Affinage

PHLPP1

PH domain leucine-rich repeat-containing protein phosphatase 1 · UniProt O60346

Length
1717 aa
Mass
184.7 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHLPP1 is a PP2C-family serine/threonine phosphatase that functions as a central negative regulator of AGC kinase and MAPK signaling by directly dephosphorylating the hydrophobic motif of Akt isoforms, PKC, and S6K1, as well as RAF1 at Ser338, STAT1 at Ser727 in the nucleus, and AMPK at Thr172, thereby suppressing cell survival, growth, and inflammatory signaling (PMID:15808505, PMID:18162466, PMID:21986499, PMID:24530606, PMID:31408005, PMID:29499326). Membrane recruitment of PHLPP1 to its substrates requires its PH domain and scaffold proteins including Scribble and NHERF1, while SRPK1 and FKBP51 modulate PHLPP1–Akt complex assembly (PMID:21701506, PMID:21804599, PMID:24703948, PMID:30734931). PHLPP1 protein stability is controlled by β-TrCP/CKI/GSK-3β-dependent ubiquitination and NEDD4-2/TMEPAI-mediated degradation, counterbalanced by the deubiquitinase USP46, while its translation is regulated by mTORC1/S6K1/4E-BP1 signaling (PMID:19797085, PMID:22391563, PMID:34638419, PMID:21177869). In neurons, calpain-dependent degradation of the PHLPP1β/SCOP splice variant gates ERK/CREB activation required for memory formation, and PHLPP1β exhibits circadian oscillatory expression in the suprachiasmatic nucleus and basolateral amygdala where it regulates anxiety-related behavior (PMID:17382888, PMID:10570941, PMID:27640726).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 Medium

    The initial discovery of SCOP (later PHLPP1β) established that the gene encodes a multi-domain protein with PH, leucine-rich repeat, and PP2C phosphatase domains, expressed in a circadian pattern in the SCN, raising the question of its enzymatic targets and physiological role.

    Evidence Differential display cloning from rat SCN with domain architecture analysis

    PMID:10570941

    Open questions at the time
    • No substrate or enzymatic activity demonstrated
    • Circadian regulation mechanism not defined
    • Function inferred solely from domain architecture
  2. 2005 High

    Identification of Akt Ser473 (hydrophobic motif) as the direct substrate of PHLPP1 established the gene as a bona fide tumor suppressor phosphatase that terminates PI3K/Akt survival signaling, answering the key question of what PHLPP1 dephosphorylates.

    Evidence In vitro phosphatase assay on Akt, S473D phosphomimetic rescue, cellular overexpression/knockdown, and tumor xenograft suppression

    PMID:15808505

    Open questions at the time
    • Selectivity among Akt isoforms not yet addressed
    • Mechanism of membrane recruitment unknown
    • Other substrates not explored
  3. 2007 High

    Two parallel advances revealed that PHLPP1 dephosphorylates PKCβII hydrophobic motif to promote PKC degradation and that calpain-mediated degradation of SCOP/PHLPP1β in hippocampal neurons is required for ERK/CREB activation and memory formation, broadening PHLPP1 from an Akt-specific phosphatase to a multi-pathway regulator with brain-specific proteolytic regulation.

    Evidence PH domain deletion mutagenesis with PKC dephosphorylation/degradation assays; in vitro calpain cleavage, calpain inhibitors, inducible transgenic SCOP overexpression with novel object recognition behavioral test

    PMID:17382888 PMID:18162466

    Open questions at the time
    • Whether calpain regulation occurs outside neurons unknown
    • Direct structural basis of PH domain requirement for PKC substrate access not resolved
    • Relationship between PKC and Akt dephosphorylation activities unclear
  4. 2009 High

    Discovery of SCF(β-TrCP)-mediated ubiquitin-proteasomal degradation of PHLPP1, dependent on CKI/GSK-3β phosphorylation and suppressed by PI3K/Akt activation, established the first feedback loop controlling PHLPP1 protein levels and explained how Akt signaling sustains itself by destabilizing its own phosphatase.

    Evidence Co-IP, dominant-negative β-TrCP, siRNA, ubiquitination assays, pharmacological PI3K/Akt modulation

    PMID:19797085

    Open questions at the time
    • Degron sequence on PHLPP1 not fully mapped
    • Whether other E3 ligases cooperate with β-TrCP not tested
    • Tissue-specific regulation of this feedback not explored
  5. 2010 High

    Multiple 2010 studies collectively established that PHLPP1 protein abundance is controlled at the translational level by mTORC1/S6K/4E-BP1, that UCH-L1 can modulate PHLPP1 ubiquitination, that PHLPP1 localizes to mitochondria in cardiomyocytes where it regulates ischemia/reperfusion injury, and that PHLPP1 splice variants have divergent subcellular localization and opposing effects on Akt in hippocampal neurons.

    Evidence Rapamycin/TSC2/4E-BP1 genetic epistasis; UCH-L1 transgenic mice; mitochondrial fractionation with PHLPP1 KO ischemia/reperfusion model; isoform-specific expression in neurons with subcellular fractionation

    PMID:20574456 PMID:20576936 PMID:20819118 PMID:21177869

    Open questions at the time
    • How mTORC1-dependent translation couples to specific PHLPP1 mRNA features (e.g., 5' UTR structure) not defined
    • UCH-L1 effect on PHLPP1 appears opposite to expected deubiquitinase stabilization — mechanism unclear
    • Whether mitochondrial PHLPP1 has substrates beyond Akt unknown
  6. 2011 High

    Scaffold-dependent membrane recruitment of PHLPP1 was established: Scribble and NHERF1 independently recruit PHLPP1 to the plasma membrane to enable Akt dephosphorylation, while S6K1 was identified as an Akt-independent PHLPP1 substrate, and PHLPP1 was shown to control Treg function via Akt suppression.

    Evidence Scribble/NHERF1 Co-IP, subcellular fractionation, knockdown with Akt phosphorylation readout; S6K1 dephosphorylation with polysome/cell size analysis; PHLPP1 KO mice with Treg suppression assays

    PMID:21498666 PMID:21701506 PMID:21804599 PMID:21986499 PMID:22044669

    Open questions at the time
    • Whether Scribble and NHERF1 operate in the same or distinct cell types not resolved
    • Direct in vitro dephosphorylation of S6K1 not shown
    • Mechanism of isoform selectivity (PHLPP1→Akt2, PHLPP2→Akt1) not structurally explained
  7. 2012 High

    USP46 was identified as a deubiquitinase that directly stabilizes PHLPP1 by removing polyubiquitin chains, establishing the first positive regulator of PHLPP1 protein stability and completing the ubiquitin-cycle picture (β-TrCP degrades, USP46 stabilizes).

    Evidence In vitro deubiquitination assay, cellular ubiquitination assay, USP46 overexpression/knockdown with PHLPP1 and Akt readouts

    PMID:22391563

    Open questions at the time
    • Whether USP46 and β-TrCP compete on the same ubiquitin chains not tested
    • Tissue-specific deployment of USP46-PHLPP1 axis unknown
    • Structural basis of USP46 recognition of PHLPP1 not defined
  8. 2014 High

    PHLPP1 was shown to directly dephosphorylate RAF1 at Ser338, placing it as a negative regulator of RAF-MEK-ERK signaling in addition to PI3K/Akt, and SRPK1 was identified as a modulator of PHLPP1-Akt complex assembly where both loss and excess of SRPK1 decouple PHLPP1 from Akt.

    Evidence In vitro phosphatase assay on RAF1, ApcMin/Phlpp1−/− mouse colorectal tumor model; phosphoproteomics, Co-IP, SRPK1 KO MEFs

    PMID:24530606 PMID:24703948

    Open questions at the time
    • Whether PHLPP1 dephosphorylates other MAPK pathway components unknown
    • SRPK1 phosphorylation sites on PHLPP1 not mapped
    • ApcMin model conflates Akt and RAF1 dephosphorylation contributions
  9. 2015 High

    PHLPP1 was found to localize to the lysosomal membrane where it opposes mTORC2-mediated Akt phosphorylation to regulate chaperone-mediated autophagy (CMA) translocation complex assembly, extending PHLPP1 function to organelle-specific proteostasis.

    Evidence Lysosomal membrane fractionation, Co-IP, siRNA, CMA activity assays

    PMID:26118642

    Open questions at the time
    • How PHLPP1 is recruited specifically to lysosomes not defined
    • Whether PHLPP1 dephosphorylates LAMP-2A or CMA substrates directly not tested
    • Relationship to macroautophagy regulation unknown
  10. 2019 High

    Three major advances expanded PHLPP1 function: it acts as a quality-control phosphatase during PKC maturation by selectively dephosphorylating aberrantly active (non-autoinhibited) PKC species; it dephosphorylates nuclear STAT1 at Ser727 via a bipartite NLS to suppress innate immune gene expression; and FKBP51 scaffolds a PHLPP1-Akt complex whose assembly is regulated by Pink1 phosphorylation.

