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FLASH GENE
Symbol CDK5 contributors: mct/pgu/shn - updated : 24-06-2017
HGNC name cyclin-dependent kinase 5
HGNC id 1774
Location 7q36.1      Physical location : 150.750.898 - 150.755.052
Synonym name
  • neuronal Cdc2-like kinase
  • serine/threonine-protein kinase PSSALRE
  • Tau protein kinase II catalytic subunit
  • TPKII catalytic subunit
  • cell division protein kinase 5
  • protein kinase CDK5 splicing
  • Synonym symbol(s) PSSALRE
    EC.number 2.7.11.22
    DNA
    TYPE functioning gene
    STRUCTURE 4.15 kb     12 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D7S1805 - D7S636 - CDK5 - D7S642 - D7S2461 - qter
    Physical map
    HIMAP4 7q36.1 immunity associated protein 4 LOC392149 7 similar to transient receptor potential cation channel, subfamily C, member 6; transient receptor potential channel 6 hIAN2 7q36.1 human immune associated nucleotide 2 HIMAP2 7q36.1 immunity associated protein 2 IMAP1 7q36.1 immunity associated protein 1 IAN4L1 7q32-q36 immune associated nucleotide 4 like 1 (mouse) LOC392150 7 similar to immune associated nucleotide 4 like 1; immunity associated protein 3 LOC392151 7 similar to BET1 homolog (Golgi vesicular membrane trafficking protein p18) (hBET1) LR8 7q36.1 LR8 protein HCA112 7q36.1 hepatocellular carcinoma-associated antigen 112 ABP1 7q34-q36 amiloride binding protein 1 (amine oxidase (copper-containing)) KCNH2 7q35-q36 potassium voltage-gated channel, subfamily H (eag-related), member 2 NOS3 7q36 nitric oxide synthase 3 (endothelial cell) FLJ39415 7q36.1 hypothetical protein FLJ39415 ABCB8 7q35-q36 ATP-binding cassette, sub-family B (MDR/TAP), member 8 ACCN3 7q35 amiloride-sensitive cation channel 3, testis CDK5 7q36 cyclin-dependent kinase 5 SLC4A2 7q35-q36 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1) FASTK 7q35 FAST kinase C7orf21 7q36.1 chromosome 7 open reading frame 21 CENTG3 7q36.17q36.1 centaurin, gamma 3 LOC392152 7 similar to gastrulation brain homeobox 1 ASB10 7q35 ankyrin repeat and SOCS box-containing 10 LOC155046 7q36.1 similar to hypothetical protein 4931409K22 LOC346545 7q36.1 similar to hypothetical protein FLJ22527 ABCF2 7q35-q36 ATP-binding cassette, sub-family F (GCN20), member 2 CSGlcA-T 7q36.1 KIAA1402 protein SMARCD3 7q35-q36 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 3 NYREN18 7q36 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 3 LOC349136 7q36.1 hypothetical protein LOC349136 CRYGN 7q36.1 crystallin, gamma N
    RNA
    TRANSCRIPTS type messenger
    text
  • calpain-mediated cleavage of p35 to p25 and the resulting aberrant activity and neurotoxicity of CDK5 have been implicated in neurological disorders, such as Alzheimer disease (PMID: 21338355)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 splicing 1111 29.5 260 - 1994 7834371
    p25
    12 splicing 1211 33.3 292 - 1994 7834371
    p35
    EXPRESSION
    Rna function CDK5 mRNA was distributed in neurons throughout the brain, spinal cord and peripheral ganglia, especially in the hippocampal pyramidal cells, cerebellar Purkinje cells, cortical neurons, olfactory mitral cells, mesencephalic and motor trigeminal nuclei and trigeminal ganglion
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivesalivary gland   moderately
    Endocrineadrenal gland   highly
    Lymphoid/Immunetonsils   moderately
    Nervousbrain   highly Homo sapiens
    Reproductivemale systemprostate  moderately
     male systemtestis  moderately Homo sapiens
    Visualeye   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  moderately
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    cell cycle     cell cycle, checkpoint, G1S
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a PSTAIRE-like motif
  • a protein kinase domain
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to cdk5, Danio rerio
    ortholog to Cdk5, Rattus norvegicus
    ortholog to Cdk5, Mus musculus
    ortholog to CDK5, Pan troglodytes
    Homologene
    FAMILY
  • protein kinase superfamily
  • CMGC Ser/Thr protein kinase family
  • CDC2/CDKX subfamily
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus
    text
  • predominance of CCNI mediates the nuclear localization of CDK5, whereas the predominance of CDK5R1 results in a membranous localization of CDK5
  • basic FUNCTION
  • importantfor brain development and neuronal differentiation and may play critical roles in neuronal cytoskeleton structure and organization
  • plays a pivotal role during development of the central nervous system
  • phosphorylates the MAP kinase kinase-1 in vivo as well as the Ras-activated MEK1 in vitro
  • directly phosphorylates c-Jun N-terminal kinase 3
  • may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway
  • has an essential role in synaptic vesicle endocytosis
  • phosphorylates synaptojanin 1 and regulates its function both in vitro and in intact synaptosomes
  • essential role in regulation of the development of motor axons and neuromuscular synapses
  • role in nociception
  • phosphorylates Wiskott-Aldrich syndrome protein (WASP)--family verprolin homologous protein 1, WAVE1
  • serine/threonine kinase phosphorylating PPP1R1B (dopamine and cAMP regulated phospho protein)
  • modulating dopamine signaling and neurofilament metabolism in axon outgrowth
  • playing a role in regulation of muscular differentiation
  • involved in the regulation of acetylcholine receptor expression at the neuromuscular junction
  • may be involved in the control of the cell cycle
  • by regulating PRDX2 activity, can determine dopaminergic neuron survival, and involved in the brain development
  • facilitates calpain-mediated proteolysis of GRIN2B and may control synaptic plasticity and learning
  • playing a role in the maintenance of a postmitotic state (nuclear CDK5 plays an active role in allowing neurons to remain postmitotic as they mature and loss of nuclear CDK5 leads to cell cycle entry)
  • has an unexpected but widespread role as a negative cell cycle regulator in postmitotic neurons
  • regulates striatal dopamine neurotransmission and behavioral responses to cocaine, modulating the effects of cocaine (including its ability to induce neuro-adaptations in signaling, behavior, and neuronal morphology)
  • directly phosphorylates PPP1R19A and controls its association with F-actin
  • regulate Kalirin function throughout development
  • having an essential role in the survival, but not proliferation, of adult-generated hippocampal neurons through both cell-intrinsic and cell-extrinsic mechanisms
  • regulates neurogenesis through both intrinsic and extrinsic mechanisms in the subgranular zone of the adult hippocampus
  • phosphorylates the talin head and inhibits its interaction with SMURF1 and its degradation
  • displays kinase activity predominantly in postmitotic neurons, and plays a central role in the morphology change of senescent cells
  • regulates cellular processes such as cell-cell and cell-matrix adhesion, cell migration and wound healing in a variety of tissues
  • implicated in the signaling pathways that regulate cell adhesion and migration of variety of cell types
  • regulates synaptic plasticity, controls neuronal and behavioral stimulus-induced excitability and may be a novel pharmacological target for cognitive and anticonvulsant therapies
  • CDK1, CDK2, CDK5, can phosphorylate human DNMT1 at Ser154, suggesting an important role for CDKs in controlling DNA methylation patterns in mammalian cells
  • implicated in a new regulatory mechanism of axon formation through CDK5-dependent phosphorylation of Axin (
  • activators of CDK5, CDK5R1, and CCNI are not required for normal kidney function, but, they play pivotal coordinated roles in maintaining podocyte survival during stress states in disease
  • a role for during the progression of a normal cell cycle
  • is a brain-specific membrane-bound protein kinase that is activated by binding to CDK5R1, CDK5R2
  • CDK5 regulates SOX6 steady state protein level that has an important role in brain development and function)
  • CDK5/CDK5R1 regulates spatial learning and memory, implicating CDK5/CDK5R1 as a therapeutic target in neurological disorders
  • subcellular localization of CDK5 is determined by its specific activators
  • plays an important role in neurotransmission and synaptic plasticity in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment
  • CDK5 and CDK5R1, encoding CDK5 activator p35, have a fundamental role in central nervous system (CNS) development and function, and are involved in the pathogenesis of several neurodegenerative disorders
  • CDK5 and FIBP have a proven essential role in cell division
  • CELLULAR PROCESS cell cycle, checkpoint
    PHYSIOLOGICAL PROCESS development
    text
  • a key regulator of neural development
  • PATHWAY
    metabolism
    signaling
    a component
  • heterodimerizing with the truncated form p25 of regulatory subunit p35 (CDK5R1)
  • CDK5, KIAA0528, FIBP form a stable complex, involved in cell growth and migration, C2CD5 and FIBP being required for the assembly and stability of the complex
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • cyclin G-associated kinase, GAK
  • neuronal-specific activator protein, p35
  • Cyclin D2
  • BRCA1 interacting proteins, BIP
  • Cables
  • neuronal Cdk5 activator, Nck5a
  • beta-amyloid precursor protein, APP
  • NUDEL
  • Protein phosphatase 1, PP1
  • Pak1
  • NR2A
  • nuclear protein SET
  • ik3-2
