA PCAT1 binds directly to FKBP51 and displaces PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP51 and suppresses AKT signaling.\",\n      \"method\": \"RIP (RNA immunoprecipitation), RNA pull-down, co-immunoprecipitation of PHLPP/FKBP51/IKKα complex, preclinical mouse model of CRPC\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and RNA pull-down demonstrating direct PCAT1-FKBP51 interaction, complex disruption assay, and in vivo validation; single lab\",\n      \"pmids\": [\"30773595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PHLPP1 splice variant PHLPP1α (but not PHLPP1β/SCOP) inhibits AKT in hippocampal neurons; PHLPP1α can be localized to the nucleus whereas other PHLPP proteins are found only in the cytosolic fraction. PHLPP1α expression increases dramatically in the hippocampus during development.\",\n      \"method\": \"Subcellular fractionation of hippocampal neurons, direct verification of AKT inhibition by PHLPP1α overexpression, developmental expression analysis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — fractionation with functional AKT inhibition assay, single lab, single study\",\n      \"pmids\": [\"20819118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A novel immunomodulatory function of PHLPP1 in macrophages: PHLPP1 suppresses LPS/IFN-γ-induced iNOS expression by dephosphorylating STAT1 Ser727. PHLPP1 reduces IFN-γ-stimulated ERK1/2 phosphorylation (contributing to STAT1 Ser727 inhibition) and suppresses LPS-induced p38-dependent IFN-β feedback that drives STAT1 Tyr701 phosphorylation.\",\n      \"method\": \"PHLPP1 overexpression and siRNA/shRNA knockdown in RAW264.7 macrophages, iNOS promoter reporter assay, STAT1 phosphorylation analysis, ERK1/2 and p38 inhibitor studies\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway dissection with gain/loss-of-function and kinase inhibitor rescue, single lab\",\n      \"pmids\": [\"24443556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHLPP1 interacts with eIF2α (demonstrated by co-immunoprecipitation) and knockdown of PHLPP1 increases eIF2α phosphorylation and expression of downstream autophagy-associated genes (eIF2α/ATF4 axis), promoting chemoresistance in colon cancer cells under ER stress.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression of degradation-resistant PHLPP1 mutant, eIF2α phosphorylation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying eIF2α interaction plus functional phosphorylation readout with gain/loss-of-function, single lab\",\n      \"pmids\": [\"34663797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHLPP1/2 are upregulated by sustained mTORC1 hyper-activation in diabetic β-cells; PHLPPs directly dephosphorylate and regulate the activities of β-cell survival kinases AKT and MST1, constituting a regulatory triangle loop controlling β-cell apoptosis. Genetic inhibition of PHLPPs markedly improves β-cell survival in experimental diabetes models and primary human T2D islets.\",\n      \"method\": \"Genetic inhibition (siRNA/KO) of PHLPP in β-cell lines and primary human islets, mTORC1 manipulation, AKT and MST1 phosphorylation assays, β-cell apoptosis/function assays in vivo and in vitro\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assays in β-cells with defined substrates (AKT, MST1), validated in primary human T2D islets and in vivo models, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34348155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHLPP1 promotes neutral lipid accumulation in macrophages through AMPK/ChREBP-dependent lipid uptake and fatty acid synthesis pathways; PHLPP1 interacts with and modestly increases ChREBP recruitment to the Fasn promoter. Pharmacological inhibition or CRISPR/Cas9-mediated disruption of PHLPP1 reduces lipid accumulation in high-fat-diet-fed zebrafish.\",\n      \"method\": \"PHLPP1 overexpression and knockdown in macrophages, RNA-Seq, co-immunoprecipitation of PHLPP1-ChREBP, Fasn promoter ChIP, CRISPR/Cas9 knockout in zebrafish, C. elegans ortholog (phlp-2) deletion\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying ChREBP interaction with ChIP and in vivo zebrafish/C. elegans validation, single lab\",\n      \"pmids\": [\"35141506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Proteolytic degradation of SCOP (PHLPP1) by calpain in hippocampal neurons is triggered by BDNF, KCl depolarization, or NMDA stimulation. SCOP negatively regulates ERK1/2 MAP kinase and CREB-mediated transcription; its degradation contributes to MAPK activation during memory formation. Transgenic mice overexpressing SCOP in the forebrain were completely blocked for novel object memory.