    Evidence In vitro phosphatase assays with PKC pseudosubstrate mutants and >5000 patient tumor protein analysis; PHLPP1 KO mice with LPS challenge, ChIP, NLS mutagenesis; Co-IP in brain and Pink1 KO neurons

    PMID:30734931 PMID:30904392 PMID:31408005

    Open questions at the time
    • Whether the PKC quality-control function is separable from bulk PKC hydrophobic motif dephosphorylation in vivo
    • Nuclear import mechanism and regulation of the NLS not fully characterized
    • Pink1-FKBP51-PHLPP1 axis relevance to Parkinson's disease pathology not established in human tissue
  11. 2021 Medium

    Additional substrates and regulators emerged: PHLPP1 dephosphorylates MST1 in pancreatic β cells downstream of mTORC1, NEDD4-2 recruited by TMEPAI provides a second E3 ligase pathway for PHLPP1 degradation, and PHLPP1 interacts with eIF2α to modulate ER stress signaling.

    Evidence β-cell KO/shRNA with AKT/MST1 phosphorylation in human T2D islets; TMEPAI-KO cells with ubiquitination assays; Co-IP of PHLPP1-eIF2α under ER stress

    PMID:34348155 PMID:34638419 PMID:34663797

    Open questions at the time
    • Direct in vitro reconstitution of MST1 dephosphorylation by PHLPP1 not performed
    • NEDD4-2 vs β-TrCP relative contributions to PHLPP1 turnover in different tissues unclear
    • Whether PHLPP1 directly dephosphorylates eIF2α or acts indirectly not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of PHLPP1's isoform-selective dephosphorylation of Akt2 versus Akt1, the mechanism by which PHLPP1 is recruited to specific organellar membranes (lysosomes, mitochondria), and whether the growing list of putative substrates (MST1, eIF2α, c-Jun) reflects direct phosphatase activity or scaffolding functions.
  • No crystal structure of PHLPP1 phosphatase domain with any substrate
  • Isoform-selectivity determinants for Akt1 vs Akt2 unknown at structural level
  • Relative physiological importance of each substrate in different tissues not systematically evaluated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 6
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 1 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
AKT1AKT2FKBP5NHERF1RAF1SCRIBSRPK1USP46
Complex memberships
PHLPP1-FKBP51-AktPHLPP1-Scribble-AktSCF(β-TrCP)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 PHLPP1 directly dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1), inactivating Akt and promoting apoptosis. The phosphatase domain is responsible for this activity, and the hydrophobic motif is identified as the primary cellular target. In vitro phosphatase assay, cellular overexpression/knockdown, S473D Akt rescue experiment, tumor growth suppression assay Molecular cell High 15808505
2007 PHLPP1 and PHLPP2 dephosphorylate the hydrophobic motif of PKCβII, shunting PKC to the detergent-insoluble fraction and promoting its degradation. The PH domain of PHLPP is necessary for effective PKCβII dephosphorylation, while the PDZ-binding motif is dispensable for this substrate. Overexpression, deletion mutagenesis, knockdown with phorbol ester treatment, detergent fractionation assay The Journal of biological chemistry High 18162466
2009 PHLPP1 is targeted for proteasomal degradation by the SCF(β-TrCP) E3 ubiquitin ligase complex in a phosphorylation-dependent manner requiring 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. Co-immunoprecipitation, overexpression of wild-type vs. ΔF-box β-TrCP mutant, siRNA knockdown, ubiquitination assays, pharmacological PI3K/Akt pathway modulation Molecular and cellular biology High 19797085
2011 PHLPP1 is recruited to the plasma membrane by binding to the scaffolding protein Scribble (Scrib), and this membrane localization is required for its negative regulation of Akt. Knockdown of Scrib redistributes PHLPP1 from membrane to cytoplasm and increases Akt phosphorylation; PHLPP1, Scrib, and Akt form a trimeric complex. Co-immunoprecipitation, subcellular fractionation, Scrib knockdown and overexpression, confocal microscopy EMBO reports High 21701506
2011 PHLPP1 dephosphorylates S6 kinase 1 (S6K1) directly, independent of its Akt dephosphorylation activity. Loss of PHLPP activates the S6K-dependent negative feedback loop, increasing IRS-1 degradation and increasing cap-dependent translation, cell size, and protein content. Overexpression and knockdown assays, phosphorylation analysis, polysome fractionation, cell size measurement Molecular and cellular biology High 21986499
2011 PHLPP1 selectively dephosphorylates Akt2, whereas PHLPP2 selectively dephosphorylates Akt1, demonstrating isoform-specific substrate selectivity. Overexpression and knockdown of PHLPP1 and PHLPP2 isoforms with isoform-specific Akt phosphorylation analysis in pancreatic cancer cells Gastroenterology Medium 22044669
2011 NHERF1 acts as a scaffold that binds PHLPP1 via PDZ domains and recruits it to the membrane; PHLPP1 requires NHERF1 for membrane localization and growth-suppressive effects in glioblastoma cells. Co-immunoprecipitation, subcellular fractionation, knockdown of NHERF1 with Akt phosphorylation and growth readouts Oncogene Medium 21804599
