P49615 (CDK5_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 5
EC=2.7.11.22

Alternative name(s):
CR6 protein kinase
Short name=CRK6
Cell division protein kinase 5
Serine/threonine-protein kinase PSSALRE
Tau protein kinase II catalytic subunit
Short name=TPKII catalytic subunit

Gene names

Name:	Cdk5
Synonyms:	Cdkn5, Crk6

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

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, oligodendrocytes differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and ATP6V0D1 (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 PCTAIRE 1/CDK16 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 elicites 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. Ref.9 Ref.11 Ref.12 Ref.13
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 ATP6V0D1 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and ATP6V0D1 (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. Ref.6
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. 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. Ref.5 Ref.8 Ref.9 Ref.12
Subcellular location	Nucleus By similarity. Cytoplasm. Cell membrane; Peripheral membrane protein By similarity. Perikaryon By similarity. Cell projection › lamellipodium. Cell projection › growth cone. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Note: In axonal growth cone with extension to the peripheral lamellipodia. 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. Ref.6
Tissue specificity	Specifically expressed in post-mitotic neurons and postsynaptic muscle. Ref.10
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.
Disruption phenotype	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. Ref.6 Ref.7 Ref.10 Ref.13
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 Reference proteome
Gene Ontology (GO)
Biological process	Schwann cell development Inferred from mutant phenotype Ref.10. Source: MGI behavioral response to cocaine Inferred from mutant phenotype. Source: MGI cell division Inferred from electronic annotation. Source: UniProtKB-KW cell-matrix adhesion Inferred from direct assay. Source: MGI central nervous system neuron development Inferred from mutant phenotype. Source: MGI cerebellar cortex formation Inferred from mutant phenotype. Source: MGI corpus callosum development Inferred from mutant phenotype. Source: MGI dendrite morphogenesis Inferred from mutant phenotype Ref.11. Source: MGI embryo development Inferred from sequence or structural similarity. Source: UniProtKB hippocampus development Inferred from mutant phenotype Ref.6. Source: MGI intracellular protein transport Inferred from mutant phenotype. Source: MGI layer formation in cerebral cortex Inferred from mutant phenotype Ref.6. Source: MGI motor axon guidance Inferred from mutant phenotype Ref.10. Source: MGI negative regulation of cell cycle Inferred from mutant phenotype. Source: MGI negative regulation of protein export from nucleus Inferred from mutant phenotype. Source: MGI negative regulation of protein ubiquitination Inferred from mutant phenotype. Source: MGI negative regulation of synaptic plasticity Inferred from mutant phenotype. Source: MGI neuron apoptosis Inferred from mutant phenotype. Source: MGI neuron migration Inferred from mutant phenotype. Source: MGI positive regulation of calcium ion-dependent exocytosis Inferred from direct assay. Source: MGI positive regulation of neuron apoptosis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein kinase activity Inferred from mutant phenotype Ref.10. Source: MGI receptor catabolic process Inferred from mutant phenotype. Source: MGI receptor clustering Inferred from mutant phenotype Ref.10. Source: MGI regulation of cell migration Inferred from mutant phenotype Ref.9. Source: MGI regulation of dendritic spine morphogenesis Inferred from mutant phenotype Ref.11. Source: UniProtKB regulation of excitatory postsynaptic membrane potential Inferred from mutant phenotype. Source: MGI sensory perception of pain Inferred from mutant phenotype. Source: MGI serine phosphorylation of STAT3 protein Inferred from direct assay. Source: MGI skeletal muscle tissue development Inferred from direct assay. Source: MGI synaptic transmission, dopaminergic Inferred from mutant phenotype. Source: MGI synaptic transmission, glutamatergic Inferred from mutant phenotype. Source: MGI visual learning Inferred from mutant phenotype. Source: MGI
Cellular component	axon Inferred from sequence or structural similarity. Source: UniProtKB cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from direct assay. Source: MGI filopodium Inferred from direct assay. Source: MGI growth cone Inferred from sequence or structural similarity. Source: UniProtKB lamellipodium Inferred from direct assay. Source: MGI neuromuscular junction Inferred from sequence or structural similarity. Source: UniProtKB 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 direct assay. Source: UniProtKB ErbB-3 class receptor binding Inferred from direct assay. Source: UniProtKB acetylcholine receptor activator activity Inferred from direct assay. Source: UniProtKB cyclin-dependent protein kinase activity Inferred from sequence or structural similarity. Source: UniProtKB p53 binding Inferred from physical interaction. Source: MGI tau-protein kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
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_0000085785
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	14	1	Phosphothreonine By similarity
	Modified residue	15	1	Phosphotyrosine; by ABL1, EPHA4 and FYN Ref.5
	Modified residue	17	1	Phosphothreonine By similarity
	Modified residue	46	1	Phosphoserine By similarity
	Modified residue	56	1	N6-acetyllysine By similarity
	Modified residue	72	1	Phosphoserine By similarity
	Modified residue	159	1	Phosphoserine By similarity
	Modified residue	239	1	Phosphotyrosine By similarity
Experimental info
	Mutagenesis	15	1	Y → F: Loss of thyrosine phosphorylations by CABLES1 and ABL1; decreased activity. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	P49615 [UniParc]. Last modified February 1, 1996. Version 1. 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]	"Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems." Ino H., Ishizuka T., Chiba T., Tatibana M. Brain Res. 661:196-206(1994) [PubMed: 7834371] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6. Tissue: Brain.
[3]	"Novel CDC2-related protein kinases produced in murine hematopoietic stem cells." Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V. Gene 124:305-306(1993) [PubMed: 8444355] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 130-165. Strain: CBA. Tissue: Bone marrow.
[4]	"Molecular cloning and chromosomal mapping of the mouse cyclin-dependent kinase 5 gene." Ohshima T., Nagle J.W., Pant H.C., Joshi J.B., Kozak C.A., Brady R.O., Kulkarni A.B. Genomics 28:585-588(1995) [PubMed: 7490100] [Abstract] Cited for: NUCLEOTIDE SEQUENCE OF 1-12.
[5]	"Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth." Zukerberg L.R., Patrick G.N., Nikolic M., Humbert S., Wu C.-L., Lanier L.M., Gertler F.B., Vidal M., Van Etten R.A., Tsai L.-H. Neuron 26:633-646(2000) [PubMed: 10896159] [Abstract] Cited for: IDENTIFICATION IN A TRIMOLECULAR COMPLEX WITH CABLES1 AND ABL1, INTERACTION WITH CABLES1, PHOSPHORYLATION AT TYR-15, MUTAGENESIS OF TYR-15.
[6]	"p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment." Ko J., Humbert S., Bronson R.T., Takahashi S., Kulkarni A.B., Li E., Tsai L.H. J. Neurosci. 21:6758-6771(2001) [PubMed: 11517264] [Abstract] Cited for: SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, ENZYME REGULATION.
[7]	"Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain." Ohshima T., Ogawa M., Veeranna A., Hirasawa M., Longenecker G., Ishiguro K., Pant H.C., Brady R.O., Kulkarni A.B., Mikoshiba K. Proc. Natl. Acad. Sci. U.S.A. 98:2764-2769(2001) [PubMed: 11226314] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[8]	"Ik3-2, a relative to ik3-1/cables, is associated with cdk3, cdk5, and c-abl." Sato H., Nishimoto I., Matsuoka M. Biochim. Biophys. Acta 1574:157-163(2002) [PubMed: 11955625] [Abstract] Cited for: INTERACTION WITH CABLES2.
[9]	"Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration." Xie Z., Sanada K., Samuels B.A., Shih H., Tsai L.H. Cell 114:469-482(2003) [PubMed: 12941275] [Abstract] Cited for: FUNCTION, INTERACTION WITH PTK2/FAK1.
[10]	"Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice." Fu A.K.Y., Ip F.C.F., Fu W.-Y., Cheung J., Wang J.H., Yung W.-H., Ip N.Y. Proc. Natl. Acad. Sci. U.S.A. 102:15224-15229(2005) [PubMed: 16203963] [Abstract] Cited for: DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
[11]	"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: 17143272] [Abstract] Cited for: FUNCTION IN DENDRITIC SPINE MORPHOGENESIS.
[12]	"The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death." Huang E., Qu D., Zhang Y., Venderova K., Haque M.E., Rousseaux M.W.C., Slack R.S., Woulfe J.M., Park D.S. Nat. Cell Biol. 12:563-571(2010) [PubMed: 20473298] [Abstract] Cited for: FUNCTION AS APEX1 KINASE, INTERACTION WITH APEX1.
[13]	"Hypomyelination Phenotype caused by impaired differentiation of oligodendrocytes in Emx1-cre mediated Cdk5 conditional knockout mice." He X., Takahashi S., Suzuki H., Hashikawa T., Kulkarni A.B., Mikoshiba K., Ohshima T. Neurochem. Res. 36:1293-1303(2011) [PubMed: 21210220] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION IN OLIGODENDROCYTES DIFFERENTIATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	D29678 mRNA. Translation: BAA06148.1. BC052007 mRNA. Translation: AAH52007.1. X64604 mRNA. Translation: CAA45888.1. S80121 Genomic DNA. No translation available.
IPI	IPI00309262.
PIR	I49592.
RefSeq	NP_031694.1. NM_007668.3.
UniGene	Mm.298798.
3D structure databases
ProteinModelPortal	P49615.
SMR	P49615. Positions 1-292.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-29353N.
MINT	MINT-4090424.
STRING	P49615.
PTM databases
PhosphoSite	P49615.
Proteomic databases
PRIDE	P49615.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000030814; ENSMUSP00000030814; ENSMUSG00000028969.
GeneID	12568.
KEGG	mmu:12568.
Organism-specific databases
CTD	1020.
MGI	MGI:101765. Cdk5.
Phylogenomic databases
eggNOG	roNOG09600.
HOGENOM	HBG755340.
HOVERGEN	HBG014652.
InParanoid	P49615.
OMA	ERISAKT.
OrthoDB	EOG4X6C8R.
PhylomeDB	P49615.
Enzyme and pathway databases
BRENDA	2.7.11.22. 3474.
Reactome	REACT_115433. Developmental Biology.
Gene expression databases
ArrayExpress	P49615.
Bgee	P49615.
CleanEx	MM_CDK5.
Genevestigator	P49615.
GermOnline	ENSMUSG00000028969. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_kinase-like_dom. IPR008271. Ser/Thr_kinase_AS. IPR002290. Ser/Thr_kinase_dom. [Graphical view]
KO	K02090.
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	281666.
SOURCE	Search...

Entry information

Entry name

CDK5_MOUSE

Accession

Primary (citable) accession number: P49615

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	February 1, 1996
Last modified:	January 25, 2012
This is version 118 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program