\",\n      \"method\": \"Calpain inhibitor experiments, Western blot for SCOP in hippocampus after stimulation and after novel object training, transgenic mouse overexpression of SCOP (inducible forebrain), novel object memory assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — calpain-dependent cleavage demonstrated in multiple stimulation paradigms, confirmed in vivo with transgenic mice and behavioral memory assay; single lab but multiple orthogonal methods and in vivo validation\",\n      \"pmids\": [\"17382888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PHLPP forms a complex with Akt and hexokinase 2 (HK2) in the mitochondrial fraction of colon cancer cells; knockdown of PHLPP enhances Akt-mediated phosphorylation and mitochondrial localization of HK2, increasing glycolytic flux and causing glucose addiction in colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of PHLPP-Akt-HK2 complex from mitochondrial fraction, siRNA knockdown, Seahorse extracellular flux assay, Akt and HK2 inhibitor rescue\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of trimeric complex from mitochondrial fraction with functional metabolic readout, single lab\",\n      \"pmids\": [\"28179998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PHLPP expression is controlled by mTOR-dependent protein translation: rapamycin treatment or mTOR knockdown decreases PHLPP protein expression; knockdown of TSC2 increases PHLPP expression; rapamycin-mediated downregulation is blocked by a rapamycin-insensitive p70S6K mutant and rescued by 4E-BP1 depletion. This represents a compensatory feedback where mTOR activity upregulates PHLPP to dampen Akt.\",\n      \"method\": \"Rapamycin treatment, mTOR siRNA knockdown, TSC2 siRNA, rapamycin-insensitive p70S6K mutant, 4E-BP1 siRNA, amino acid/glucose starvation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological perturbations of mTOR pathway converging on PHLPP protein level, single lab\",\n      \"pmids\": [\"21177869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FKBP51 canonical isoform mediates Akt ubiquitination at Lys63 via its TPR domain, an essential step for Akt activation. PHLPP silencing does not reduce Akt phosphorylation; instead PHLPP overexpression induces Akt phosphorylation by stabilizing the E3 ubiquitin ligase TRAF6 and supporting K63-ubiquitination of Akt.\",\n      \"method\": \"TPR domain mutant of FKBP51, ubiquitination assay (K63-specific), PHLPP silencing and overexpression, TRAF6 stability assay, FKBP51 interactome profiling from melanoma cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — unexpected result (PHLPP overexpression inducing rather than reducing pAkt) demonstrated by single lab; contradicts prevailing model and requires independent replication\",\n      \"pmids\": [\"36781840\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHLPP1 is a PP2C-family Ser/Thr phosphatase that terminates pro-survival signaling by directly dephosphorylating the hydrophobic motif of AGC kinases—including Akt isoforms (preferentially Akt2), PKC, and S6K1—as well as activating the pro-apoptotic kinase MST1 and dephosphorylating STAT1 Ser727 to restrain inflammatory transcription; its substrate access is governed by scaffold proteins (Scribble, NHERF1, FKBP51) that recruit it to specific subcellular compartments (plasma membrane, mitochondria, lysosomes, nucleus), while its cellular abundance is regulated by calpain-dependent proteolysis, mTOR-dependent translation, and ubiquitin-proteasome degradation controlled by the SCF(β-TrCP)/CKI/GSK-3β axis opposed by deubiquitinases USP46, USP12/WDR48, and USP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHLPP1 is a PP2C-family Ser/Thr phosphatase that terminates pro-survival and growth signaling by directly dephosphorylating the hydrophobic motif of AGC kinases, beginning with Akt at Ser473 to trigger apoptosis and suppress tumor growth [#0]. It exhibits isoform selectivity, preferentially inactivating Akt2 and thereby controlling Akt2-specific substrates HDM2 and GSK-3\\u03b1 [#1], and extends the same hydrophobic-motif dephosphorylation logic to PKC (via a PH-domain-dependent mechanism) [#2] and to S6K1, where its loss derepresses cap-dependent translation, cell size, and the S6K-IRS1 feedback loop [#8]. Beyond AGC kinases, PHLPP1 dephosphorylates RAF1 at Ser338 to restrain RAF-MEK-ERK signaling and intestinal tumorigenesis [#18], dephosphorylates AMPK at Thr172 in an ERK-primed manner [#22], activates the pro-apoptotic kinase MST1 [#7, #30], and dephosphorylates STAT1 Ser727 in the nucleus to restrain innate-immune transcription, an activity that requires a bipartite NLS in its N-terminal extension and protects mice from lethal endotoxin and bacterial challenge [#24]. PHLPP1 also serves as a quality-control checkpoint during PKC maturation, eliminating aberrantly active, non-autoinhibited PKC species\\u2014a mechanism lost through cancer-associated PKC pseudosubstrate mutations [#23]. Substrate access is dictated by scaffolds that target PHLPP1 to discrete compartments: Scribble and NHERF1 recruit it to the plasma membrane [#6, #9], it localizes to mitochondria where it limits Akt-driven hexokinase activity and cardioprotection [#5, #33], and to the lysosomal membrane where it opposes mTORC2 to control chaperone-mediated autophagy [#20]. PHLPP1 abundance is set by a multilayered control system: SCF(\\u03b2-TrCP)-mediated degradation requiring sequential CKI/GSK-3\\u03b2 phosphorylation, embedded in a PI3K/Akt feedback loop [#3], opposing deubiquitinases USP46, USP1, and USP12/WDR48 [#11, #13, #14], mTOR-dependent translation [#34], calpain-dependent proteolysis in neurons [#32], and HDAC3-mediated transcriptional repression [#15]. Through these activities PHLPP1 functions as a tumor suppressor across glioma, colorectal, and prostate cancers, and contributes to physiological control of circadian period consolidation [#4], regulatory T-cell function [#10], and \\u03b2-cell survival in diabetes [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that a dedicated phosphatase, not just kinase withdrawal, terminates Akt signaling by removing the hydrophobic-motif phosphate that defines the active kinase.\",\n      \"evidence\": \"in vitro phosphatase assay, S473D Akt rescue mutagenesis, glioblastoma reintroduction, and xenograft suppression\",\n      \"pmids\": [\"15808505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve isoform selectivity among Akt1/2/3\", \"Did not define how PHLPP1 is targeted to its substrate in vivo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved that PHLPP1 is isoform-selective, preferentially terminating Akt2 and its specific downstream substrates, distinguishing it from PHLPP2.\",\n      \"evidence\": \"reciprocal siRNA knockdown of PHLPP isoforms with Akt2-specific substrate (HDM2, GSK-3\\u03b1) readouts\",\n      \"pmids\": [\"17386267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of isoform preference unresolved\", \"How selectivity is enforced spatially not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended PHLPP1 substrate scope beyond Akt to PKC and linked its neuronal pool (SCOP) to calpain-controlled MAPK/CREB-dependent memory.\",\n      \"evidence\": \"PKC\\u03b2II deletion mutagenesis/dephosphorylation assays and calpain-inhibitor plus transgenic forebrain-overexpression behavioral assays\",\n      \"pmids\": [\"18162466\", \"17382888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PH-domain vs PDZ-motif requirements for distinct substrates only partially mapped\", \"Direct neuronal substrate downstream of SCOP not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined how PHLPP1 abundance is controlled, identifying a phosphodegron-driven SCF(\\u03b2-TrCP) degradation pathway embedded in an Akt-GSK-3\\u03b2 negative-feedback loop.\",\n      \"evidence\": \"\\u03b2-TrCP \\u0394F-box mutant, ubiquitination assays, and CKI/GSK-3\\u03b2 kinase-inhibitor dependency mapping\",\n      \"pmids\": [\"19797085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the feedback loop not tested\", \"Other degradation inputs not yet integrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified compartment-specific and physiological roles\\u2014mitochondrial Akt control with cardioprotection, mTOR-translational regulation of PHLPP, circadian period consolidation, and a nuclear-capable PHLPP1\\u03b1 splice variant.\",\n      \"evidence\": \"mitochondrial fractionation plus ischemia/reperfusion in KO mice, mTOR/rapamycin perturbations, circadian phase-shift assays in KO mice, and hippocampal fractionation of PHLPP1\\u03b1\",\n      \"pmids\": [\"20576936\", \"21177869\", \"20080691\", \"20819118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mitochondrial vs nuclear targeting incompletely defined\", \"Circadian molecular substrate not pinpointed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established scaffold-directed spatial control of PHLPP1 and broadened its tumor-suppressive substrate range to S6K1, while linking it to MST1 activation and Treg biology.\",\n      \"evidence\": \"reciprocal Scribble and NHERF1 co-IP/localization with growth readouts, S6K1 gain/loss-of-function with translational readouts, KO-mouse Treg suppression assays, and review-summarized MST1 phosphatase data\",\n      \"pmids\": [\"21701506\", \"21804599\", \"21986499\", \"21498666\", \"22340730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether scaffolds act combinatorially is unclear\", \"MST1 activation mechanism described only via review, not primary detail here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed PHLPP1 stability is positively regulated by deubiquitinases and that mislocalization of \\u03b2-TrCP can uncouple the degradation feedback loop in cancer.\",\n      \"evidence\": \"USP46 in vitro deubiquitination and reciprocal knockdown, plus \\u03b2-TrCP1 nuclear-mislocalization rescue in glioblastoma cells\",\n      \"pmids\": [\"22391563\", \"21454620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing DUBs not established\", \"Generality of \\u03b2-TrCP mislocalization across tumor types untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Added USP1 as a further deubiquitinase stabilizing PHLPP1 in lung cancer, reinforcing DUB-mediated control of PHLPP1 half-life.\",\n      \"evidence\": \"co-IP, GST pull-down, and cycloheximide-chase with USP1 knockdown\",\n      \"pmids\": [\"22426999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without reciprocal in vivo validation\", \"Relationship to USP46/USP12 redundancy unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the USP12/WDR48 complex as a PHLPP1-stabilizing deubiquitinase with a cancer-associated loss-of-function mutation, and revealed transcriptional repression of PHLPP1 by HDAC3.\",\n      \"evidence\": \"tandem affinity purification and in vitro deubiquitination with the WDR48 L580F mutant, plus HDAC3 ChIP at the PHLPP1 promoter in conditional-KO chondrocytes\",\n      \"pmids\": [\"24145035\", \"23408427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple DUBs into a single regulatory logic unresolved\", \"TGF\\u03b2/Smad control of PHLPP1 transcription only partially mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that PH-domain-targeted small molecules (tocopherols) can drive PHLPP1 to the membrane to enforce Akt Ser473 dephosphorylation, and identified a low-confidence c-Jun-binding/apoptotic role.\",\n      \"evidence\": \"PH-domain binding-affinity and membrane-recruitment assays with xenografts; separate co-IP with PHLPP1 overexpression and dominant-negative c-Jun rescue\",\n      \"pmids\": [\"23512990\", \"25281487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"c-Jun interaction rests on a single low-confidence study lacking reciprocal validation\", \"Pharmacological PH-domain targeting not validated genetically\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded PHLPP1 to direct RAF-MEK-ERK control via RAF1 Ser338 dephosphorylation, SRPK1-mediated recruitment to Akt, and STAT1 Ser727-dependent macrophage immunomodulation.\",\n      \"evidence\": \"in vitro RAF1 dephosphorylation with Apc(Min)/Phlpp1-/- mice, phosphoproteomics plus SRPK1-PHLPP1-Akt co-IP in KO MEFs, and macrophage gain/loss-of-function with kinase-inhibitor dissection\",\n      \"pmids\": [\"24530606\", \"24703948\", \"24443556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SRPK1 dosage bidirectionally controls recruitment mechanistically unclear\", \"Crosstalk between RAF1 and Akt branches not integrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a lysosomal PHLPP1 pool that opposes mTORC2 to govern chaperone-mediated autophagy, and connected PHLPP1 loss to FoxO1/FGF18-driven chondrocyte ERK activity.\",\n      \"evidence\": \"lysosomal fractionation with CMA translocation-complex assays, and KO-chondrocyte multi-substrate phosphorylation with FGFR-inhibitor rescue\",\n      \"pmids\": [\"26118642\", \"25953896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of lysosomal targeting of PHLPP1 unresolved\", \"Direct vs indirect FoxO1 regulation not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PHLPP1 restrains glycolytic metabolism through a mitochondrial PHLPP-Akt-HK2 complex, linking the phosphatase to cancer metabolic dependency.\",\n      \"evidence\": \"mitochondrial co-IP of the trimeric complex with Seahorse flux and inhibitor rescue in colon cancer cells\",\n      \"pmids\": [\"28179998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without in vivo metabolic validation\", \"Whether PHLPP1 dephosphorylates HK2 directly or acts via Akt unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established AMPK Thr172 as a direct PHLPP1 substrate and showed ERK1/2 phosphorylation of PHLPP1\\u03b1 Ser932 licenses this interaction under ER stress.