SubmitCancel

Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

Q03114

- CDK5_RAT

UniProt

Q03114 - CDK5_RAT

(max 400 entries)x

Your basket is currently empty.

Select item(s) and click on "Add to basket" to create your own collection here
(400 entries max)

Protein
Cyclin-dependent kinase 5
Gene
Cdk5, Cdkn5
Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.1 Publication

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei33 – 331ATP By similarity
Active sitei126 – 1261Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi10 – 189ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. ErbB-2 class receptor binding Source: UniProtKB
  3. ErbB-3 class receptor binding Source: UniProtKB
  4. acetylcholine receptor activator activity Source: UniProtKB
  5. cyclin-dependent protein serine/threonine kinase activity Source: UniProtKB
  6. cytoskeletal protein binding Source: BHF-UCL
  7. ephrin receptor binding Source: UniProtKB
  8. kinase activity Source: UniProtKB
  9. protein binding Source: UniProtKB
  10. protein kinase activity Source: MGI
  11. protein serine/threonine kinase activity Source: UniProtKB
  12. tau-protein kinase activity Source: UniProtKB

GO - Biological processi

  1. Schwann cell development Source: Ensembl
  2. axon extension Source: UniProtKB
  3. behavioral response to cocaine Source: Ensembl
  4. calcium ion import Source: Ensembl
  5. cell division Source: UniProtKB-KW
  6. cell-matrix adhesion Source: Ensembl
  7. central nervous system development Source: RGD
  8. central nervous system neuron development Source: Ensembl
  9. cerebellar cortex formation Source: Ensembl
  10. corpus callosum development Source: Ensembl
  11. cortical actin cytoskeleton organization Source: RGD
  12. dendrite morphogenesis Source: Ensembl
  13. embryo development Source: UniProtKB
  14. exocytosis Source: RGD
  15. hippocampus development Source: Ensembl
  16. intracellular protein transport Source: Ensembl
  17. layer formation in cerebral cortex Source: Ensembl
  18. motor neuron axon guidance Source: Ensembl
  19. negative regulation of axon extension Source: Ensembl
  20. negative regulation of cell cycle Source: Ensembl
  21. negative regulation of protein export from nucleus Source: Ensembl
  22. negative regulation of protein ubiquitination Source: Ensembl
  23. negative regulation of synaptic plasticity Source: Ensembl
  24. negative regulation of transcription, DNA-templated Source: Ensembl
  25. neuron apoptotic process Source: RGD
  26. neuron differentiation Source: UniProtKB
  27. neuron migration Source: Ensembl
  28. neuron projection development Source: UniProtKB
  29. neuron projection morphogenesis Source: RGD
  30. nucleocytoplasmic transport Source: RGD
  31. oligodendrocyte differentiation Source: Ensembl
  32. peptidyl-serine phosphorylation Source: RGD
  33. peptidyl-threonine phosphorylation Source: Ensembl
  34. positive regulation of calcium ion-dependent exocytosis Source: Ensembl
  35. positive regulation of neuron apoptotic process Source: UniProtKB
  36. positive regulation of protein binding Source: Ensembl
  37. positive regulation of protein kinase activity Source: Ensembl
  38. positive regulation of protein targeting to membrane Source: Ensembl
  39. positive regulation of receptor activity Source: GOC
  40. protein autophosphorylation Source: RGD
  41. protein localization to synapse Source: Ensembl
  42. protein phosphorylation Source: MGI
  43. receptor catabolic process Source: Ensembl
  44. receptor clustering Source: Ensembl
  45. regulated secretory pathway Source: RGD
  46. regulation of cell migration Source: Ensembl
  47. regulation of dendritic spine morphogenesis Source: UniProtKB
  48. regulation of excitatory postsynaptic membrane potential Source: Ensembl
  49. regulation of synaptic plasticity Source: UniProtKB
  50. response to wounding Source: RGD
  51. rhythmic process Source: UniProtKB-KW
  52. sensory perception of pain Source: Ensembl
  53. serine phosphorylation of STAT3 protein Source: Ensembl
  54. skeletal muscle tissue development Source: UniProtKB
  55. synapse assembly Source: Ensembl
  56. synaptic transmission, dopaminergic Source: Ensembl
  57. synaptic transmission, glutamatergic Source: Ensembl
  58. synaptic vesicle endocytosis Source: RGD
  59. 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. 5301.
ReactomeiREACT_196232. Factors involved in megakaryocyte development and platelet production.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclin-dependent kinase 5 (EC:2.7.11.22)
Alternative name(s):
Cell division protein kinase 5
Serine/threonine-protein kinase PSSALRE
Tau protein kinase II catalytic subunit
Short name:
TPKII catalytic subunit
Gene namesi
Name:Cdk5
Synonyms:Cdkn5
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494: Chromosome 4

Organism-specific databases

RGDi70514. Cdk5.

