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Q02399 - CDK5_BOVIN

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Cyclin-dependent-like kinase 5



Bos taurus (Bovine)
Reviewed - Annotation score: 5 out of 5- 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 (By similarity).By similarity

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)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei33 – 331ATPPROSITE-ProRule annotation
Active sitei126 – 1261Proton acceptorPROSITE-ProRule annotation


Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi10 – 189ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. acetylcholine receptor activator activity Source: AgBase
  2. ATP binding Source: UniProtKB-KW
  3. cyclin-dependent protein serine/threonine kinase activity Source: UniProtKB
  4. ErbB-2 class receptor binding Source: AgBase
  5. ErbB-3 class receptor binding Source: UniProtKB
  6. histone kinase activity Source: UniProtKB
  7. kinase activity Source: AgBase
  8. protein serine/threonine kinase activity Source: AgBase
  9. tau-protein kinase activity Source: AgBase

GO - Biological processi

  1. axonogenesis Source: AgBase
  2. behavioral response to cocaine Source: Ensembl
  3. calcium ion import Source: Ensembl
  4. cell cycle Source: UniProtKB-KW
  5. cell division Source: UniProtKB-KW
  6. cell-matrix adhesion Source: AgBase
  7. cell migration Source: AgBase
  8. central nervous system neuron development Source: Ensembl
  9. cerebellar cortex formation Source: Ensembl
  10. corpus callosum development Source: Ensembl
  11. dendrite morphogenesis Source: Ensembl
  12. hippocampus development Source: Ensembl
  13. histone phosphorylation Source: GOC
  14. intracellular protein transport Source: Ensembl
  15. layer formation in cerebral cortex Source: Ensembl
  16. motor neuron axon guidance Source: Ensembl
  17. negative regulation of axon extension Source: Ensembl
  18. negative regulation of cell cycle Source: Ensembl
  19. negative regulation of neuron death Source: Ensembl
  20. negative regulation of protein export from nucleus Source: Ensembl
  21. negative regulation of protein ubiquitination Source: Ensembl
  22. negative regulation of proteolysis Source: Ensembl
  23. negative regulation of synaptic plasticity Source: Ensembl
  24. negative regulation of transcription, DNA-templated Source: Ensembl
  25. neuron apoptotic process Source: Ensembl
  26. neuron differentiation Source: AgBase
  27. neuron migration Source: Ensembl
  28. neuron projection development Source: AgBase
  29. oligodendrocyte differentiation Source: Ensembl
  30. peptidyl-threonine phosphorylation Source: Ensembl
  31. positive regulation of calcium ion-dependent exocytosis Source: Ensembl
  32. positive regulation of neuron apoptotic process Source: UniProtKB
  33. positive regulation of protein binding Source: Ensembl
  34. positive regulation of protein kinase activity Source: Ensembl
  35. positive regulation of protein targeting to membrane Source: Ensembl
  36. protein localization to synapse Source: Ensembl
  37. receptor catabolic process Source: Ensembl
  38. receptor clustering Source: Ensembl
  39. regulation of cell migration Source: AgBase
  40. regulation of dendritic spine morphogenesis Source: UniProtKB
  41. regulation of excitatory postsynaptic membrane potential Source: Ensembl
  42. regulation of synaptic plasticity Source: UniProtKB
  43. rhythmic process Source: UniProtKB-KW
  44. Schwann cell development Source: Ensembl
  45. sensory perception of pain Source: Ensembl
  46. serine phosphorylation of STAT3 protein Source: Ensembl
  47. skeletal muscle tissue development Source: Ensembl
  48. synapse assembly Source: Ensembl
  49. synaptic transmission, dopaminergic Source: Ensembl
  50. synaptic transmission, glutamatergic Source: Ensembl
  51. visual learning Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Apoptosis, Biological rhythms, Cell cycle, Cell division, Neurogenesis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.22. 908.
ReactomeiREACT_205490. DARPP-32 events.
REACT_215067. Factors involved in megakaryocyte development and platelet production.
REACT_217740. CRMPs in Sema3A signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent-like kinase 5 (EC:
Alternative name(s):
Cell division protein kinase 5
Proline-directed protein kinase 33 kDa subunit
Short name:
Serine/threonine-protein kinase PSSALRE
Tau protein kinase II catalytic subunit
Short name:
TPKII catalytic subunit
Gene namesi
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
ProteomesiUP000009136: Chromosome 4

Subcellular locationi

Cytoplasm By similarity. Cell membrane By similarity; Peripheral membrane protein By similarity. Perikaryon By similarity. Cell projectionlamellipodium By similarity. Cell projectiongrowth cone By similarity. Nucleus By similarity. Cell junctionsynapsepostsynaptic cell membranepostsynaptic density By similarity
Note: In axonal growth cone with extension to the peripheral lamellipodia (By similarity). Under neurotoxic stress and neuronal injury conditions, CDK5R1 (p35) is cleaved by calpain to generate CDK5R1 (p25) in response to increased intracellular calcium. The elevated level of p25, when in complex with CDK5, leads to its subcellular misallocation as well as its hyperactivation. Colocalizes with CTNND2 in the cell body of neuronal cells, and with CTNNB1 in the cell-cell contacts and plasma membrane of undifferentiated and differentiated neuroblastoma cells. Reversibly attached to the plasma membrane in an inactive form when complexed to dephosphorylated p35 or CDK5R2 (p39), p35 phosphorylation releases this attachment and activates CDK5 (By similarity).By similarity