\",\n      \"evidence\": \"endogenous co-IP, in vitro AMPK dephosphorylation, Ser932 phospho-site mutagenesis, and validation in knockdown mice\",\n      \"pmids\": [\"29499326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where AMPK regulation dominates over Akt regulation unclear\", \"Structural basis of Ser932-dependent substrate switching unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined PHLPP1 as a PKC maturation proofreader and a nuclear STAT1 Ser727 phosphatase, plus FKBP51/lncRNA-PCAT1-regulated scaffolding to Akt and an eIF2\\u03b1 interaction influencing chemoresistance.\",\n      \"evidence\": \"PKC pseudosubstrate-mutant stability analysis across >5,000 tumors, STAT1 Ser727 dephosphorylation with NLS mutagenesis and in vivo infection models, FKBP51/Akt/PHLPP brain co-IP with neuronal survival assays, RIP/RNA pull-down showing PCAT1-FKBP51, and eIF2\\u03b1 co-IP\",\n      \"pmids\": [\"30904392\", \"31408005\", \"30734931\", \"30773595\", \"34663797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single phosphatase coordinates cytoplasmic, mitochondrial, lysosomal and nuclear pools is not integrated\", \"eIF2\\u03b1 regulation rests on a single co-IP-based study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported a contrarian observation that PHLPP overexpression can increase Akt phosphorylation via TRAF6/K63-ubiquitination, challenging the canonical phosphatase model.\",\n      \"evidence\": \"FKBP51 TPR-mutant and K63-ubiquitination assays with PHLPP silencing/overexpression in melanoma cells\",\n      \"pmids\": [\"36781840\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Contradicts the prevailing model and awaits independent replication\", \"Mechanism by which a phosphatase would stabilize an E3 ligase unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PHLPP1/2 form an mTORC1-driven regulatory loop controlling \\u03b2-cell apoptosis through AKT and MST1, with therapeutic relevance in diabetes.\",\n      \"evidence\": \"genetic inhibition of PHLPP in \\u03b2-cell lines and primary human T2D islets with AKT/MST1 phosphorylation and apoptosis readouts in vivo\",\n      \"pmids\": [\"34348155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of AKT vs MST1 branches to \\u03b2-cell death not separated\", \"Translational targeting strategy not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked PHLPP1 to macrophage lipid metabolism via an AMPK/ChREBP-dependent program, with conserved roles across zebrafish and C. elegans.\",\n      \"evidence\": \"PHLPP1 gain/loss-of-function with RNA-Seq, ChREBP co-IP, Fasn ChIP, and CRISPR/ortholog deletion in vivo\",\n      \"pmids\": [\"35141506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the lipid phenotype is a direct ChREBP effect or downstream of AMPK dephosphorylation unresolved\", \"Single-lab in vivo models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHLPP1 integrates its many scaffold-defined subcellular pools and competing degradation/stabilization inputs into substrate selection in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of substrate/scaffold recognition\", \"Rules governing which substrate dominates in a given compartment are unknown\", \"Reconciliation of the contrarian Akt-stabilizing report with the canonical phosphatase model is outstanding\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 8, 18, 22, 24, 30]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 18, 22, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 23, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 9, 17]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 33]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [24, 27]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8, 18, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 7, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 24, 28]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20, 29]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [22, 31, 33]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 23, 30]}\n    ],\n    \"complexes\": [\n      \"Scribble-PHLPP1-Akt complex\",\n      \"NHERF1-PHLPP1-PTEN complex\",\n      \"FKBP51-Akt-PHLPP complex\",\n      \"PHLPP-Akt-HK2 mitochondrial complex\"\n    ],\n    \"partners\": [\n      \"AKT2\",\n      \"Scribble\",\n      \"NHERF1\",\n      \"FKBP51\",\n      \"SRPK1\",\n      \"USP46\",\n      \"WDR48\",\n      \"BTRC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}