2011 PHLPP1 expression is elevated in regulatory T cells (Tregs) compared to conventional T cells, suppressing Akt activation; knockdown of PHLPP1 restores TCR-mediated Akt activation in Tregs and impairs their suppressive capacity. PHLPP1 KO mice show impaired induced Treg development. PHLPP1 KO mice, shRNA knockdown, Akt phosphorylation analysis, Treg suppression functional assay Journal of immunology High 21498666
2012 The deubiquitinase USP46 directly removes polyubiquitin chains from PHLPP1 (both isoforms) in vitro and in cells, stabilizing PHLPP1 protein levels and maintaining Akt inhibition. Co-immunoprecipitation, in vitro deubiquitination assay, ubiquitination assay in cells, USP46 overexpression/knockdown Oncogene High 22391563
2014 PHLPP1 and PHLPP2 directly dephosphorylate RAF1 at Ser338, inhibiting its kinase activity. Knockdown of PHLPP increases the amplitude and duration of RAF-MEK-ERK signaling, and PHLPP1 KO in ApcMin mice promotes colorectal tumor progression with epithelial-mesenchymal transition. Co-immunoprecipitation, in vitro kinase/phosphatase assays, shRNA knockdown, ApcMin/Phlpp1-/- mouse model Gastroenterology High 24530606
2014 SRPK1 regulates PHLPP1 recruitment to Akt; downregulated SRPK1 impairs PHLPP1 recruitment to Akt, causing constitutive Akt activation, while excess SRPK1 squelches PHLPP1 away from Akt, also causing constitutive activation. Genome-wide phosphoproteomics, co-immunoprecipitation, MEF transformation assay, SRPK1 KO cells Molecular cell High 24703948
2010 PHLPP1 localizes to mitochondria in cardiomyocytes and negatively regulates Akt activity (specifically Ser473 but not Thr308 phosphorylation) in the heart; PHLPP1 KO mice show increased p-Akt in mitochondrial fractions after ischemia/reperfusion and reduced infarct size. Mitochondria/cytosol fractionation, siRNA knockdown in neonatal cardiomyocytes, PHLPP1 KO mice, ischemia/reperfusion model Circulation research High 20576936
2010 UCH-L1 deubiquitinase downregulates PHLPP1 protein levels in a deubiquitinase activity-dependent manner, boosting Akt signaling and promoting lymphomagenesis in vivo. UCH-L1 transgenic mice, deubiquitinase activity mutant rescue, immunoblotting for PHLPP1 and Akt phosphorylation Leukemia Medium 20574456
2010 mTOR controls PHLPP protein expression through p70S6K- and 4E-BP1-dependent translation; rapamycin reduces PHLPP protein expression, and this contributes to rapamycin resistance in colon cancer cells. Rapamycin treatment, TSC2/mTOR/4E-BP1 knockdown, rapamycin-insensitive p70S6K mutant expression, protein synthesis inhibitor assays The Journal of biological chemistry High 21177869
2015 PHLPP1 associates with the lysosomal membrane and counteracts mTORC2-mediated inhibitory phosphorylation of CMA. Lysosomal Akt, regulated by the mTORC2/PHLPP1 kinase-phosphatase pair, controls the assembly and disassembly of the CMA translocation complex at the lysosomal membrane. Lysosomal membrane fractionation, co-immunoprecipitation, siRNA knockdown, CMA activity assays Molecular cell High 26118642
2019 PHLPP1 acts as a proofreading phosphatase during PKC maturation, opposing phosphorylation of aberrantly active PKC species that fail to become autoinhibited, thereby targeting them for degradation. Cancer-associated pseudosubstrate mutations in PKCβ result in dephosphorylated, unstable enzymes dependent on this PHLPP1 quality-control step. In vitro phosphatase assays, cancer hotspot mutagenesis, protein-level analysis in >5000 patient tumors, PHLPP1 KO cells Molecular cell High 30904392
2019 PHLPP1 dephosphorylates STAT1 at Ser727 in the nucleus to inhibit its transcriptional activity and reduce the expression of innate immunity and cytokine signaling genes. This function depends on a bipartite nuclear localization signal in the unique N-terminal extension of PHLPP1. PHLPP1 KO mice (LPS challenge model), macrophage nuclear fractionation, ChIP for STAT1 promoter occupancy, NLS mutagenesis, in vitro dephosphorylation assays eLife High 31408005
2018 PHLPP1 directly dephosphorylates AMPK at Thr172 in myoblasts, suppressing AMPK activity and facilitating ER stress. This interaction is enhanced by ERK1/2-mediated phosphorylation of PHLPP1α at Ser932 under ER stress conditions. Co-immunoprecipitation of endogenous proteins, in vitro dephosphorylation assay, ERK1/2 phosphorylation of PHLPP1, PHLPP1 knockdown mice Biochimica et biophysica acta. Molecular basis of disease Medium 29499326
2019 lncRNA PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of both AKT and NF-κB signaling in castration-resistant prostate cancer. RNA immunoprecipitation (RIP), RNA pulldown assay, co-immunoprecipitation, PCAT1 overexpression/knockdown Nucleic acids research Medium 30773595
