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FLASH GENE
Symbol PPP1R15A contributors: mct - updated : 25-05-2016
HGNC name protein phosphatase 1, regulatory (inhibitor) subunit 15A
HGNC id 14375
Location 19q13.33      Physical location : 49.375.648 - 49.379.318
Synonym name
  • growth arrest and DNA-damage inducible transcript 34
  • myeloid differentiation primary response protein MyD116 homolog
  • Synonym symbol(s) GADD34, MYD116
    DNA
    TYPE functioning gene
    STRUCTURE 3.67 kb     3 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 - 2399 73.3 674 - 2003 12813455
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Endocrinepancreas    
    Nervousbrain    
    Respiratorylung    
    Urinarykidneytubuleconvoluted tubuleproximal tubule 
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialabsorptive excretoryrenal tubular epithelium  
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Endocrineislet cell (alpha,beta...)
    Respiratoryalveolar macrophage
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a serie of 34AA repeats in its center portion
  • a region of homology with the herpes simplex virus type 1 ICP34.5 protein that is involved in the prevention of apoptosis in infected cells
  • EIF2S1-binding motif to the C terminus of PPP1R15A in a region distinct from where PP1 binds to PPP1R15A
  • HOMOLOGY
    interspecies homolog to murine Gadd34
    Homologene
    FAMILY
  • PPP1R15 family
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,outer
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    text
  • association of with ER modulates intracellular trafficking and proteasomal degradation of PPP1R15A, and in turn, its ability to modify ER morphology
  • basic FUNCTION
  • likely involved in apoptosis, cell cycle arrest, DNA damage response
  • cellular stress response protein mediating growth arrest and apoptosis in response to DNA damage, negative growth signals, and protein malfolding
  • cross talk between stress-inducible PPP1R15A and the MTOR signaling pathway plays a critical role in antiviral defense
  • physiological importance of PPP1R15A turnover in protein processing in the endoplasmic reticulum and potential impact of prolonged PPP1R15A expression in human disease as Cystic fibrosis
  • involved in EIF2A dephosphorylation, which is the predominant role of PPP1R15A and PPP1R15B in mammalian development
  • negatively regulates cell migration in wound healing via expression of myosin IIA
  • starvation-induced PPP1R15A suppresses MTOR and, thereby, induces autophagy
  • regulates mTOR signaling pathways for protein synthetic machinery in response to environmental stress
  • functions as a negative regulator of the MTOR pathway by binding to and dephosphorylating TSC2 during starvation period
  • plays an important role in cell protection in mutant huntingtin expressing cells
  • specific EIF2S1 phosphatases, PPP1R15A and PPP1R15B, play crucial roles in the recovery of protein synthesis following the initial insult
  • works to inhibit the proliferation and differentiation of Hematopoietic stem cells (HSCs) or myeloid precursor cells and maintains homeostatic differentiation of neutrophil-lineage cells to avoid early immunological senescence
  • PPP1R15A and its viral orthologs direct specific dephosphorylation of EIF2S1 by interacting with both PP1 and EIF2S1 through independent binding motifs
  • plays a vital role in promoting cell death following proteasome inhibition via enhancing protein synthesis to activate death-associated mechanisms, including ER stress, ROS production and autophagy formation
  • preferentially translated PPP1R15A and constitutively expressed PPP1R15B function to dephosphorylate EIF2S1-Phosphorylated and restore protein synthesis
  • attenuates LPS-induced sepsis and acute tissue injury through suppressing macrophage activation
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    text cell cycle arrest
    PATHWAY
    metabolism
    signaling
  • novel redox signaling pathway, involving NOX4-PPP1R15A interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains EIF2S1 phosphorylation to protect tissues under stress
  • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binds to protein phosphatase PP1(stimulated by SMARCB1)
  • also interacted with CUEDC2
  • interacts with protein phosphatase 1 to dephosphorylate EIF2A, resulting in a negative feedback loop to recover protein synthesis and allow translation of stress-induced transcripts
  • EIF2AK4 activation and phosphorylation of EIFS1 in response to MTOR inhibition are necessary for autophagy
  • enhances autophagy and suppresses apoptosis stimulated by LPS combined with amino acid deprivation through regulation of mTOR signaling pathway in macrophages
  • PPP1R15A associates with the broadly acting serine/threonine protein phosphatase 1 (PP1) to dephosphorylate EIF2S1
  • PPP1R15A and its viral orthologs direct specific dephosphorylation of EIF2S1 by interacting with both PP1 and EIF2S1 through independent binding motifs
  • preferentially translated PPP1R15A and constitutively expressed PPP1R15B function to dephosphorylate EIF2S1 and restore protein synthesis
  • coordinate regulation of UPR by the PPP1R15A- and PPP1R15B-containing EIF2S1 phosphatases to control cell viability
  • cell & other
    REGULATION
    induced by ionizing radiation,stressful growth arrest conditions and DNA-damaging agents
    IL6
    a variety of stressors, including DNA damage, heat shock, nutrient deprivation, energy depletion, and endoplasmic reticulum stress
    by various cellular stresses, such as DNA damage, endoplasmic reticulum stress, and amino-acid deprivation
    Other induced in liver under starvation conditions
    PPP1R15A expression is regulated through the activity of the zinc finger transcription factor NMP4 (ZNF384)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    increased in neurons of human Alzheimer disease (AD) brains
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyinflammatory 
    targeting the anti-inflammatory role of PPP1R15A may be a promising area for the development of therapeutic agents to regulate inflammatory disorders
    neurologyneurodegenerativealzheimer
    could be a therapeutic target for preventing ER stress in neuronal cells in AD
    ANIMAL & CELL MODELS
  • with age Gadd34-deficient mice become obese, developing fatty liver followed by liver cirrhosis, hepatocellular carcinoma, and insulin resistance