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FLASH GENE
Symbol DMPK contributors: mct/npt/shn - updated : 01-04-2016
HGNC name dystrophia myotonica-protein kinase
HGNC id 2933
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • five distinct domains
  • N terminal stretch leucine-rich
  • a kinase domain S/T type subfamily, with presence, also in LATS2, of two negative pockets in the peptide binding groove provides an explanation for the substrate preference
  • a coiled-coil domain modulating multimerization, substrate binding, kinase activity and subcellular localization characteristics
  • a five AA sequence with unknown function
  • an hydrophobic C terminus
  • an alpha helical domain at various C termini possibly acting as self-association domain or membrane anchor
    • HOMOLOGY
    interspecies ortholog to DMPK, Pan troglodytes
    ortholog to Dmpk, Rattus norvegicus
    ortholog to Dmpk, Mus musculus
    intraspecies homolog to DMR-B15
    Homologene
    FAMILY
  • multidomain protein kinases
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    intracellular,nuclear envelope
    text
  • localised prominently at sites of neuromuscular and myotendinous junctions and rodent skeletal muscles
  • highly enriched in the sarcoplasmic reticulum of cardiac myocytes
  • DMPK A and C proteins both localized to mitochondria
    • basic FUNCTION
  • myotonin serine threonine kinase, modulator of the Ca++ homeostasis in skeletal muscle cell presenting a replication discrepancy between the normal and the mutant allele in cells with the CTG repeat expansion
  • involved in the organization of sarcoplasmic reticulum in skeletal muscle
  • playing a critical role for the modulation of cardiac contractility and the maintenance of proper cardiac conduction activity
  • phosphorylating phospholamban and regulating calcium uptake in cardiomyocyte sarcoplasmic reticulum
  • a kinase with pronounced expression in diverse muscle and neural tissues that are affected in DM1 (Oude 20096)
  • a key role in myocyte differentiation
  • necessary for myogenin expression in differentiating C2C12 myoblasts
  • a critical component of the nuclear envelope
    • CELLULAR PROCESS cell organization/biogenesis
    PHYSIOLOGICAL PROCESS
    text Ca2+ homeostasis in skeletal muscle
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • DMPK-binding protein, MKBP
  • actin cytoskeleton-linked GTPase Rac-1 and Raf-1 kinase
  • phospholamban, PLN
  • Lamin-A/C
  • DDX6 can remodel and release nuclear DMPK messenger ribonucleoprotein foci, leading to normalization of pathogenic alternative splicing events
    • cell & other
    REGULATION
    activated by HSPB2, RAC1, RAF1 suggesting that DMPK plays a role as a nexus between the repetitive pathways af these signals
    induced by intracellular signaling pathways that induce myotonic dystrophy protein kinase expression during myogenesis
    Other enhanced by DMPK-binding protein, MKBP
    ASSOCIATED DISORDERS
    corresponding disease(s) DM1
    Susceptibility
    Variant & Polymorphism repeat associated to spontaneous chromosome loss and colcemid resistance in lymphocytes of DM1
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • mice expressing the CUG expansion in an unrelated mRNA develop myotonia and myopathy, and show abnormal tau expression in the brain
  • overexpression of the DMPK 3'-UTR including either wild-type (11) or expanded (91) CTG repeats results in aberrant and delayed muscle development in fetal transgenic mice, and mice display muscle atrophy at 3 months of age
  • overexpression of DMPK mRNA and protein transgene products in cardiac, skeletal and smooth muscles of transgenic murine line carrying approximately 25 extra copies of a complete hDMPK gene with all exons and an intact promoter region resulted in deficient exercise endurance, hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy
  • PLN is hypo-phosphorylated in SR vesicles from DMPK(-/-) mice compared with wild-type mice
  • mice overexpressing a normal DMPK 3' UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusion
  • inductible DM1 mouse model misregulation of developmentally regulated alternative splicing events, myotonia, characteristic histological abnormalities, and increased CUGBP1 protein levels
  • Overexpression of DMPK induces cell rounding and apoptosis in myocytes
  • Overexpression of DMPK in HeLa cells or C2C12 myoblasts disrupts Lamin-A/C and Lamin-B1 localization and causes nuclear fragmentation, and depletion of DMPK disrupts nuclear envelope lamina