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FLASH GENE
Symbol CDKL5 contributors: mct/npt - updated : 28-01-2017
HGNC name cyclin-dependent kinase-like 5
HGNC id 11411
RNA
TRANSCRIPTS type messenger
text
  • identification of a novel exon, which is referred to as exon 16b, within the cyclin-dependent kinase (CDK)-like 5 (CDKL5) gene that is implicated in the X-linked infantile spasm syndrome and the early-onset seizure variant of Rett syndrome (PMID: 21124335)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    21 - 3434 115 1030 in a variety of tissues 2012 21748340
    both isoforms differ in the 5prime untranslated exons
    22 - 3430 115 1030 in testis only 2012 21748340
    both isoforms differ in the 5prime untranslated exons
    - - - 107 - in brain and all other tissues 2012 21748340
  • including a novel exon (16b)
  • alternative C-terminus that terminates in intron 18
  • major CDKL5 transcript
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunethymus   highly
    Nervousbrain   highly
    Reproductivefemale systemovary   
     male systemtestis  highly
     male systemprostate   
    Respiratorylung    
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, pregnancy
    Text placenta, neural cells, neocortex, hippocampus
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal catalytic domain highly homologous to members of the mitogen-activated protein (MAP) kinase and cyclin-dependent (CDK) kinase families
  • a TXY sequence, activation motif of classic MAP kinases
  • C-terminal domain, which is frequently deleted in pathogenic mutations, is involved in an active nuclear export mechanism modulating the subcellular distribution of the kinase
  • HOMOLOGY
    interspecies homolog to murine Stk9
    homolog to C.elegans zk254.4
    Homologene
    FAMILY
  • protein kinase superfamily
  • CMGC Ser/Thr protein kinase family
  • CDC2/CDKX subfamily
  • CATEGORY enzyme , receptor membrane serine/threonine kinase
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
    text
  • CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the C-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions
  • shuttles between the two main cellular compartments and the relative concentrations in each compartment seem to vary in different brain areas and during development
  • localizes to specific nuclear foci referred to as nuclear speckles in both cell lines and tissue (Nemos 2009)
  • localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments
  • basic FUNCTION
  • having protein kinase, ATP binding activities
  • involved in protein amino acid phosphorylation
  • autophosphorylates (can self-associate and mediate the phosphorylation of its own TEY [Thr-Glu-Tyr] motif)and mediating the phosphorylation of the methyl-CpG-binding protein 2 (MECP2)
  • shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export
  • regulates the dynamic behaviour of nuclear speckles, and controls nuclear speckle morphology probably by regulating the phosphorylation state of splicing regulatory proteins (Ricciardi 2009)
  • involved indirectly in pre-mRNA processing, by controlling splicing factor dynamics (Ricciardi 2009)
  • functional axis between MYCN and CDKL5 governing both neuron proliferation rate and differentiation
  • localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity
  • critical role of the palmitoylation-dependent CDKL5-DLG4 interaction in localizing CDKL5 to synapses for normal spine development
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with MECP2 (could dephosphorylate MECP2, and form a protein complex, the catalytic activity of CDKL5 mediating the phosphorylation of MECP2)
  • subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-D-aspartate receptors and suggest regulation of CDKL5 by cell death pathways
  • MYCN acts as a direct repressor of the CDKL5 promoter
  • CDKL5 binds and phosphorylates the cell adhesion molecule LRRC4C (this phosphorylation event ensures a stable association between LRRC4C and DLG4)
  • AMPH is the cytoplasmic substrate for CDKL5 and its phosphorylation may play crucial roles in the neuronal development
  • binds to the scaffolding protein postsynaptic density DLG4, and this binding promotes the targeting of CDKL5 to excitatory synapses
  • CDKL5 regulates microtubule dynamics via phosphorylation of MAP1S
  • cell & other
    REGULATION
    activated by phosphorylation on tyrosine and threonine
    inhibited by by MYCN, a transcription factor that promotes cell proliferation during brain development and plays a relevant role in neuroblastoma biology
    ASSOCIATED DISORDERS
    corresponding disease(s) ISSX , EIEE2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    leading to severe neurodevelopmental disorders
    constitutional       loss of function
    absence or reduction of CDKL5 kinase functions have a greater impact on the nervous system than a gain of activity
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS