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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003159 21 - 3434 NP_003150 115 1030 in a variety of tissues 2012 21748340 both isoforms differ in the 5prime untranslated exons NM_001037343 22 - 3430 NP_001032420 115 1030 in testis only 2012 21748340 both isoforms differ in the 5prime untranslated exons CDKL5 v3 - - - 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)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune thymus       highly Nervous brain       highly Reproductive female system ovary         male system testis     highly   male system prostate       Respiratory lung         Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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