GO - Cellular componenti

  1. axon Source: AgBase
  2. cell junction Source: UniProtKB-KW
  3. cytoplasm Source: AgBase
  4. cytosol Source: AgBase
  5. dendrite Source: AgBase
  6. filopodium Source: AgBase
  7. growth cone Source: AgBase
  8. lamellipodium Source: AgBase
  9. membrane Source: AgBase
  10. neuromuscular junction Source: AgBase
  11. neuronal cell body Source: AgBase
  12. nucleus Source: AgBase
  13. perikaryon Source: UniProtKB-SubCell
  14. postsynaptic density Source: UniProtKB
  15. postsynaptic membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

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

Pathology & Biotechi

Keywords - Diseasei


PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 292292Cyclin-dependent-like kinase 5PRO_0000085783Add

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei15 – 151Phosphotyrosine; by ABL1, EPHA4 and FYNBy similarity
Modified residuei56 – 561N6-acetyllysineBy similarity
Modified residuei72 – 721PhosphoserineBy similarity
Modified residuei159 – 1591PhosphoserineBy similarity

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



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 (By similarity). 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 EPHA4. Interacts with PTK2/FAK1. The complex p35/CDK5 interacts with CLOCK (By similarity).By similarity

Protein-protein interaction databases

BioGridi158435. 1 interaction.
IntActiQ02399. 3 interactions.


3D structure databases

SMRiQ02399. Positions 1-292.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini4 – 286283Protein kinasePROSITE-ProRule annotationAdd

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases


Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]


Sequence statusi: Complete.

Q02399-1 [UniParc]FASTAAdd to Basket

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        10         20         30         40         50
60 70 80 90 100
110 120 130 140 150
160 170 180 190 200
210 220 230 240 250
260 270 280 290
Mass (Da):33,288
Last modified:November 13, 2007 - v2

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti61 – 611K → E in AAI20084. 1 PublicationCurated
Sequence conflicti151 – 1511F → L in AAI20084. 1 PublicationCurated
Sequence conflicti169 – 1691P → S in AAA30606. (PubMed:1464604)Curated

Sequence databases

Select the link destinations:
Links Updated
L04798 mRNA. Translation: AAA30606.1.
X82440 mRNA. Translation: CAA57821.1.
BC120083 mRNA. Translation: AAI20084.1.
RefSeqiNP_776442.1. NM_174017.2.

Genome annotation databases

EnsembliENSBTAT00000010212; ENSBTAP00000010212; ENSBTAG00000007766.


Sequence databases

Select the link destinations:
Links Updated
L04798 mRNA. Translation: AAA30606.1 .
X82440 mRNA. Translation: CAA57821.1 .
BC120083 mRNA. Translation: AAI20084.1 .
RefSeqi NP_776442.1. NM_174017.2.
UniGenei Bt.51.

3D structure databases

ProteinModelPortali Q02399.
SMRi Q02399. Positions 1-292.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 158435. 1 interaction.
IntActi Q02399. 3 interactions.

Proteomic databases

PRIDEi Q02399.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSBTAT00000010212 ; ENSBTAP00000010212 ; ENSBTAG00000007766 .
GeneIDi 281066.
KEGGi bta:281066.

Organism-specific databases

CTDi 1020.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00760000119154.
HOGENOMi HOG000233024.
InParanoidi Q02399.
KOi K02090.
OrthoDBi EOG7966H8.
TreeFami TF101023.

Enzyme and pathway databases

BRENDAi 908.
Reactomei REACT_205490. DARPP-32 events.
REACT_215067. Factors involved in megakaryocyte development and platelet production.
REACT_217740. CRMPs in Sema3A signaling.

Miscellaneous databases

NextBioi 20805147.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...


« Hide 'large scale' publications
  1. "Brain proline-directed protein kinase is a neurofilament kinase which displays high sequence homology to p34cdc2."
    Lew J., Winkfein R.J., Paudel H.K., Wang J.H.
    J. Biol. Chem. 267:25922-25926(1992) [PubMed] [Europe PMC] [Abstract]
    Tissue: Brain.
  2. "A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule."
    Kobayashi S., Ishiguro K., Omori A., Takamatsu M., Arioka M., Imahori K., Uchida T.
    FEBS Lett. 335:171-175(1993) [PubMed] [Europe PMC] [Abstract]
    Tissue: Brain.
  3. NIH - Mammalian Gene Collection (MGC) project
    Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases
    Strain: Hereford.
    Tissue: Fetal cerebellum.

Entry informationi

Entry nameiCDK5_BOVIN
AccessioniPrimary (citable) accession number: Q02399
Secondary accession number(s): Q0VCN5, Q6LBE2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: November 13, 2007
Last modified: January 7, 2015
This is version 134 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome


  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.