Q02399 (CDK5_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 5
EC=2.7.11.22

Alternative name(s):
Cell division protein kinase 5
Proline-directed protein kinase 33 kDa subunit
Short name=PDPK
Serine/threonine-protein kinase PSSALRE
Tau protein kinase II catalytic subunit
Short name=TPKII catalytic subunit

Gene names

Name:	CDK5
Synonyms:	CDKN5

Organism

Bos taurus (Bovine) [Reference proteome]

Taxonomic identifier

9913 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Bovinae › Bos

Protein attributes

Sequence length	292 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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 By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	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.
Subunit structure	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 By similarity.
Subcellular location	Cytoplasm By similarity. Cell membrane; Peripheral membrane protein By similarity. Perikaryon By similarity. Cell projection › lamellipodium By similarity. Cell projection › growth cone By similarity. Nucleus By similarity. Cell junction › synapse › postsynaptic cell membrane › postsynaptic 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. Co-localizes 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.
Post-translational modification	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.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Cell division Neurogenesis
Cellular component	Cell junction Cell membrane Cell projection Cytoplasm Membrane Nucleus Postsynaptic cell membrane Synapse
Disease	Neurodegeneration
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Schwann cell development Inferred from electronic annotation. Source: Compara axonogenesis Inferred from sequence or structural similarity. Source: AgBase behavioral response to cocaine Inferred from electronic annotation. Source: Compara calcium ion import Inferred from electronic annotation. Source: Compara cell division Inferred from electronic annotation. Source: UniProtKB-KW cell migration Inferred from sequence or structural similarity. Source: AgBase cell-matrix adhesion Inferred from sequence or structural similarity. Source: AgBase central nervous system neuron development Inferred from electronic annotation. Source: Compara cerebellar cortex formation Inferred from electronic annotation. Source: Compara corpus callosum development Inferred from electronic annotation. Source: Compara dendrite morphogenesis Inferred from electronic annotation. Source: Compara embryo development Inferred from sequence or structural similarity. Source: AgBase hippocampus development Inferred from electronic annotation. Source: Compara intracellular protein transport Inferred from electronic annotation. Source: Compara layer formation in cerebral cortex Inferred from electronic annotation. Source: Compara motor neuron axon guidance Inferred from electronic annotation. Source: Compara negative regulation of cell cycle Inferred from electronic annotation. Source: Compara negative regulation of protein export from nucleus Inferred from electronic annotation. Source: Compara negative regulation of protein ubiquitination Inferred from electronic annotation. Source: Compara negative regulation of synaptic plasticity Inferred from electronic annotation. Source: Compara negative regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: Compara neuron apoptotic process Inferred from electronic annotation. Source: Compara neuron migration Inferred from electronic annotation. Source: Compara oligodendrocyte differentiation Inferred from electronic annotation. Source: Compara peptidyl-threonine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of calcium ion-dependent exocytosis Inferred from electronic annotation. Source: Compara positive regulation of neuron apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein binding Inferred from electronic annotation. Source: Compara positive regulation of protein kinase activity Inferred from electronic annotation. Source: Compara positive regulation of protein targeting to membrane Inferred from electronic annotation. Source: Compara protein localization to synapse Inferred from electronic annotation. Source: Compara receptor catabolic process Inferred from electronic annotation. Source: Compara receptor clustering Inferred from electronic annotation. Source: Compara regulation of cell migration Inferred from sequence or structural similarity. Source: AgBase regulation of dendritic spine morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB regulation of excitatory postsynaptic membrane potential Inferred from electronic annotation. Source: Compara regulation of synaptic plasticity Inferred from sequence or structural similarity. Source: UniProtKB sensory perception of pain Inferred from electronic annotation. Source: Compara serine phosphorylation of STAT3 protein Inferred from electronic annotation. Source: Compara skeletal muscle tissue development Inferred from electronic annotation. Source: Compara synapse assembly Inferred from electronic annotation. Source: Compara synaptic transmission, dopaminergic Inferred from electronic annotation. Source: Compara synaptic transmission, glutamatergic Inferred from electronic annotation. Source: Compara visual learning Inferred from electronic annotation. Source: Compara
Cellular_component	axon Inferred from sequence or structural similarity. Source: AgBase cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from sequence or structural similarity. Source: AgBase filopodium Inferred from sequence or structural similarity. Source: AgBase growth cone Inferred from sequence or structural similarity. Source: AgBase lamellipodium Inferred from sequence or structural similarity. Source: AgBase membrane Inferred from sequence or structural similarity. Source: AgBase neuromuscular junction Inferred from sequence or structural similarity. Source: AgBase neuronal cell body Inferred from sequence or structural similarity. Source: AgBase nucleus Inferred from sequence or structural similarity. Source: AgBase perikaryon Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell postsynaptic density Inferred from sequence or structural similarity. Source: UniProtKB postsynaptic membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW ErbB-2 class receptor binding Inferred from sequence or structural similarity. Source: AgBase ErbB-3 class receptor binding Inferred from sequence or structural similarity. Source: UniProtKB acetylcholine receptor activator activity Inferred from sequence or structural similarity. Source: AgBase cyclin-dependent protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB histone kinase activity Traceable author statement PubMed 8846918. Source: UniProtKB tau-protein kinase activity Inferred from sequence or structural similarity. Source: AgBase
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 292	292	Cyclin-dependent kinase 5		PRO_0000085783
Regions
	Domain	4 – 286	283	Protein kinase
	Nucleotide binding	10 – 18	9	ATP By similarity
Sites
	Active site	126	1	Proton acceptor By similarity
	Binding site	33	1	ATP By similarity
Amino acid modifications
	Modified residue	15	1	Phosphotyrosine; by ABL1, EPHA4 and FYN By similarity
	Modified residue	56	1	N6-acetyllysine By similarity
	Modified residue	72	1	Phosphoserine By similarity
	Modified residue	159	1	Phosphoserine By similarity
Experimental info
	Sequence conflict	61	1	K → E in AAI20084. Ref.3
	Sequence conflict	151	1	F → L in AAI20084. Ref.3
	Sequence conflict	169	1	P → S in AAA30606. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q02399 [UniParc]. Last modified November 13, 2007. Version 2. Checksum: 4CB11CED9017D535	FASTA	292	33,288
	10 20 30 40 50 60 MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR EICLLKELKH 70 80 90 100 110 120 KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP EIVKSFLFQL LKGLGFCHSR 130 140 150 160 170 180 NVLHRDLKPQ NLLINRNGEL KLADFGLARA FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS 190 200 210 220 230 240 TSIDMWSAGC IFAELANAGR PLFPGNDVDD QLKRIFRLLG TPTEEQWPAM TKLPDYKPYP 250 260 270 280 290 MYPATTSLVN VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 14-20 AND 218-251. 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] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[3]	NIH - Mammalian Gene Collection (MGC) project Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: Hereford. Tissue: Fetal cerebellum.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L04798 mRNA. Translation: AAA30606.1. X82440 mRNA. Translation: CAA57821.1. BC120083 mRNA. Translation: AAI20084.1.
IPI	IPI00689812.
RefSeq	NP_776442.1. NM_174017.2.
UniGene	Bt.51.
3D structure databases
ProteinModelPortal	Q02399.
SMR	Q02399. Positions 1-292.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q02399. 3 interactions.
Proteomic databases
PRIDE	Q02399.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSBTAT00000010212; ENSBTAP00000010212; ENSBTAG00000007766.
GeneID	281066.
KEGG	bta:281066.
Organism-specific databases
CTD	1020.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00600000083998.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	Q02399.
KO	K02090.
OMA	TVKSFMY.
OrthoDB	EOG4X6C8R.
Enzyme and pathway databases
BRENDA	2.7.11.22. 908.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	20805147.

Entry information

Entry name

CDK5_BOVIN

Accession

Primary (citable) accession number: Q02399
Secondary accession number(s): Q0VCN5, Q6LBE2

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	November 13, 2007
Last modified:	May 1, 2013
This is version 118 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program