2019 FKBP5 interacts with both AKT and PHLPP, forming a trimeric complex; in the absence of Pink1, FKBP5 interaction with AKT and PHLPP is increased, promoting AKT dephosphorylation by PHLPP and neuronal death. Co-immunoprecipitation in HEK293 cells and mouse brain, in vitro kinase assay (Pink1 phosphorylates FKBP5), Pink1 KO primary neurons Journal of neurochemistry Medium 30734931
2021 PHLPP1 directly dephosphorylates and regulates MST1 activity as well as AKT in pancreatic β cells; mTORC1 hyperactivation is the primary upstream mechanism driving PHLPP upregulation that leads to β-cell apoptosis in diabetes. Genetic inhibition (KO, shRNA) in β-cell lines, mouse models, and primary human T2D islets; phosphorylation analysis of AKT and MST1 Cell reports Medium 34348155
2021 PHLPP1 interacts with eIF2α and this interaction is enhanced by ER stress; knockdown of PHLPP1 increases eIF2α phosphorylation and downstream ATF4/autophagy signaling, improving cell survival under ER stress. Co-immunoprecipitation, siRNA knockdown, overexpression of degradation-resistant PHLPP1 mutant, eIF2α phosphorylation analysis Cell death & disease Medium 34663797
2021 NEDD4-2 E3 ubiquitin ligase is recruited by TMEPAI (via its PPxY motifs) to form a complex with PHLPP1, promoting PHLPP1 polyubiquitination and proteasomal degradation in triple-negative breast cancer cells, sustaining AKT Ser473 phosphorylation. Co-immunoprecipitation, ubiquitination assay, TMEPAI-KO cells, PY motif mutagenesis Cancers Medium 34638419
1999 SCOP (suprachiasmatic nucleus circadian oscillatory protein), later identified as PHLPP1β, was identified as a novel brain protein with a pleckstrin homology domain, leucine-rich repeats, and a PP2C-like phosphatase domain, expressed in a circadian manner in the rat SCN. Differential display of SCN mRNA, molecular cloning and domain analysis FEBS letters Medium 10570941
2007 SCOP/PHLPP1β is proteolyzed by calpain in hippocampal neurons upon stimulation (BDNF, KCl depolarization, NMDA), and this degradation is required for ERK1/2 MAP kinase and CREB-mediated transcription activation during memory formation. Transgenic overexpression of SCOP in the forebrain completely blocks novel object memory. In vitro calpain cleavage assay, calpain inhibitor treatment, inducible transgenic mouse overexpression, novel object memory behavioral test Cell High 17382888
2013 Vitamin E (α-tocopherol and γ-tocopherol) facilitates Akt Ser473 dephosphorylation by promoting PH domain-dependent co-recruitment of Akt and PHLPP1 to the plasma membrane; both PH domains bind tocopherols with selectivity over other PH domain-containing proteins. Membrane recruitment assay, PH domain binding affinity measurement, molecular modeling, in vitro Akt phosphorylation assay Science signaling Medium 23512990
2010 PHLPP1 splice variants (PHLPP1α and PHLPP1β/SCOP) have divergent functions in hippocampal neurons: PHLPP1α inhibits AKT, whereas PHLPP1β/SCOP promotes AKT activation. Only PHLPP1α localizes to the nucleus in adult hippocampal neurons. Subcellular fractionation, isoform-specific expression in hippocampal neurons, AKT phosphorylation analysis Journal of neurochemistry Medium 20819118
2016 SCOP/PHLPP1β in the basolateral amygdala (BLA) is required for circadian expression of anxiety-like behavior in mice; viral-mediated BLA-specific knockout of Scop abolishes the circadian variation in anxiety-like behavior. Virus-mediated BLA-specific Cre-mediated KO, elevated plus maze behavioral assay, circadian time-point analysis Scientific reports Medium 27640726
2014 PHLPP1 binds to c-Jun protein and mediates its dephosphorylation/inactivation; this interaction blocks c-Jun phosphorylation at Ser63/73, inhibiting p53 induction and apoptosis. Co-immunoprecipitation, ectopic PHLPP1 overexpression, c-Jun phosphorylation analysis, cell transformation assay Cancer prevention research Low 25281487
2010 In the retina, both PHLPP and PHLPPL enzymatic activities are significantly decreased by insulin in a PI3K-dependent manner, demonstrating that PHLPP phosphatase activity is regulated by the insulin receptor/PI3K/Akt pathway. Ex vivo retinal phosphatase activity assay, LY294002 PI3K inhibition, insulin stimulation Journal of neurochemistry Medium 20089132
2023 FKBP51 mediates K63-linked ubiquitination of Akt (required for Akt activation) via its TPR domain; PHLPP stabilizes the E3 ubiquitin ligase TRAF6 and supports K63-ubiquitination of Akt, revealing a non-canonical pro-activation role for PHLPP in addition to its phosphatase function. Co-immunoprecipitation, ubiquitination assay (K63-Ub linkage-specific), PHLPP silencing/overexpression, interactome profiling Cell death & disease Medium 36781840
2014 Small molecule inhibitors of PHLPP phosphatase activity were identified by chemical and virtual screening against the phosphatase domain of PHLPP2; two structurally diverse compounds selectively inhibit PHLPP in vitro, increase Akt signaling in cells, and prevent apoptosis. In vitro phosphatase activity screen (NCI Diversity Set), virtual docking into phosphatase domain model, cellular Akt phosphorylation assay Journal of medicinal chemistry Medium 20836557

