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Cyclin-dependent-like kinase 5



Mus musculus (Mouse)
Reviewed-Annotation score: -Experimental evidence at protein leveli


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.5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

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 (By similarity).By similarity


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei33ATPPROSITE-ProRule annotation1
Active sitei126Proton acceptorPROSITE-ProRule annotation1


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi10 – 18ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • acetylcholine receptor activator activity Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • cyclin-dependent protein serine/threonine kinase activity Source: UniProtKB
  • cytoskeletal protein binding Source: MGI
  • ephrin receptor binding Source: MGI
  • ErbB-2 class receptor binding Source: UniProtKB
  • ErbB-3 class receptor binding Source: UniProtKB
  • Hsp90 protein binding Source: ARUK-UCL
  • kinase activity Source: UniProtKB
  • p53 binding Source: MGI
  • protein kinase activity Source: MGI
  • protein kinase binding Source: MGI
  • protein serine/threonine kinase activity Source: MGI
  • tau-protein kinase activity Source: UniProtKB

GO - Biological processi

  • apoptotic process Source: MGI
  • associative learning Source: MGI
  • axonogenesis Source: MGI
  • behavioral response to cocaine Source: MGI
  • calcium ion import Source: MGI
  • cell cycle Source: UniProtKB-KW
  • cell division Source: UniProtKB-KW
  • cell-matrix adhesion Source: MGI
  • cell migration Source: MGI
  • cellular response to amyloid-beta Source: MGI
  • central nervous system neuron development Source: MGI
  • cerebellar cortex development Source: MGI
  • cerebellar cortex formation Source: MGI
  • cerebellum development Source: MGI
  • cerebral cortex development Source: MGI
  • corpus callosum development Source: MGI
  • cortical actin cytoskeleton organization Source: MGI
  • dendrite morphogenesis Source: MGI
  • excitatory postsynaptic potential Source: MGI
  • exocytosis Source: MGI
  • forebrain development Source: MGI
  • hippocampus development Source: MGI
  • intracellular protein transport Source: MGI
  • layer formation in cerebral cortex Source: MGI
  • mitochondrion organization Source: MGI
  • motor neuron axon guidance Source: MGI
  • negative regulation of axon extension Source: MGI
  • negative regulation of cell cycle Source: MGI
  • negative regulation of neuron death Source: MGI
  • negative regulation of protein export from nucleus Source: MGI
  • negative regulation of protein ubiquitination Source: MGI
  • negative regulation of proteolysis Source: MGI
  • negative regulation of synaptic plasticity Source: MGI
  • negative regulation of transcription, DNA-templated Source: MGI
  • neuron apoptotic process Source: MGI
  • neuron differentiation Source: MGI
  • neuron migration Source: MGI
  • neuron projection development Source: UniProtKB
  • neuron projection morphogenesis Source: MGI
  • nucleocytoplasmic transport Source: MGI
  • oligodendrocyte differentiation Source: MGI
  • peptidyl-serine phosphorylation Source: MGI
  • peptidyl-threonine phosphorylation Source: MGI
  • phosphorylation Source: MGI
  • positive regulation of calcium ion-dependent exocytosis Source: MGI
  • positive regulation of glial cell apoptotic process Source: MGI
  • positive regulation of neuron apoptotic process Source: UniProtKB
  • positive regulation of neuron death Source: MGI
  • positive regulation of protein binding Source: MGI
  • positive regulation of protein kinase activity Source: MGI
  • positive regulation of protein phosphorylation Source: MGI
  • positive regulation of protein targeting to membrane Source: MGI
  • protein autophosphorylation Source: MGI
  • protein localization to synapse Source: MGI
  • protein phosphorylation Source: MGI
  • receptor catabolic process Source: MGI
  • receptor clustering Source: MGI
  • regulated exocytosis Source: MGI
  • regulation of cell migration Source: MGI
  • regulation of dendritic spine morphogenesis Source: UniProtKB
  • regulation of postsynaptic membrane potential Source: MGI
  • regulation of protein localization to plasma membrane Source: ARUK-UCL
  • regulation of synaptic plasticity Source: UniProtKB
  • regulation of synaptic transmission, glutamatergic Source: ARUK-UCL
  • response to cocaine Source: MGI
  • response to wounding Source: MGI
  • rhythmic process Source: UniProtKB-KW
  • Schwann cell development Source: MGI
  • sensory perception of pain Source: MGI
  • serine phosphorylation of STAT protein Source: MGI
  • skeletal muscle tissue development Source: MGI
  • synapse assembly Source: MGI
  • synaptic transmission, dopaminergic Source: MGI
  • synaptic transmission, glutamatergic Source: MGI
  • synaptic vesicle endocytosis Source: MGI
  • synaptic vesicle transport Source: GO_Central
  • telencephalon development Source: MGI
  • visual learning Source: MGI


Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Biological rhythms, Cell cycle, Cell division, Neurogenesis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.22 3474
ReactomeiR-MMU-180024 DARPP-32 events
R-MMU-399956 CRMPs in Sema3A signaling
R-MMU-6804756 Regulation of TP53 Activity through Phosphorylation

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent-like kinase 5 (EC:
Alternative name(s):
CR6 protein kinase
Short name:
Cell division protein kinase 5
Serine/threonine-protein kinase PSSALRE
Tau protein kinase II catalytic subunit
Short name:
TPKII catalytic subunit
Gene namesi
Synonyms:Cdkn5, Crk6
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
  • UP000000589 Componenti: Chromosome 5

Organism-specific databases

MGIiMGI:101765 Cdk5

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell junction, Cell membrane, Cell projection, Cytoplasm, Membrane, Nucleus, Postsynaptic cell membrane, Synapse

Pathology & Biotechi

Disruption phenotypei

Perinatal mortality associated with severe disruption of the cytoarchitecture of the brain cortex as a result of defects in neuronal migration and cohesiveness, and degenerative changes in large neurons of the brain stem, such as motor neurons in the lower cranial nerve nuclei and spinal cord. Disruption of lamination in the cerebral cortex, hippocampus, and cerebellum. Hypomyelination caused by impaired differentiation of oligodendrocytes.4 Publications


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi15Y → F: Loss of tyrosine phosphorylations by CABLES1 and ABL1; decreased activity. 1 Publication1

Keywords - Diseasei


Chemistry databases


PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000857851 – 292Cyclin-dependent-like kinase 5Add BLAST292

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei15Phosphotyrosine; by ABL1, EPHA4 and FYN1 Publication1
Modified residuei17PhosphothreonineBy similarity1
Modified residuei56N6-acetyllysineCombined sources1
Modified residuei72PhosphoserineBy similarity1
Modified residuei159PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by casein kinase 1 promotes kinase activity. By contrast, phosphorylation at Thr-14 inhibits activity (By similarity).By similarity
Phosphorylation at Ser-159 is essential for maximal catalytic activity.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases


PTM databases



Tissue specificityi

Specifically expressed in post-mitotic neurons and postsynaptic muscle.1 Publication

Gene expression databases

ExpressionAtlasiP49615 baseline and differential
GenevisibleiP49615 MM


Subunit structurei

Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Under neurotoxic stress and neuronal injury conditions, p35 is cleaved by calpain to generate p25 that hyperactivates CDK5, that becomes functionally disabled and often toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts with CABLES1 and CABLES2. Interacts with AATK and GSTP1. Binds to HDAC1 when in complex with p25. Interaction with myristoylation p35 promotes CDK5 association with membranes. Both isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons (By similarity). Interacts with EPHA4; may mediate the activation of NGEF by EPHA4M. Interacts with PTK2/FAK1. The complex p35/CDK5 interacts with CLOCK (By similarity). Interacts with HTR6 (PubMed:25078650).By similarity1 Publication

Binary interactionsi


GO - Molecular functioni

  • cytoskeletal protein binding Source: MGI
  • ephrin receptor binding Source: MGI
  • ErbB-2 class receptor binding Source: UniProtKB
  • ErbB-3 class receptor binding Source: UniProtKB
  • Hsp90 protein binding Source: ARUK-UCL
  • p53 binding Source: MGI
  • protein kinase binding Source: MGI

Protein-protein interaction databases

BioGridi198646, 10 interactors
ComplexPortaliCPX-3143 Cyclin-dependent protein kinase 5 holoenzyme complex, p35 variant
CPX-3144 Cyclin-dependent protein kinase 5 holoenzyme complex, p25 variant
CPX-3145 Cyclin-dependent protein kinase 5 holoenzyme complex, p39 variant
IntActiP49615, 14 interactors


3D structure databases


Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 286Protein kinasePROSITE-ProRule annotationAdd BLAST283

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0594 Eukaryota

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE


Sequence statusi: Complete.

P49615-1 [UniParc]FASTAAdd to basket

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Mass (Da):33,288
Last modified:February 1, 1996 - v1

Sequence databases

Select the link destinations:
Links Updated
D29678 mRNA Translation: BAA06148.1
BC052007 mRNA Translation: AAH52007.1
X64604 mRNA Translation: CAA45888.1
S80121 Genomic DNA No translation available.
RefSeqiNP_031694.1, NM_007668.3

Genome annotation databases

EnsembliENSMUST00000030814; ENSMUSP00000030814; ENSMUSG00000028969
UCSCiuc008wrl.1 mouse

Similar proteinsi

Entry informationi

Entry nameiCDK5_MOUSE
AccessioniPrimary (citable) accession number: P49615
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: July 18, 2018
This is version 185 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

Complete proteome, Reference proteome


  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

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