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Cyclin-dependent kinase 5 activator 1 (CDK5 activator 1) (Cyclin-dependent kinase 5 regulatory subunit 1) (TPKII regulatory subunit) [Cleaved into: Cyclin-dependent kinase 5 activator 1, p35 (p35); Cyclin-dependent kinase 5 activator 1, p25 (p25) (Tau protein kinase II 23 kDa subunit) (p23)]

 CD5R1_MOUSE             Reviewed;         307 AA.
P61809; Q62938;
07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
07-JUN-2004, sequence version 1.
25-OCT-2017, entry version 131.
RecName: Full=Cyclin-dependent kinase 5 activator 1;
Short=CDK5 activator 1;
AltName: Full=Cyclin-dependent kinase 5 regulatory subunit 1;
AltName: Full=TPKII regulatory subunit;
Contains:
RecName: Full=Cyclin-dependent kinase 5 activator 1, p35;
Short=p35;
Contains:
RecName: Full=Cyclin-dependent kinase 5 activator 1, p25;
Short=p25;
AltName: Full=Tau protein kinase II 23 kDa subunit;
Short=p23;
Flags: Precursor;
Name=Cdk5r1; Synonyms=Cdk5r, Nck5a;
Mus musculus (Mouse).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
Muroidea; Muridae; Murinae; Mus; Mus.
NCBI_TaxID=10090;
[1]
NUCLEOTIDE SEQUENCE [MRNA].
STRAIN=129/Sv;
Nilden F., Backstrom A., Bark I.C.;
"Differential mRNA expression of the CDK5 activators P35 and P39 in
the developing mouse brain.";
Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
STRAIN=129/SvJ; TISSUE=Brain;
PubMed=8661152; DOI=10.1006/geno.1996.0370;
Ohshima T., Kozak C.A., Nagle J.W., Pant H.C., Brady R.O.,
Kulkarni A.B.;
"Molecular cloning and chromosomal mapping of the mouse gene encoding
cyclin-dependent kinase 5 regulatory subunit p35.";
Genomics 35:372-375(1996).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
STRAIN=C57BL/6J; TISSUE=Brain;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[4]
PROTEOLYTIC CLEAVAGE BY CALPAIN.
PubMed=10830966; DOI=10.1038/35012636;
Lee M.-S., Kwon Y.T., Li M., Peng J., Friedlander R.M., Tsai L.-H.;
"Neurotoxicity induces cleavage of p35 to p25 by calpain.";
Nature 405:360-364(2000).
[5]
INTERACTION WITH CDK5; CDK5RAP1; CDK5RAP2 AND CDK5RAP3, AND
MUTAGENESIS OF GLU-157.
PubMed=11882646; DOI=10.1074/jbc.C200032200;
Ching Y.-P., Pang A.S.H., Lam W.-H., Qi R.Z., Wang J.H.;
"Identification of a neuronal Cdk5 activator-binding protein as Cdk5
inhibitor.";
J. Biol. Chem. 277:15237-15240(2002).
[6]
FUNCTION IN DENDRITIC SPINE MORPHOGENESIS, INTERACTION WITH NGEF, AND
SUBCELLULAR LOCATION.
PubMed=17143272; DOI=10.1038/nn1811;
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.;
"Cdk5 regulates EphA4-mediated dendritic spine retraction through an
ephexin1-dependent mechanism.";
Nat. Neurosci. 10:67-76(2007).
[7]
FUNCTION, AND INTERACTION WITH CLOCK.
PubMed=24235147; DOI=10.1074/jbc.M113.494856;
Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H.,
Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.;
"Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK
protein by direct phosphorylation.";
J. Biol. Chem. 288:36878-36889(2013).
-!- FUNCTION: p35 is a neuron specific activator of CDK5. The complex
p35/CDK5 is required for neurite outgrowth and cortical
lamination. Involved in dendritic spine morphogenesis by mediating
the EFNA1-EPHA4 signaling. Activator of TPKII. 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.
{ECO:0000269|PubMed:17143272, ECO:0000269|PubMed:24235147}.
-!- SUBUNIT: Heterodimer composed of CDK5 and CDK5R (p25) and
macromolecular complex composed of at least CDK5, CDK5R (p35) and
CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows
kinase activity. Interacts with RASGRF2 (By similarity). Interacts
with EPHA4 and NGEF; may mediate the activation of NGEF by EPHA4.
The complex p35/CDK5 interacts with CLOCK. {ECO:0000250,
ECO:0000269|PubMed:11882646, ECO:0000269|PubMed:17143272,
ECO:0000269|PubMed:24235147}.