Subcellular locationi

Cytoplasm By similarity. Cell membrane; 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.1 Publication

GO - Cellular componenti

  1. axon Source: UniProtKB
  2. cell junction Source: RGD
  3. cyclin-dependent protein kinase 5 holoenzyme complex Source: RGD
  4. cytoplasm Source: UniProtKB
  5. cytoskeleton Source: RGD
  6. cytosol Source: Ensembl
  7. dendrite Source: UniProtKB
  8. filopodium Source: Ensembl
  9. growth cone Source: UniProtKB
  10. lamellipodium Source: UniProtKB-SubCell
  11. membrane Source: UniProtKB
  12. neuromuscular junction Source: UniProtKB
  13. neuronal cell body Source: UniProtKB
  14. nucleus Source: UniProtKB
  15. perikaryon Source: UniProtKB-SubCell
  16. postsynaptic density Source: UniProtKB
  17. 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

Neurodegeneration

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 292292Cyclin-dependent kinase 5
PRO_0000085786Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei15 – 151Phosphotyrosine; by ABL1, EPHA4 and FYN By similarity
Modified residuei56 – 561N6-acetyllysine By similarity
Modified residuei72 – 721Phosphoserine By similarity
Modified residuei159 – 1591Phosphoserine By 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.
Phosphorylation at Ser-159 is essential for maximal catalytic activity By similarity.

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PRIDEiQ03114.

PTM databases

PhosphoSiteiQ03114.

Expressioni

Tissue specificityi

Expressed predominantly in post-mitotic neurons of the central and peripheral nervous system.

Gene expression databases

GenevestigatoriQ03114.

Interactioni

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. Interacts with PTK2/FAK1 By similarity. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. The complex p35/CDK5 interacts with CLOCK By similarity.2 Publications

Protein-protein interaction databases

BioGridi250852. 6 interactions.
DIPiDIP-29351N.
IntActiQ03114. 3 interactions.
MINTiMINT-246942.
STRINGi10116.ENSRNOP00000011052.

Structurei

3D structure databases

ProteinModelPortaliQ03114.
SMRiQ03114. Positions 1-292.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini4 – 286283Protein kinase
Add
BLAST

Sequence similaritiesi

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00600000083998.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiQ03114.
KOiK02090.
OMAiTMTKLPD.
OrthoDBiEOG7966H8.
PhylomeDBiQ03114.
TreeFamiTF101023.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q03114-1 [UniParc]FASTAAdd to Basket

« Hide

MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR    50
EICLLKELKH KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP 100
EIVKSLLFQL LKGLGFCHSR NVLHRDLKPQ NLLINRNGEL KLADFGLARA 150
FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS TSIDMWSAGC IFAELANAGR 200
PLFPGNDVDD QLKRIFRLLG TPTEEQWPAM TKLPDYKPYP MYPATTSLVN 250
VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP 292
Length:292
Mass (Da):33,254
Last modified:October 1, 1993 - v1
Checksum:i4CBFF80794F931DF
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
L02121 mRNA. Translation: AAA40902.1.
PIRiA46365.
RefSeqiNP_543161.1. NM_080885.1.
UniGeneiRn.10749.

Genome annotation databases

EnsembliENSRNOT00000011052; ENSRNOP00000011052; ENSRNOG00000008017.
GeneIDi140908.
KEGGirno:140908.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
L02121 mRNA. Translation: AAA40902.1 .
PIRi A46365.
RefSeqi NP_543161.1. NM_080885.1.
UniGenei Rn.10749.

3D structure databases

ProteinModelPortali Q03114.
SMRi Q03114. Positions 1-292.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 250852. 6 interactions.
DIPi DIP-29351N.
IntActi Q03114. 3 interactions.
MINTi MINT-246942.
STRINGi 10116.ENSRNOP00000011052.

Chemistry

BindingDBi Q03114.
ChEMBLi CHEMBL5901.

PTM databases

PhosphoSitei Q03114.

Proteomic databases

PRIDEi Q03114.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSRNOT00000011052 ; ENSRNOP00000011052 ; ENSRNOG00000008017 .
GeneIDi 140908.
KEGGi rno:140908.

Organism-specific databases

CTDi 1020.
RGDi 70514. Cdk5.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00600000083998.
HOGENOMi HOG000233024.
HOVERGENi HBG014652.
InParanoidi Q03114.
KOi K02090.
OMAi TMTKLPD.
OrthoDBi EOG7966H8.
PhylomeDBi Q03114.
TreeFami TF101023.

Enzyme and pathway databases

BRENDAi 2.7.11.22. 5301.
Reactomei REACT_196232. Factors involved in megakaryocyte development and platelet production.

Miscellaneous databases

NextBioi 620745.
PROi Q03114.

Gene expression databases

Genevestigatori Q03114.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
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.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA."
    Xiong Y., Zhang H., Beach D.H.
    Cell 71:505-514(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression."
    Hellmich M.R., Pant H.C., Wada E., Battey J.F.
    Proc. Natl. Acad. Sci. U.S.A. 89:10867-10871(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Brain.
  3. Cited for: INTERACTION WITH AATK.
  4. "Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism."
    Fu W.Y., Chen Y., Sahin M., Zhao X.S., Shi L., Bikoff J.B., Lai K.O., Yung W.H., Fu A.K., Greenberg M.E., Ip N.Y.
    Nat. Neurosci. 10:67-76(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH EPHA4, SUBCELLULAR LOCATION.
  5. "Critical role of CDK5 and Polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity."
    Seeburg D.P., Feliu-Mojer M., Gaiottino J., Pak D.T., Sheng M.
    Neuron 58:571-583(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF SIPA1L1.

Entry informationi

Entry nameiCDK5_RAT
AccessioniPrimary (citable) accession number: Q03114
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1993
Last sequence update: October 1, 1993
Last modified: September 3, 2014
This is version 133 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi