CDK5 - Cyclin-dependent kinase 5 - human protein (Function)
 
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CDK5 »  Cyclin-dependent kinase 5   [ EC 2.7.11.22 ]
 
Protein also known as:  Serine/threonine-protein kinase PSSALRE.
Gene name:  CDK5
Entry whose protein(s) existence is based on evidence at protein level
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1 158 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.  
21
  • CuratedUniProtKB
GO molecular function 
Acetylcholine receptor activator activitydefinition[GO:0030549]  
  • ISSOrtholog Curator
ATP bindingdefinition[GO:0005524]  
  • IEAUniProtKB KW
Cyclin-dependent protein serine/threonine kinase activitydefinition[GO:0004693]  
  • IEAEC 2 GO
Ephrin receptor bindingdefinition[GO:0046875] silver  
  • IEAOrtholog Compara
ErbB-2 class receptor bindingdefinition[GO:0005176]  
  • ISSOrtholog Curator
ErbB-3 class receptor bindingdefinition[GO:0043125]  
  • ISSOrtholog Curator
Kinase activitydefinition[GO:0016301]  
  • ISSOrtholog Curator
P53 bindingdefinition[GO:0002039] silver  
  • IEAOrtholog Compara
Protein bindingdefinition[GO:0005515]  
8
  • IPIIntAct
  • IPIUniProtKB
Protein kinase activitydefinition[GO:0004672]  
2
  • TASPINC
Protein serine/threonine kinase activitydefinition[GO:0004674]  
2
  • IDAUniProtKB
  • IDADFLAT
  • ISSOrtholog Curator
Tau-protein kinase activitydefinition[GO:0050321]  
  • ISSOrtholog Curator
GO biological process 
Axon extensiondefinition[GO:0048675]  
1
  • TASUniProtKB
Behavioral response to cocainedefinition[GO:0048148] silver  
  • IEAOrtholog Compara
Calcium ion importdefinition[GO:0070509] silver  
  • IEAOrtholog Compara
Cell cycledefinition[GO:0007049]  
  • IEAUniProtKB KW
Cell divisiondefinition[GO:0051301]  
  • IEAUniProtKB KW
Cell proliferationdefinition[GO:0008283]  
1
  • TASPINC
Cell-matrix adhesiondefinition[GO:0007160] silver  
  • IEAOrtholog Compara
Central nervous system neuron developmentdefinition[GO:0021954] silver  
  • IEAOrtholog Compara
Cerebellar cortex formationdefinition[GO:0021697] silver  
  • IEAOrtholog Compara
Corpus callosum developmentdefinition[GO:0022038] silver  
  • IEAOrtholog Compara
Cortical actin cytoskeleton organizationdefinition[GO:0030866] silver  
  • IEAOrtholog Compara
Dendrite morphogenesisdefinition[GO:0048813] silver  
  • IEAOrtholog Compara
Embryo developmentdefinition[GO:0009790]  
  • ISSOrtholog Curator
Hippocampus developmentdefinition[GO:0021766] silver  
  • IEAOrtholog Compara
Intracellular protein transportdefinition[GO:0006886] silver  
  • IEAOrtholog Compara
Layer formation in cerebral cortexdefinition[GO:0021819] silver  
  • IEAOrtholog Compara
Motor neuron axon guidancedefinition[GO:0008045] silver  
  • IEAOrtholog Compara
Negative regulation of axon extensiondefinition[GO:0030517] silver  
  • IEAOrtholog Compara
Negative regulation of cell cycledefinition[GO:0045786] silver  
  • IEAOrtholog Compara
Negative regulation of neuron deathdefinition[GO:1901215]  
1
  • IDAParkinsonsUK-UCL
Negative regulation of protein export from nucleusdefinition[GO:0046826] silver  
  • IEAOrtholog Compara
Negative regulation of protein ubiquitinationdefinition[GO:0031397] silver  
  • IEAOrtholog Compara
Negative regulation of proteolysisdefinition[GO:0045861]  
1
  • IMPParkinsonsUK-UCL
Negative regulation of synaptic plasticitydefinition[GO:0031914] silver  
  • IEAOrtholog Compara
Negative regulation of transcription, DNA-templateddefinition[GO:0045892]  
1
  • IMPDFLAT
Neuron apoptotic processdefinition[GO:0051402]  
1
  • TASUniProtKB
Neuron differentiationdefinition[GO:0030182]  
1
  • TASUniProtKB
  • ISSOrtholog Curator
Neuron migrationdefinition[GO:0001764]  
1
  • TASUniProtKB
Neuron projection developmentdefinition[GO:0031175]  
  • ISSOrtholog Curator
Nucleocytoplasmic transportdefinition[GO:0006913] silver  
  • IEAOrtholog Compara
Oligodendrocyte differentiationdefinition[GO:0048709]  
1
  • IDAUniProtKB
Peptidyl-serine phosphorylationdefinition[GO:0018105]  
1
  • IDAUniProtKB
Peptidyl-threonine phosphorylationdefinition[GO:0018107] silver  
  • IEAOrtholog Compara
Phosphorylationdefinition[GO:0016310]  
1
  • IDADFLAT
Positive regulation of actin cytoskeleton reorganizationdefinition[GO:2000251]  
1
  • TASUniProtKB
Positive regulation of calcium ion-dependent exocytosisdefinition[GO:0045956] silver  
  • IEAOrtholog Compara
Positive regulation of neuron apoptotic processdefinition[GO:0043525]  
  • ISSOrtholog Curator
Positive regulation of protein bindingdefinition[GO:0032092] silver  
  • IEAOrtholog Compara
Positive regulation of protein kinase activitydefinition[GO:0045860] silver  
  • IEAOrtholog Compara
Positive regulation of protein targeting to membranedefinition[GO:0090314] silver  
  • IEAOrtholog Compara
Positive regulation of receptor activitydefinition[GO:2000273]  
  • IEAOrtholog Compara
  • ISSOrtholog Curator
Protein autophosphorylationdefinition[GO:0046777] silver  
  • IEAOrtholog Compara
Protein localization to synapsedefinition[GO:0035418] silver  
  • IEAOrtholog Compara
Receptor catabolic processdefinition[GO:0032801] silver  
  • IEAOrtholog Compara
Receptor clusteringdefinition[GO:0043113] silver  
  • IEAOrtholog Compara
Regulated secretory pathwaydefinition[GO:0045055] silver  
  • IEAOrtholog Compara
Regulation of apoptotic processdefinition[GO:0042981]  
1
  • TASUniProtKB
Regulation of cell cycle arrestdefinition[GO:0071156]  
1
  • TASUniProtKB
Regulation of cell migrationdefinition[GO:0030334] silver  
  • IEAOrtholog Compara
Regulation of dendritic spine morphogenesisdefinition[GO:0061001]  
  • ISSOrtholog Curator
Regulation of excitatory postsynaptic membrane potentialdefinition[GO:0060079] silver  
  • IEAOrtholog Compara
Regulation of synaptic plasticitydefinition[GO:0048167]  
1
  • TASUniProtKB
  • ISSOrtholog Curator
Rhythmic processdefinition[GO:0048511]  
  • IEAUniProtKB KW
Schwann cell developmentdefinition[GO:0014044] silver  
  • IEAOrtholog Compara
Sensory perception of paindefinition[GO:0019233] silver  
  • IEAOrtholog Compara
Serine phosphorylation of STAT3 proteindefinition[GO:0033136] silver  
  • IEAOrtholog Compara
Skeletal muscle tissue developmentdefinition[GO:0007519] silver  
  • IEAOrtholog Compara
Synapse assemblydefinition[GO:0007416]  
1
  • TASUniProtKB
Synaptic transmissiondefinition[GO:0007268]  
1
  • TASUniProtKB
Synaptic transmission, dopaminergicdefinition[GO:0001963] silver  
  • IEAOrtholog Compara
Synaptic transmission, glutamatergicdefinition[GO:0035249] silver  
  • IEAOrtholog Compara
Synaptic vesicle endocytosisdefinition[GO:0048488]  
1
  • TASUniProtKB
Synaptic vesicle exocytosisdefinition[GO:0016079]  
1
  • TASUniProtKB
Visual learningdefinition[GO:0008542] silver  
  • IEAOrtholog Compara
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.11.22: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
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.  
5
  • CuratedUniProtKB
 
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.  
  • CuratedUniProtKB
 

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