-!- INTERACTION:
P09803:Cdh1; NbExp=2; IntAct=EBI-7840438, EBI-984420;
P49615:Cdk5; NbExp=4; IntAct=EBI-7840438, EBI-6510052;
Q80U04:Pja2; NbExp=2; IntAct=EBI-7840438, EBI-1801691;
Q8CFH6:Sik2; NbExp=3; IntAct=EBI-7840438, EBI-16094102;
-!- SUBCELLULAR LOCATION: Cyclin-dependent kinase 5 activator 1, p35:
Cell membrane {ECO:0000250}; Lipid-anchor {ECO:0000250};
Cytoplasmic side {ECO:0000250}.
-!- SUBCELLULAR LOCATION: Cyclin-dependent kinase 5 activator 1, p25:
Nucleus {ECO:0000250}. Cytoplasm, perinuclear region
{ECO:0000250}. Note=The conversion of p35 to p25 relocalizes the
protein from the cell periphery to the cytoplasm, in nuclear and
perinuclear regions. {ECO:0000250}.
-!- TISSUE SPECIFICITY: Brain and neuron specific.
-!- PTM: The p35 form is proteolytically cleaved by calpain, giving
rise to the p25 form. P35 has a 5 to 10 fold shorter half-life
compared to p25. The conversion results in deregulation of the
CDK5 kinase: p25/CDK5 kinase displays an increased and altered tau
phosphorylation in comparison to the p35/CDK5 kinase in vivo.
{ECO:0000269|PubMed:10830966}.
-!- PTM: Myristoylated. A proper myristoylation signal is essential
for the proper distribution of p35 (By similarity). {ECO:0000250}.
-!- PTM: Ubiquitinated. Degradation of p35 by proteasome results in
down-regulation of CDK5 activity. During this process, CDK5
phosphorylates p35 and induces its ubiquitination and subsequent
degradation (By similarity). {ECO:0000250}.
-!- PTM: Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents
calpain-mediated proteolysis. {ECO:0000250}.
-!- SIMILARITY: Belongs to the cyclin-dependent kinase 5 activator
family. {ECO:0000305}.
-----------------------------------------------------------------------
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-----------------------------------------------------------------------
EMBL; U89527; AAB49474.1; -; mRNA.
EMBL; Y11335; CAA72176.1; -; Genomic_DNA.
EMBL; S82819; AAB46777.1; -; Genomic_DNA.
EMBL; BC046823; AAH46823.1; -; mRNA.
EMBL; BC050768; AAH50768.1; -; mRNA.
EMBL; BC058697; AAH58697.1; -; mRNA.
CCDS; CCDS25134.1; -.
RefSeq; NP_034001.1; NM_009871.3.
UniGene; Mm.142275; -.
UniGene; Mm.474282; -.
ProteinModelPortal; P61809; -.
SMR; P61809; -.
BioGrid; 198647; 2.
CORUM; P61809; -.
DIP; DIP-29354N; -.
IntAct; P61809; 7.
STRING; 10090.ENSMUSP00000099514; -.
iPTMnet; P61809; -.
PhosphoSitePlus; P61809; -.
PaxDb; P61809; -.
PRIDE; P61809; -.
Ensembl; ENSMUST00000053413; ENSMUSP00000099514; ENSMUSG00000048895.
GeneID; 12569; -.
KEGG; mmu:12569; -.
UCSC; uc007kmg.1; mouse.
CTD; 8851; -.
MGI; MGI:101764; Cdk5r1.
eggNOG; KOG3932; Eukaryota.
eggNOG; ENOG410YFUI; LUCA.
GeneTree; ENSGT00390000008812; -.
HOVERGEN; HBG050853; -.
InParanoid; P61809; -.
KO; K11716; -.
OMA; LSIINLM; -.
OrthoDB; EOG091G0OB3; -.
PhylomeDB; P61809; -.
TreeFam; TF101036; -.
Reactome; R-MMU-399956; CRMPs in Sema3A signaling.
Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation.
Reactome; R-MMU-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
ChiTaRS; Cdk5r1; mouse.
PRO; PR:P61809; -.
Proteomes; UP000000589; Chromosome 11.
Bgee; ENSMUSG00000048895; -.
ExpressionAtlas; P61809; baseline and differential.
Genevisible; P61809; MM.
GO; GO:0030424; C:axon; ISS:UniProtKB.
GO; GO:0043292; C:contractile fiber; ISS:UniProtKB.
GO; GO:0016533; C:cyclin-dependent protein kinase 5 holoenzyme complex; IEA:Ensembl.
GO; GO:0005737; C:cytoplasm; IDA:MGI.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0030425; C:dendrite; ISS:UniProtKB.
GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
GO; GO:0030426; C:growth cone; ISS:UniProtKB.
GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
GO; GO:0016020; C:membrane; ISS:UniProtKB.
GO; GO:0031594; C:neuromuscular junction; ISS:UniProtKB.
GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
GO; GO:0005654; C:nucleoplasm; ISO:MGI.
GO; GO:0005634; C:nucleus; IDA:MGI.
GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
GO; GO:0005886; C:plasma membrane; TAS:Reactome.
GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
GO; GO:0045296; F:cadherin binding; ISS:UniProtKB.
GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
GO; GO:0016534; F:cyclin-dependent protein kinase 5 activator activity; IMP:MGI.
GO; GO:0008092; F:cytoskeletal protein binding; TAS:MGI.
GO; GO:0046875; F:ephrin receptor binding; IEA:Ensembl.
GO; GO:0016301; F:kinase activity; ISS:UniProtKB.
GO; GO:0019901; F:protein kinase binding; ISO:MGI.
GO; GO:0043539; F:protein serine/threonine kinase activator activity; ISS:UniProtKB.
GO; GO:0007411; P:axon guidance; IMP:UniProtKB.
GO; GO:0007413; P:axonal fasciculation; IMP:UniProtKB.
GO; GO:0007420; P:brain development; IMP:UniProtKB.
GO; GO:0021549; P:cerebellum development; IMP:MGI.
GO; GO:0021799; P:cerebral cortex radially oriented cell migration; IMP:DFLAT.
GO; GO:0009790; P:embryo development; ISS:UniProtKB.
GO; GO:0048013; P:ephrin receptor signaling pathway; IMP:UniProtKB.
GO; GO:0007213; P:G-protein coupled acetylcholine receptor signaling pathway; ISS:UniProtKB.
GO; GO:0021766; P:hippocampus development; IGI:MGI.
GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
GO; GO:0021819; P:layer formation in cerebral cortex; IGI:MGI.
GO; GO:0030517; P:negative regulation of axon extension; IGI:MGI.
GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:MGI.
GO; GO:0007158; P:neuron cell-cell adhesion; IMP:UniProtKB.
GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
GO; GO:0001764; P:neuron migration; IDA:UniProtKB.
GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:MGI.
GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISO:MGI.
GO; GO:0071158; P:positive regulation of cell cycle arrest; IMP:MGI.
GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
GO; GO:0045860; P:positive regulation of protein kinase activity; IGI:MGI.
GO; GO:0090314; P:positive regulation of protein targeting to membrane; IDA:MGI.
GO; GO:0032956; P:regulation of actin cytoskeleton organization; IMP:DFLAT.
GO; GO:0061001; P:regulation of dendritic spine morphogenesis; IMP:UniProtKB.
GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IMP:DFLAT.
GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
GO; GO:0042501; P:serine phosphorylation of STAT protein; IDA:MGI.
GO; GO:0021722; P:superior olivary nucleus maturation; IGI:MGI.
Gene3D; 1.10.472.10; -; 1.
InterPro; IPR004944; CDK5_activator.
InterPro; IPR036915; Cyclin-like_sf.
Pfam; PF03261; CDK5_activator; 1.
PIRSF; PIRSF009324; Cdk5_activator; 1.
SUPFAM; SSF47954; SSF47954; 1.
1: Evidence at protein level;
Biological rhythms; Cell membrane; Complete proteome; Cytoplasm;
Lipoprotein; Membrane; Myristate; Nucleus; Phosphoprotein;
Reference proteome; Ubl conjugation.
INIT_MET 1 1 Removed. {ECO:0000250|UniProtKB:Q15078}.
CHAIN 2 307 Cyclin-dependent kinase 5 activator 1,
p35.
/FTId=PRO_0000004796.
CHAIN 99 307 Cyclin-dependent kinase 5 activator 1,
p25.
/FTId=PRO_0000004797.
SITE 98 99 Cleavage; by calpain.
MOD_RES 8 8 Phosphoserine; by CDK5.
{ECO:0000250|UniProtKB:Q15078}.
MOD_RES 138 138 Phosphothreonine; by CDK5.
{ECO:0000250|UniProtKB:Q15078}.
LIPID 2 2 N-myristoyl glycine. {ECO:0000250}.
MUTAGEN 157 157 E->Q: Abolishes the binding to CDK5RAP1,
CDK5RAP2, CDKRAP3, but not to CDK5.
{ECO:0000269|PubMed:11882646}.
SEQUENCE 307 AA; 34031 MW; 165AA0747410B0C0 CRC64;
MGTVLSLSPS YRKATLFEDG AATVGHYTAV QNSKNAKDKN LKRHSIISVL PWKRIVAVSA
KKKNSKKAQP NSSYQSNIAH LNNENLKKSL SCANLSTFAQ PPPAQPPAPP ASQLSGSQTG
VSSSVKKAPH PAITSAGTPK RVIVQASTSE LLRCLGEFLC RRCYRLKHLS PTDPVLWLRS
VDRSLLLQGW QDQGFITPAN VVFLYMLCRD VISSEVGSDH ELQAVLLTCL YLSYSYMGNE
ISYPLKPFLV ESCKEAFWDR CLSVINLMSS KMLQINADPH YFTQVFSDLK NESGQEDKKR
LLLGLDR


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