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FLASH GENE
Symbol PHLPP1 contributors: mct/npt/pgu - updated : 19-09-2016
HGNC name PH domain and leucine rich repeat protein phosphatase
HGNC id 20610
Location 18q21.33      Physical location : 60.382.671 - 60.647.665
Synonym name
  • pleckstrin homology domain containing, family E (with leucine rich repeats) member 1
  • SCN circadian oscillatory protein
  • suprachiasmatic nucleus circadian oscillatory protein
  • Synonym symbol(s) KIAA0606, SCOP, PLEKHE1, MGC161555, PHLPP
    EC.number 3.1.3.16
    DNA
    TYPE functioning gene
    STRUCTURE 265.00 kb     17 Exon(s)
    motif
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    text
  • a splice variant with additional 5-prime sequence that encodes a deduced 1,717-amino acid protein (PMID: 17386267)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    18 - 6401 - 1717 - 2007 17386267
  • also called variant 1 or PHLPP1 alpha
  • differ in an amino-terminal extension on PHLPP1 beta
  • PH domain of PHLPP1 playing a critical role in PHLPP-mediated dephosphorylation of PKC
  • specifically modulates the phosphorylation of HDM2 and GSK-3alpha through AKT2
  • - - - - - - 2007 17386267
  • also called PHLPP2
  • having a PP2C-like phosphatase domain
  • functions as a phosphatase for PKC
  • specifically modulates the phosphorylation of p27 through AKT3
  • - - - - - - 2008 18162466
  • also called PHLPP1 beta
  • differ in an amino-terminal extension on PHLPP1 alpha
  • PH domain playing a critical role in PHLPP-mediated dephosphorylation of PKC
  • EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  moderately
     mouth   highly
    Endocrineparathyroid   moderately
     thyroid   moderately
    Hearing/Equilibriumearinnercochlea highly
    Lymphoid/Immunelymph node   highly
    Nervousbraindiencephalonhypothalamussuprachiasmatic nucleihighly
    Reproductivemale systemtestis  moderately
    Skin/Tegumentskin   moderately
    Visualeye   predominantly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  moderately
    Connectivebone  moderately
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a pleckstrin homology domain (PH)
  • nineteen leucine-rich repeats (LRR)
  • phosphatase domain effectively dephosphorylates synthetic and peptidic substrates, its activity is modulated by metals and lipophilic compounds, and it has relatively high thermal stability
  • a protein phosphatase 2C-like domain
  • a glutamine-rich region
  • HOMOLOGY
    interspecies homolog to rattus Phlpp (94.9 pc)
    homolog to murine Phlpp (94.7 pc)
    Homologene
    FAMILY
  • Ser/Thr protein phosphatases family
  • CATEGORY enzyme , regulatory , tumor suppressor , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • acting as a circadian oscillator
  • mediating specifically dephosphorylation of 'Ser-473' of AKT1
  • may act as a negative regulator of K-Ras signaling in the membrane rafts
  • contributing to activation of MAPK during memory formation, by degradation by calpain
  • controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation
  • function as tumor suppressor protein, and important physiological regulator of cell growth and of cellular stress signaling
  • negative regulator of Akt and protein kinase C by dephosphorylating the kinases directly
  • involved in the regulation of cell proliferation
  • exerts a previously unappreciated role in circadian control, governing the consolidation of circadian periodicity after resetting
  • plays a role in the differential response to short and long lights which implicates it in SCN neuronal plasticity
  • plays a central role in controlling the amplitude of growth factor signaling by directly dephosphorylating and thereby inactivating AKT1
  • enhances PARP1 inhibitor-induced apoptotic cell death by the attenuation of AKT1 phosphorylation
  • functions as a tumor suppressor by negatively regulating AKT1 signaling in cancer cells
  • is a novel player involved in regulating protein translation initiation and cell size via direct dephosphorylation of RPS6KB1
  • PHLPP1, PHLPP2 dephosphorylate AKT1 to limit its activity
  • similar to PHLPP1 function, WDR48 and USP12 negatively regulate AKT1 activation and thus promote cellular apoptosis
  • WDR48 and USP12 are novel PHLPP1 regulators and potential suppressors of tumor cell survival
  • PHLPP1 plays an important role in the assembly of kinetochores by counteracting RNF41-mediated SUGT1 degradation
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS circadian , nervous system
    PATHWAY
    metabolism
    signaling signal transduction
    a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding, cofactor,
  • Mn2+ (2 ions per subunit)
  • protein
  • interacting with nucleotide free form K-Ras (KRAS) via its LRR repeats
  • dephosphorylates the hydrophobic motif of PKCs, effectively terminating the lifetime of PKC
  • BTRC interacting with PHLPP1 (cellular localization of BTRC is altered in glioblastoma, resulting in dysregulation of PHLPP1 and other substrates such as beta-catenin)
  • functional interaction between PHLPP1 and SCRIB in negatively regulating AKT signalling (Pubmed 21701506)
  • requires SLC9A3R1 for membrane localization and growth-suppressive effects
  • RPS6KB1 is a novel substrate of PHLPP1
  • USP46 binds to PHLPP1 and directly removes the polyubiquitin chains from PHLPP1 in cells
  • USP12, in complex with WDR48 and WDR20, directly deubiquitinates and stabilises the AKT1 phosphatases PHLPP1 and PHLPP2 resulting in decreased levels of active AKT1
  • RNF7 is an E3 ligase that promotes ubiquitylation and degradation of PHLPP1 and DEPTOR, leading to activation of the PI3K/AKT/MTOR axis, whereas RNF7 knockdown caused their accumulation
  • PHLPP1 interacted with the essential outer-kinetochore protein SUGT1 and stabilized its protein levels
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in several colon cancer and glioblastoma cell lines with elevates AKT1 phosphorylation
    tumoral        
    lost expression in colorectal cancers
    tumoral     --over  
    enhances the PARP1 inhibitor-induced downregulation of AKT1 phosphorylation and increases tumor cell death
    tumoral     --other  
    significant disruption of all three members of the PTEN-SLC9A3R1-PHLPP1 tumor suppressor network in high-grade glioma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • a transgenic mouse strain for the inducible overexpression of SCOP in the forebrain
  • PHLPP1-null mice, although displaying normal circadian rhythmicity, have a drastically impaired capacity to stabilize the circadian period after light-induced resetting, producing a large phase shift after light resetting