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FLASH GENE
Symbol PDE4D contributors: mct - updated : 03-12-2018
HGNC name phosphodiesterase 4D, cAMP-specific
HGNC id 8783
Corresponding disease
ACDS acrodysostosis
Location 5q11.2      Physical location : 58.264.865 - 59.783.925
Synonym name
  • phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)
  • cAMP-specific phosphodiesterase PDE4D6
  • dunce-like phosphodiesterase E3
  • cAMP-specific phosphodiesterase 4D
  • Synonym symbol(s) DPDE3, HSPDE4D, STRK1, FLJ97311, PDE43, ACRDYS2, PDE43N2
    EC.number 3.1.4.17/ 3.1.4.53
    DNA
    TYPE functioning gene
    STRUCTURE 924.76 kb     15 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    Binding site   cAMP
    text structure a cAMP-responsive region, a number of GC-rich regions, and binding sites for SP1, AP1 and AP2
    MAPPING cloned Y linked N status confirmed
    Physical map
    PPAP2A 5q11 phosphatidic acid phosphatase type 2A LOC379013  ring finger protein 138 pseudogene LOC391785 5 similar to Adenylate kinase isoenzyme 4, mitochondrial (ATP-AMP transphosphorylase) FLJ90709 5q11.2 hypothetical protein FLJ90709 DDX4 5q11.2-q12 DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 LOC391786 5 similar to heterogeneous nuclear ribonucleoprotein H CRL3 5q11.2 gp130-like monocyte receptor IL6ST 5q11.1-q11.2 interleukin 6 signal transducer (gp130, oncostatin M receptor) FLJ11795 5q11.2 hypothetical protein FLJ11795 LOC345645 5q11.2 similar to protease (prosome, macropain) 26S subunit, ATPase 1 LOC347593 5q11.2 60S ribosomal protein L26 pseudogene MAP3K1 5q11.2 mitogen-activated protein kinase kinase kinase 1 MGC33648 5q11.2 hypothetical protein MGC33648 FLJ35954 5q11.2 hypothetical protein FLJ35954 DKFZp761C169 5q11.2 vasculin LOC133374 5q11.2 similar to hypothetical protein FLJ10534 LOC391787 5 similar to sal-like 4 LOC345651 5q12.1 similar to RIKEN cDNA 4732495G21 gene SNK 5q12.1-q13.2 serum-inducible kinase FLJ33641 5q12.1 hypothetical protein FLJ33641 RAB3C 5q13 RAB3C, member RAS oncogene family PDE4D 5q12 phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) LOC391788 5 similar to PDE4D protein LOC389291 5 similar to cAMP-specific phosphodiesterase PDE4D7 LOC391789 5 similar to ribosomal protein L31 LOC345659 5q12.1 similar to template acyivating factor-I alpha PART1 5q12.1 similar to template acyivating factor-I alpha XTP1 5q12.1 HBxAg transactivated protein 1 LOC391790 5 similar to KRT8 protein FLJ23563 5q12.1 hypothetical protein FLJ23563 CKN1 5q11.1-q11.2 Cockayne syndrome 1 (classical) FLJ12595 5q12.1 hypothetical protein FLJ12595 LOC91942 5q12.1 hypothetical protein LOC91942 LOC389292 5 LOC389292 LOC57399 5q12.1 uncharacterized gastric protein ZA52P ZSWIM6 5q12.1 zinc finger, SWIM domain containing 6 FLJ37543 5q12.1-q12.2 hypothetical protein FLJ37543 KIF2 5q12-q13 kinesin heavy chain member 2 HSA9761 5q11-q14 putative dimethyladenosine transferase IPO11 5q12.1 importin 11
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 splicing 7801 - 585 - 2003 14517540
    also called PDE4D1, isoform 8
    11 splicing 7715 - 507 - 2012 22464252
  • also called PDE4D2, isoform 7
  • part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9
  • lack the N-terminal UCR1 domain, which regulates catalytic activity along with UCR2
  • 15 splicing 7783 76.3 673 - 2003 14517540
  • PDE4D3, isoform 2
  • found in the cardiac ryanodine receptor (RyR2)/calcium-release-channel complex (required for excitation-contraction coupling in heart muscle)and playing a protective role in the heart against heart failure and arrhythmias
  • reduced in failing human hearts, contributing to PKA-hyperphosphorylated, "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias
  • contains a regulatory domain target for phosphorylation at the amino terminus of the protein and that Ser54 in this domain plays a crucial role in activation (PMID: 8663227)
  • is responsible for maintaining a microdomain with low cAMP concentration at the centrosome (PMID: 22908311)
  • 15 splicing 8240 - 809 - 2012 22464252
  • also called PDE4D4
  • isoform 1
  • two highly evolutionarily conserved upstream regions (UCR1 and UCR2) and the large catalytic domain
  • 15 splicing 7979 - 745 - 2012 22464252
  • also called PDE4D5, isoform 4
  • promoter up-regulated reporter gene expression in response to increased cell cAMP
  • binding to GNB2L1 via its unique N-terminus
  • interaction of PDE4D5 with both the N- and C-domains of ARRB2 are essential for beta2-AR (ADRB2) regulation (PMID: 17288540)
  • can be sumoylated (PMID: 20196770)
  • two highly evolutionarily conserved upstream regions (UCR1 and UCR2) and the large catalytic domain
  • TRPV1 association with ARRB2 is critical to receptor desensitization via its ability to scaffold the phosphodiesterase PDE4D5 to the receptor, regulating TRPV1 phosphorylation (PMID: 23360390)
  • RACK1 and ARRB2 inhibit the dimerization of PDE4D5 (PMID: 26257302)
  • 10 splicing 7591 59.1 518 only in brain 2012 22464252
  • also called PDE4D6, isoform 9
  • lack the N-terminal UCR1 domain, which regulates catalytic activity along with UCR2
  • 17 splicing 8130 84.7 748 - 2012 22464252
  • PDE4D7, isoform 3
  • two highly evolutionarily conserved upstream regions (UCR1 and UCR2) and the large catalytic domain
  • 15 splicing 7757 77.7 687 heart, muscle, lung 2003 12834813
  • also called PDE4D8, isoform 5
  • ADRB1 associates with PDE4D8 through the receptor C-terminal PDZ motif-dependent binding to synaptic-associated protein 97 (DLG1)
  • 14 splicing 8395 76.8 679 - 2003 14517540
  • also called PDE4D9, isoform 6
  • mitotic activation of the DISC1-inducible cyclic PDE4D9, through multi-site phosphorylation, influences cell cycle progression (PMID: 24815749)
  • 18 - 8203 - 738 - 2012 22464252
    17 - 8153 - 799 - 2012 22464252
    17 - 8129 - 553 - 2012 22464252
    17 - 8110 - 748 - 2012 22464252
    PDE4D7
    8 - 1484 - 222 - 2012 22464252
    2 - 3388 - 152 - 2012 22464252
    6 - 1595 - 219 - 2012 22464252
    16 - 8247 - 507 - 2012 22464252
    14 - 8824 - 553 - 2012 22464252
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon moderately
     liver   highly
    Endocrineneuroendocrinepituitary  moderately
    Hearing/Equilibriumear   highly
    Lymphoid/Immunethymus    
    Reproductivefemale systemuterus  moderately
     male systemprostate  highly
     male systemtestis   
    Respiratorylung     Homo sapiens
     nasopharynx   moderately
     respiratory tractlarynx  highly
     respiratory tracttrachea  moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal moderately
    cells
    SystemCellPubmedSpeciesStageRna symbol
    not specificfibroblast Homo sapiens
    cell lineage
    cell lines
    fluid/secretion blood
    at STAGE
    physiological period fetal, pregnancy
    Text placenta, eye, trabecular meshwork
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a variable N-terminus containing UCR1 and UCR2
  • a C-terminal catalytic core
  • mono polymer homomer , monomer , dimer
    HOMOLOGY
    interspecies homolog to Drosophila dunce gene
    ortholog to rattus Pde4d (98.1pc)
    ortholog to murine Pde4d (98.6pc)
    homolog to Drosophila dnc (64.6pc)
    Homologene
    FAMILY
  • cyclic nucleotide phosphodiesterase family
  • CATEGORY enzyme , signaling
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus
    intracellular,nuclear envelope
    text
  • in the soluble fraction
  • associated with membranes
  • associated with the cytoskeleton and the centrosome
  • basic FUNCTION
  • cAMP specific nucleotide phosphodiesterase may be involved in signal transduction
  • playing a pivotal role in the regulation of airway smooth muscle relaxation by catalyzing the hydrolysis of cAMP
  • plays a critical role in the memory and hippocampal neurogenesis mediated by cAMP signaling
  • regulating the levels of cAMP in the cell
  • regulator of airway smooth-muscle contractility
  • role of PDE4D in BRAF-mutated melanoma as regulator of cell invasion
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism nucleic
    signaling signal transduction
    cyclic nucleotide metabolism
    a component
  • homodimer for the long isoforms
  • monomeric for isoforms with truncated N-termini
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
    two divalent metal cations per subunit :
  • Zn2+ (preferentially in site 1)
  • Mg2+ and/or Mn2+ (preferentially in site 2)
  • protein
  • RYR2 channel
  • upregulation of NOX4 leads to an upregulation of PDE4A, PDE4B, and PDE4D and increased hydrolysis of cAMP which in turn augments cell replication and angiogenesis
  • PRKACA and PDE4D anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome
  • CC2D1A is a novel regulator of PDE4D
  • PDE4D interacts directly with Neuropilins, positive regulators of HH pathway
  • cell & other
    REGULATION
    activated by phosphatidic acid
    inhibited by rolipram
    ASSOCIATED DISORDERS
    corresponding disease(s) ACDS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    causing defective RyR2-channel function associated with heart failure and arrhythmias
    constitutional germinal mutation      
    are associated with ischemic stroke, due to increased cardiac risk factor as well as augmented risk of atrial fibrillation
    Susceptibility
  • to ischemic strocke
  • to asthma
  • Variant & Polymorphism SNP , other
  • polymorphism increasing the risk of cerebral infarction, exclusively to current smokers
  • SNPs associated with asthma
  • association between PDE4D polymorphism SNP83 and ischemic stroke
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    mental retardationother 
    CC2D1A and/or PDE4D may be promising targets for therapeutic interventions in many disorders with impaired PDE4D function
    cancerskin 
    potential as a target for preventing metastatic dissemination in melanomas
    cancerbrain 
    is a promising target to treat HH-related tumors
    ANIMAL & CELL MODELS
  • Pde4d-null mice exhibit reduced growth and midface hypoplasia
  • isolated Pde4d(-/-) murine cardiomyocytes showed increased whole-cell Ca2+ transient amplitudes and sarcoplasmic reticulum Ca2+content but unchanged L-type calcium current