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 SCOP: a structural classification of proteins database for the investigation of sequences and structures. Journal of molecular biology 4560 7723011
2005 PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Molecular cell 761 15808505
2007 Data growth and its impact on the SCOP database: new developments. Nucleic acids research 700 18000004
2004 SCOP database in 2004: refinements integrate structure and sequence family data. Nucleic acids research 671 14681400
2013 SCOPe: Structural Classification of Proteins--extended, integrating SCOP and ASTRAL data and classification of new structures. Nucleic acids research 520 24304899
2020 The SCOP database in 2020: expanded classification of representative family and superfamily domains of known protein structures. Nucleic acids research 250 31724711
2015 Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. Molecular cell 228 26118642
2007 The phosphatase PHLPP controls the cellular levels of protein kinase C. The Journal of biological chemistry 167 18162466
2019 LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex. Nucleic acids research 150 30773595
2008 Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis. Oncogene 138 19079341
2011 PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma. Oncogene 137 21804599
2014 Turning off AKT: PHLPP as a drug target. Annual review of pharmacology and toxicology 118 24392697
1999 A systematic comparison of protein structure classifications: SCOP, CATH and FSSP. Structure (London, England : 1993) 117 10508779
2010 The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling. Leukemia 113 20574456
2014 Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt. Molecular cell 112 24703948
2010 PHLPP-1 negatively regulates Akt activity and survival in the heart. Circulation research 105 20576936
2017 LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1α translation. Oncogene 104 28263966
2012 The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer. Oncogene 98 22391563
2016 Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3-mediated repression of PHLPP1 expression. Oncotarget 96 27248326
2007 Proteolytic degradation of SCOP in the hippocampus contributes to activation of MAP kinase and memory. Cell 96 17382888
2011 miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis. Toxicological sciences : an official journal of the Society of Toxicology 91 21750348
2012 Suppression of survival signalling pathways by the phosphatase PHLPP. The FEBS journal 89 22340730
2009 beta-TrCP-mediated ubiquitination and degradation of PHLPP1 are negatively regulated by Akt. Molecular and cellular biology 89 19797085
2011 The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology 80 22044669
2020 The miR-92a-2-5p in exosomes from macrophages increases liver cancer cells invasion via altering the AR/PHLPP/p-AKT/β-catenin signaling. Cell death and differentiation 76 32587378
2011 PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth. Molecular and cellular biology 76 21986499
2014 PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice. Gastroenterology 74 24530606
2016 PHLPPing through history: a decade in the life of PHLPP phosphatases. Biochemical Society transactions 73 27913677
1999 SCOP, a novel gene product expressed in a circadian manner in rat suprachiasmatic nucleus. FEBS letters 70 10570941
2010 Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening. Journal of medicinal chemistry 65 20836557
2011 Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP): a new player in cell signaling. The Journal of biological chemistry 64 22144674
2015 MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1. Expert opinion on therapeutic targets 62 26107137
2011 Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. Journal of immunology (Baltimore, Md. : 1950) 61 21498666
2011 Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance. Diabetologia 60 21461637
2011 Scribble-mediated membrane targeting of PHLPP1 is required for its negative regulation of Akt. EMBO reports 60 21701506
2010 mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells. The Journal of biological chemistry 60 21177869
2018 Activation of GSK3β/β-TrCP axis via PHLPP1 exacerbates Nrf2 degradation leading to impairment in cell survival pathway during diabetic nephropathy. Free radical biology & medicine 54 29655866
2014 Physiological activation of Akt by PHLPP1 deletion protects against pathological hypertrophy. Cardiovascular research 52 25411382
2009 Systematic comparison of SCOP and CATH: a new gold standard for protein structure analysis. BMC structural biology 51 19374763
2020 Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway. PeerJ 50 32435528
2013 Downregulation of PHLPP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells. Molecular and cellular biology 47 24061475
2013 NF-κB1 p50 promotes p53 protein translation through miR-190 downregulation of PHLPP1. Oncogene 44 23396362
2019 Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer. Molecular cell 43 30904392
1971 Isolation of Mesophyll Cells and Bundle Sheath Cells from Digitaria sanguinalis (L.) Scop. Leaves and a Scanning Microscopy Study of the Internal Leaf Cell Morphology. Plant physiology 43 16657571
2015 Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. Osteoarthritis and cartilage 42 26746148
2018 GYY4137 protects against myocardial ischemia/reperfusion injury via activation of the PHLPP-1/Akt/Nrf2 signaling pathway in diabetic mice. The Journal of surgical research 40 29605032
2019 Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP. Journal of neurochemistry 39 30734931
2015 Loss of PHLPP protects against colitis by inhibiting intestinal epithelial cell apoptosis. Biochimica et biophysica acta 38 26187040
2012 USP1 regulates AKT phosphorylation by modulating the stability of PHLPP1 in lung cancer cells. Journal of cancer research and clinical oncology 38 22426999
2013 Vitamin E facilitates the inactivation of the kinase Akt by the phosphatase PHLPP1. Science signaling 37 23512990
2014 Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the cheliensisin a inhibition of cell transformation. Cancer prevention research (Philadelphia, Pa.) 35 25281487
2013 Oncogenic suppression of PHLPP1 in human melanoma. Oncogene 35 24121273
2020 Inhibition of PHLPP1 ameliorates cardiac dysfunction via activation of the PI3K/Akt/mTOR signalling pathway in diabetic cardiomyopathy. Journal of cellular and molecular medicine 31 32150791
2010 PHLPP1 splice variants differentially regulate AKT and PKCα signaling in hippocampal neurons: characterization of PHLPP proteins in the adult hippocampus. Journal of neurochemistry 30 20819118
2019 PHLPP1 counter-regulates STAT1-mediated inflammatory signaling. eLife 28 31408005
2017 PHLPP: a putative cellular target during insulin resistance and type 2 diabetes. The Journal of endocrinology 28 28428363
2016 Mutual inhibition of insulin signaling and PHLPP-1 determines cardioprotective efficiency of Akt in aged heart. Aging 28 27019292
1998 SCOP, Structural Classification of Proteins database: applications to evaluation of the effectiveness of sequence alignment methods and statistics of protein structural data. Acta crystallographica. Section D, Biological crystallography 28 10089491
2018 ERK1/2 activated PHLPP1 induces skeletal muscle ER stress through the inhibition of a novel substrate AMPK. Biochimica et biophysica acta. Molecular basis of disease 27 29499326
2002 Automated assignment of SCOP and CATH protein structure classifications from FSSP scores. Proteins 27 11835515
2021 miR-190-5p Alleviates Myocardial Ischemia-Reperfusion Injury by Targeting PHLPP1. Disease markers 26 34868398
2017 Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 26 29068480
2019 Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice. Cell death & disease 25 31582730
2009 SCOP/PHLPP and its functional role in the brain. Molecular bioSystems 25 20024065
2017 SNORA74B gene silencing inhibits gallbladder cancer cells by inducing PHLPP and suppressing Akt/mTOR signaling. Oncotarget 24 28212545
2019 Deficiency in the phosphatase PHLPP1 suppresses osteoclast-mediated bone resorption and enhances bone formation in mice. The Journal of biological chemistry 22 31189651
2020 PHLPPing the Script: Emerging Roles of PHLPP Phosphatases in Cell Signaling. Annual review of pharmacology and toxicology 21 32997603
2019 CXCL13 is a differentiation- and hypoxia-induced adipocytokine that exacerbates the inflammatory phenotype of adipocytes through PHLPP1 induction. The Biochemical journal 21 31710352
2018 Clusterin enhances AKT2-mediated motility of normal and cancer prostate cells through a PTEN and PHLPP1 circuit. Journal of cellular physiology 21 30565691