  • alpha-actinin-1 and the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II, CaMKIIalpha
  • associated with plexin-A2 through the active state of Fyn
  • nestin
  • Sds3
  • p27
  • Parkin
  • p53
  • CDK5 activation in cells that overexpress CCNG1 leads to MYC phosphorylation on Ser-62, which is responsible for CCNG1-mediated transcriptional activation of CCNB1
  • GOLGA2
  • talin
  • SNTB2 is a CDK5 substrate that restrains the motility of insulin secretory granules
  • CDK5-dependent phosphorylation of CDK16 at Ser95 plays an important role in dendrite development
  • CAST
  • N-terminal domain of DNMT1
  • regulates DLG4 ubiquitination and interactes with TFAP2B
  • phosphorylation of NDEL1 by CDK5 not only reduces inhibition of NDEL1 but also allows PAFAH1B1 to further stimulate the cargo transport capacity of dynein
  • is activated by both CCNI and the noncyclin activator CDK5R1 in terminally differentiated cells such as kidney podocytes and neurons
  • induction of CDK5 activity is a novel mechanism through which ASH1L may regulate migration in lung carcinogenesis
  • ARHGEF9 and CDK5 are involved in regulating the phosphorylation of GPHN at postsynaptic membrane specializations
  • UCHL1 physically interacts with CDK1, CDK4, and CDK5, enhancing their kinase activity
  • CDK5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling
  • CDK5 controls the abundance of both normal and polyQ-expanded ataxin-2 protein in neurons
  • SOX6 is a direct nuclear target of CDK5
  • CDK5 plays likely an essential role for the stability of GPHN-dependent GABAA receptor clusters in hippocampal neurons
  • specific expression and CDK5-dependent phosphorylation of RAPGEF2 during multipolar-bipolar transition within the intermediate zone are essential for proper neuronal migration and wiring of the cerebral cortex
  • sumoylation of CDK5R1 increased the activity of the CDK5R1/CDK5 complex
  • CDK5, a predominantly cytoplasmic serine/threonine kinase, is an important regulator of DLC1 functions
  • CDK5 activates CCDC88A to orchestrate migration-proliferation dichotomy
  • link between TPPP and BACE1 in AD (Alzheimer disease) brains, suggesting that upregulated CDK5 activation by TPPP accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation
  • CDK5 cooperates likely with GABRA5 to regulate neuronal development
  • CDK5 binding partner, regulating cell proliferation and migration
  • cell & other
    REGULATION
    activated by p35
    p39
    CDK5R1 (CDK5R1 is required for the activation of CDK5 in the process of cellular senescence)
    oxidative stress
    neuronal-specific activator protein p35
    inhibited by GSTP1 by dislodging p25/p35, and indirectly by eliminating oxidative stress
    Phosphorylated by PC12 cell lysate and casein kinase I
    Other dysregulated by p25 cleavage form of CDK5R1 (p35),also dysregulated by p29 cleavage form of CDK5R2 (p39)
    CDK5 phosphorylation of the synaptic mediator protein delta-catenin can alter its localization at the synapse to impact neuronal synaptic activity
    regulated by glutathione-S-transferase pi 1, GSTP1
    SOX6 steady state levels are regulated by CDK5
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in Alzheimer disease (cycling neurons are characterized by a predominantly cytoplasmic distribution of CDK5)
    constitutional     --other  
    dysregulation dramatically affects striatal-dependent brain function and may be relevant to non-neurodegenerative disorders involving dopamine neurotransmission
    constitutional       loss of function
    results in abnormal development of the nervous system accompanied by massive disruptions in cortical migration and lamination, therefore impacting synaptic activity
    constitutional       gain of function
    in several neurodegenerative diseases where Golgi disassembly also occurs, this may be a common mechanism among multiple disorders
    constitutional     --over  
    significantly increased in AD, leading to nuclear envelope dispersion and contributing to all three hallmarks: neurotoxic amyloid-beta (Abeta), neurofibrillary tangles (NFT), and extensive cell death
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Cdk5(-/-) mice exhibit unique lesions in the central nervous system associated with perinatal mortality
  • cdk5-deficient cultured cortical neurons exhibit increased sensitivity to apoptotic stimuli, and elevated JNK3 activity and c-Jun phosphorylation
  • Sema3A-induced growth cone collapse responses were attenuated in cdk5-deficient mice
  • Cdk5 conditional knockout mice with restricted deletion of the Cdk5 gene in specific neurons display neuronal migration defects
  • Cdk5-/- mice display morphological abnormalities at the neuromuscular junction pre- and postsynaptically