CDK5 - Cyclin-dependent-like kinase 5 - human protein (Function)
 
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CDK5 »  Cyclin-dependent-like kinase 5   [ EC 2.7.11.1 ]
 
Protein also known as:  Tau protein kinase II catalytic subunit (TPKII catalytic subunit).
Gene name:  CDK5
Entry whose protein(s) existence is based on evidence at protein level
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1 162 2
GENE REF ISO

Function

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Overview 
Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution.  
22
  • UniProtKB
GO molecular function 
Acetylcholine receptor activator activitydefinition[GO:0030549]  
1
  • Ortholog Curator
ATP bindingdefinition[GO:0005524]  
1
  • UniProtKB KW
Cyclin-dependent protein serine/threonine kinase activitydefinition[GO:0004693] silver  
1
  • Ortholog Compara
Cytoskeletal protein bindingdefinition[GO:0008092] silver  
1
  • Ortholog Compara
Ephrin receptor bindingdefinition[GO:0046875] silver  
1
  • Ortholog Compara
ErbB-2 class receptor bindingdefinition[GO:0005176]  
1
  • Ortholog Curator
ErbB-3 class receptor bindingdefinition[GO:0043125]  
1
  • Ortholog Curator
Kinase activitydefinition[GO:0016301]  
1
  • Ortholog Curator
P53 bindingdefinition[GO:0002039] silver  
1
  • Ortholog Compara
Protein bindingdefinition[GO:0005515]  
9
  • IntAct
  • UniProtKB
Protein kinase activitydefinition[GO:0004672]  
2
  • PINC
Protein serine/threonine kinase activitydefinition[GO:0004674]  
3
  • UniProtKB
  • DFLAT
  • Ortholog Curator
Tau-protein kinase activitydefinition[GO:0050321]  
1
  • Ortholog Curator
GO biological process 
Axon extensiondefinition[GO:0048675]  
1
  • UniProtKB
Behavioral response to cocainedefinition[GO:0048148] silver  
1
  • Ortholog Compara
Calcium ion importdefinition[GO:0070509] silver  
1
  • Ortholog Compara
Cell cycledefinition[GO:0007049]  
1
  • UniProtKB KW
Cell divisiondefinition[GO:0051301]  
1
  • UniProtKB KW
Cell proliferationdefinition[GO:0008283]  
1
  • PINC
Cell-matrix adhesiondefinition[GO:0007160] silver  
1
  • Ortholog Compara
Central nervous system neuron developmentdefinition[GO:0021954] silver  
1
  • Ortholog Compara
Cerebellar cortex formationdefinition[GO:0021697] silver  
1
  • Ortholog Compara
Corpus callosum developmentdefinition[GO:0022038] silver  
1
  • Ortholog Compara
Cortical actin cytoskeleton organizationdefinition[GO:0030866] silver  
1
  • Ortholog Compara
Dendrite morphogenesisdefinition[GO:0048813] silver  
1
  • Ortholog Compara
Embryo developmentdefinition[GO:0009790] silver  
1
  • Ortholog Compara
Hippocampus developmentdefinition[GO:0021766] silver  
1
  • Ortholog Compara
Intracellular protein transportdefinition[GO:0006886] silver  
1
  • Ortholog Compara
Layer formation in cerebral cortexdefinition[GO:0021819] silver  
1
  • Ortholog Compara
Motor neuron axon guidancedefinition[GO:0008045] silver  
1
  • Ortholog Compara
Negative regulation of axon extensiondefinition[GO:0030517] silver  
1
  • Ortholog Compara
Negative regulation of cell cycledefinition[GO:0045786] silver  
1
  • Ortholog Compara
Negative regulation of neuron deathdefinition[GO:1901215]  
1
  • ParkinsonsUK-UCL
Negative regulation of protein export from nucleusdefinition[GO:0046826] silver  
1
  • Ortholog Compara
Negative regulation of protein ubiquitinationdefinition[GO:0031397] silver  
1
  • Ortholog Compara
Negative regulation of proteolysisdefinition[GO:0045861]  
1
  • ParkinsonsUK-UCL
Negative regulation of synaptic plasticitydefinition[GO:0031914] silver  
1
  • Ortholog Compara
Negative regulation of transcription, DNA-templateddefinition[GO:0045892]  
1
  • DFLAT
Neuron apoptotic processdefinition[GO:0051402]  
1
  • UniProtKB
Neuron differentiationdefinition[GO:0030182]  
2
  • UniProtKB
  • Ortholog Curator
Neuron migrationdefinition[GO:0001764]  
1
  • UniProtKB
Neuron projection developmentdefinition[GO:0031175]  
1
  • Ortholog Curator
Nucleocytoplasmic transportdefinition[GO:0006913] silver  
1
  • Ortholog Compara
Oligodendrocyte differentiationdefinition[GO:0048709]  
1
  • UniProtKB
Peptidyl-serine phosphorylationdefinition[GO:0018105]  
1
  • UniProtKB
Peptidyl-threonine phosphorylationdefinition[GO:0018107] silver  
1
  • Ortholog Compara
Phosphorylationdefinition[GO:0016310]  
1
  • DFLAT
Positive regulation of actin cytoskeleton reorganizationdefinition[GO:2000251]  
1
  • UniProtKB
Positive regulation of calcium ion-dependent exocytosisdefinition[GO:0045956] silver  
1
  • Ortholog Compara
Positive regulation of neuron apoptotic processdefinition[GO:0043525]  
1
  • Ortholog Curator
Positive regulation of protein bindingdefinition[GO:0032092] silver  
1
  • Ortholog Compara
Positive regulation of protein kinase activitydefinition[GO:0045860] silver  
1
  • Ortholog Compara
Positive regulation of protein targeting to membranedefinition[GO:0090314] silver  
1
  • Ortholog Compara
Positive regulation of receptor activitydefinition[GO:2000273] silver  
1
  • Ortholog Compara
Protein autophosphorylationdefinition[GO:0046777] silver  
1
  • Ortholog Compara
Protein localization to synapsedefinition[GO:0035418] silver  
1
  • Ortholog Compara
Receptor catabolic processdefinition[GO:0032801] silver  
1
  • Ortholog Compara
Receptor clusteringdefinition[GO:0043113] silver  
1
  • Ortholog Compara
Regulated secretory pathwaydefinition[GO:0045055] silver  
1
  • Ortholog Compara
Regulation of apoptotic processdefinition[GO:0042981]  
1
  • UniProtKB
Regulation of cell cycle arrestdefinition[GO:0071156]  
1
  • UniProtKB
Regulation of cell migrationdefinition[GO:0030334] silver  
1
  • Ortholog Compara
Regulation of dendritic spine morphogenesisdefinition[GO:0061001]  
1
  • Ortholog Curator
Regulation of excitatory postsynaptic membrane potentialdefinition[GO:0060079] silver  
1
  • Ortholog Compara
Regulation of synaptic plasticitydefinition[GO:0048167]  
2
  • UniProtKB
  • Ortholog Curator
Regulation of synaptic vesicle recyclingdefinition[GO:1903421]  
1
  • ParkinsonsUK-UCL
Rhythmic processdefinition[GO:0048511]  
1
  • UniProtKB KW
Schwann cell developmentdefinition[GO:0014044] silver  
1
  • Ortholog Compara
Sensory perception of paindefinition[GO:0019233] silver  
1
  • Ortholog Compara
Serine phosphorylation of STAT3 proteindefinition[GO:0033136] silver  
1
  • Ortholog Compara
Skeletal muscle tissue developmentdefinition[GO:0007519] silver  
1
  • Ortholog Compara
Synapse assemblydefinition[GO:0007416]  
1
  • UniProtKB
Synaptic transmissiondefinition[GO:0007268]  
1
  • UniProtKB
Synaptic transmission, dopaminergicdefinition[GO:0001963] silver  
1
  • Ortholog Compara
Synaptic transmission, glutamatergicdefinition[GO:0035249] silver  
1
  • Ortholog Compara
Synaptic vesicle endocytosisdefinition[GO:0048488]  
1
  • UniProtKB
Synaptic vesicle exocytosisdefinition[GO:0016079]  
1
  • UniProtKB
Visual learningdefinition[GO:0008542] silver  
1
  • Ortholog Compara
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
1
  • UniProtKB
It is regulated in the following manner
Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine. Activated by CDK5R1 (p35) and CDK5R2 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (p39) by proteasome result in down regulation of kinase activity, during this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Kinase activity is mainly determined by the amount of p35 available and subcellular location; reversible association to plasma membrane inhibits activity. Long-term inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5 triggers cell death. The pro-death activity of hyperactivated CDK5 is suppressed by membrane association of CDK5, via myristoylation of p35. Brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor (NGF), retinoic acid, laminin and neuregulin promote activity. Neurotoxicity enhances nuclear activity, thus leading to MEF2 phosphorylation and inhibition prior to apoptosis of cortical neurons. Repression by GSTP1 via p25/p35 translocation prevents neurodegeneration.  
6
  • UniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Alzheimer's disease  hsa05010+1020  
Axon guidance  hsa04360+1020  
According to Reactome, this protein belongs to the following pathways:
CRMPs in Sema3A signaling  REACT_19199  
DARPP-32 events  REACT_15334  
Factors involved in megakaryocyte development and platelet production  REACT_24970  
Note 
Dysregulation of CDK5 is associated with neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis.  
1
  • UniProtKB
 

Keywords

Biological process 
Apoptosis  definition   [KW-0053]
Biological rhythms  definition   [KW-0090]
Cell cycle  definition   [KW-0131]
Cell division  definition   [KW-0132]
Neurogenesis  definition   [KW-0524]
Molecular function 
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: Cyclin-dependent_kinase_5
GenomeRNAi: 1020
PRO: PR:Q00535
Chemistry
GuidetoPHARMACOLOGY: 1977