2016 PHLPP negatively regulates cell motility through inhibition of Akt activity and integrin expression in pancreatic cancer cells. Oncotarget 21 26760962
2014 The N-terminal region of p27 inhibits HIF-1α protein translation in ribosomal protein S6-dependent manner by regulating PHLPP-Ras-ERK-p90RSK axis. Cell death & disease 21 25412313
2013 SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells. Molecular biology reports 21 23440515
2021 Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes. Cell reports 20 34348155
2021 Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer. Cell death & disease 20 34663797
2020 Heat shock protein 47 promotes tumor survival and therapy resistance by modulating AKT signaling via PHLPP1 in colorectal cancer. Cancer biology & medicine 19 32587773
2020 P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures. International journal of molecular sciences 19 32899862
2015 MiR-522 contributes to cell proliferation of human glioblastoma cells by suppressing PHLPP1 expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 25776496
2020 Phenolic Profile, Toxicity, Enzyme Inhibition, In Silico Studies, and Antioxidant Properties of Cakile maritima Scop. (Brassicaceae) from Southern Portugal. Plants (Basel, Switzerland) 18 31979182
2010 Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL. Journal of neurochemistry 18 20089132
2021 Reduced PHLPP Expression Leads to EGFR-TKI Resistance in Lung Cancer by Activating PI3K-AKT and MAPK-ERK Dual Signaling. Frontiers in oncology 17 34168988
2018 Biologically active compounds from two members of the Asteraceae family: Tragopogon dubius Scop. and Tussilago farfara L. Journal of biomolecular structure & dynamics 17 30058457
2016 Role of PHLPP1 in inflammation response: Its loss contributes to gliomas development and progression. International immunopharmacology 17 26971226
2014 A novel immunomodulatory function of PHLPP1: inhibition of iNOS via attenuation of STAT1 ser727 phosphorylation in mouse macrophages. Journal of leukocyte biology 17 24443556
2022 PHLPP1 promotes neutral lipid accumulation through AMPK/ChREBP-dependent lipid uptake and fatty acid synthesis pathways. iScience 16 35141506
2019 MIR-190B Alleviates Cell Autophagy and Burn-Induced Skeletal Muscle Wasting via Modulating PHLPP1/Akt/FoxO3A Signaling Pathway. Shock (Augusta, Ga.) 16 30407372
2019 Autophagy-mediated Mir6981 degradation exhibits CDKN1B promotion of PHLPP1 protein translation. Autophagy 16 30821592
2018 Silencing of PHLPP1 promotes neuronal apoptosis and inhibits functional recovery after spinal cord injury in mice. Life sciences 16 30114409
2016 Inhibitory Kinetics and Mechanism of Flavonoids Extracted from Cotinus coggygria Scop. Against Glioblastoma Cancer. Nutrition and cancer 16 27673410
2021 PMEPA1/TMEPAI Is a Unique Tumorigenic Activator of AKT Promoting Proteasomal Degradation of PHLPP1 in Triple-Negative Breast Cancer Cells. Cancers 15 34638419
2019 Biological properties of Cakile maritima Scop. (Brassicaceae) extracts. European review for medical and pharmacological sciences 15 30915777
2018 Acute Physiology and Neurologic Outcomes after Brain Injury in SCOP/PHLPP1 KO Mice. Scientific reports 15 29739983
2018 Genome-wide mRNA-miRNA profiling uncovers a role of the microRNA miR-29b-1-5p/PHLPP1 signalling pathway in Helicobacter pylori-driven matrix metalloproteinase production in gastric epithelial cells. Cellular microbiology 15 29749704
2018 Tumor necrosis factor-alpha upregulated PHLPP1 through activating nuclear factor-kappa B during myocardial ischemia/reperfusion. Life sciences 14 29940243
2015 Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting Survivin phosphorylation and nuclear export in gallbladder cancer. Oncotarget 14 25895131
2013 NFκB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis. Molecular biology of the cell 14 24068327
2023 SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma. Molecules and cells 13 36694914
2023 FKBP51 plays an essential role in Akt ubiquitination that requires Hsp90 and PHLPP. Cell death & disease 13 36781840
2022 CircRNA_45478 promotes ischemic AKI by targeting the miR-190a-5p/PHLPP1 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13 36315192
2020 USP46 Inhibits Cell Proliferation in Lung Cancer through PHLPP1/AKT Pathway. BioMed research international 13 33029497
2016 SCOP/PHLPP1β in the basolateral amygdala regulates circadian expression of mouse anxiety-like behavior. Scientific reports 13 27640726