P97377 (CDK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 2
EC=2.7.11.22

Alternative name(s):
Cell division protein kinase 2

Gene names

Name:	Cdk2
Synonyms:	Cdkn2

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	346 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 By similarity. Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Ref.5 Ref.6 Ref.7 Ref.8
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it. Stimulated by MYC. Inactivated by CDKN1A (p21) By similarity.
Subunit structure	Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 By similarity. Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC. Found in a complex with both SPDYA and CDKN1B/KIP1. Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1 By similarity. May interact with CEP63 By similarity. Ref.4
Subcellular location	Cytoplasm › cytoskeleton › centrosome By similarity. Nucleus › Cajal body By similarity. Cytoplasm By similarity. Endosome By similarity. Note: Localized at the centrosomes in late G2 phase after separation of the centrosomes but before the start of prophase. Nuclear-cytoplasmic trafficking is mediated during the inhibition by 1,25-(OH)2D3 By similarity.
Post-translational modification	Phosphorylated at Thr-160 by CDK7 in a CAK complex. Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A By similarity. Ref.4 Nitrosylated after treatment with nitric oxide (DETA-NO) By similarity.
Disruption phenotype	Reduced body size and impaired neural progenitor cell proliferation. Sterility due to defective meiosis; no effect on mitotic cells. Premature translocation of CDK1 from the cytoplasm to the nucleus compensating CDK2 loss. Prolonged and impaired DNA repair activity upon DNA damage by gamma-irradiation. Ref.6 Ref.7 Ref.8
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	Cell cycle Cell division DNA damage DNA repair Meiosis Mitosis
Cellular component	Cytoplasm Cytoskeleton Endosome Nucleus
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Magnesium Metal-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	DNA repair Inferred from electronic annotation. Source: UniProtKB-KW Ras protein signal transduction Inferred from electronic annotation. Source: Compara cell division Inferred from electronic annotation. Source: UniProtKB-KW meiosis Inferred from electronic annotation. Source: UniProtKB-KW mitosis Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of DNA-dependent DNA replication initiation Inferred from genetic interaction PubMed 20215406. Source: MGI positive regulation of cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of transcription, DNA-dependent Inferred from genetic interaction PubMed 16137671. Source: MGI potassium ion transport Inferred from genetic interaction PubMed 16393152. Source: MGI regulation of gene silencing Inferred from electronic annotation. Source: Compara
Cellular_component	Cajal body Inferred from electronic annotation. Source: UniProtKB-SubCell X chromosome Inferred from direct assay PubMed 17784788. Source: MGI Y chromosome Inferred from direct assay PubMed 17784788. Source: MGI chromosome, telomeric region Inferred from direct assay PubMed 17784788. Source: MGI condensed chromosome Inferred from direct assay PubMed 17784788. Source: MGI cyclin-dependent protein kinase holoenzyme complex Inferred from physical interaction PubMed 12970760. Source: MGI endosome Inferred from electronic annotation. Source: UniProtKB-SubCell microtubule organizing center Inferred from electronic annotation. Source: UniProtKB-SubCell transcription factor complex Inferred from direct assay PubMed 10082561. Source: MGI
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 12970171PubMed 12970760. Source: MGI histone kinase activity Inferred from electronic annotation. Source: Compara metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Ccna2	P51943	3	EBI-847048,EBI-846980
Ccne1	Q61457	2	EBI-847048,EBI-643090

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform CDK2-beta (identifier: P97377-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform CDK2-alpha (identifier: P97377-2)

The sequence of this isoform differs from the canonical sequence as follows:
     197-244: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 346	346	Cyclin-dependent kinase 2		PRO_0000085771
Regions
	Domain	4 – 334	331	Protein kinase
	Nucleotide binding	10 – 18	9	ATP By similarity
	Nucleotide binding	81 – 83	3	ATP By similarity
	Nucleotide binding	129 – 132	4	ATP By similarity
Sites
	Active site	127	1	Proton acceptor By similarity
	Metal binding	132	1	Magnesium; catalytic By similarity
	Metal binding	145	1	Magnesium; catalytic By similarity
	Binding site	33	1	ATP By similarity
	Binding site	86	1	ATP By similarity
	Binding site	145	1	ATP By similarity
	Site	9	1	CDK7 binding By similarity
	Site	88 – 89	2	CDK7 binding By similarity
	Site	166	1	CDK7 binding By similarity
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine By similarity
	Modified residue	6	1	N6-acetyllysine By similarity
	Modified residue	14	1	Phosphothreonine By similarity
	Modified residue	15	1	Phosphotyrosine; by WEE1 Ref.4 Ref.9
	Modified residue	19	1	Phosphotyrosine By similarity
	Modified residue	160	1	Phosphothreonine; by CAK and CCRK By similarity
Natural variations
	Alternative sequence	197 – 244	48	Missing in isoform CDK2-alpha.		VSP_004800
Experimental info
	Mutagenesis	15	1	Y → F: Loss of thyrosine phosphorylation by WEE1 and CABLES1. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform CDK2-beta [UniParc]. Last modified May 30, 2000. Version 2. Checksum: D806BC2F150AEDFC	FASTA	346	38,978
	10 20 30 40 50 60 MENFQKVEKI GEGTYGVVYK AKNKLTGEVV ALKKIRLDTE TEGVPSTAIR EISLLKELNH 70 80 90 100 110 120 PNIVKLLDVI HTENKLYLVF EFLHQDLKKF MDASALTGIP LPLIKSYLFQ LLQGLAFCHS 130 140 150 160 170 180 HRVLHRDLKP QNLLINAEGS IKLADFGLAR AFGVPVRTYT HEVVTLWYRA PEILLGCKYY 190 200 210 220 230 240 STAVDIWSLG CIFAEMHLVC TQHHAKCCGE HRRNGRHSLC PLCSYLEVAA SQGGGMTAVS 250 260 270 280 290 300 APHPVTRRAL FPGDSEIDQL FRIFRTLGTP DEVVWPGVTS MPDYKPSFPK WARQDFSKVV 310 320 330 340 PPLDEDGRSL LSQMLHYDPN KRISAKAALA HPFFQDVTKP VPHLRL
	Isoform CDK2-alpha [UniParc]. Checksum: FB28DBD8BA587BDA	FASTA	298	33,887
	10 20 30 40 50 60 MENFQKVEKI GEGTYGVVYK AKNKLTGEVV ALKKIRLDTE TEGVPSTAIR EISLLKELNH 70 80 90 100 110 120 PNIVKLLDVI HTENKLYLVF EFLHQDLKKF MDASALTGIP LPLIKSYLFQ LLQGLAFCHS 130 140 150 160 170 180 HRVLHRDLKP QNLLINAEGS IKLADFGLAR AFGVPVRTYT HEVVTLWYRA PEILLGCKYY 190 200 210 220 230 240 STAVDIWSLG CIFAEMVTRR ALFPGDSEID QLFRIFRTLG TPDEVVWPGV TSMPDYKPSF 250 260 270 280 290 PKWARQDFSK VVPPLDEDGR SLLSQMLHYD PNKRISAKAA LAHPFFQDVT KPVPHLRL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Exon-intron organization of the murine cyclin-dependent kinase-2 genes Cdk2-alpha and Cdk2-beta." Jun D., Lee Y.H., Park H.K., Kim Y.H. Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CDK2-ALPHA). Strain: C57BL/6.
[2]	"The 39 kDa form of CDK2 arises through alternative splicing, is expressed in many but not all mammals, and is an active kinase." Ellenrieder C., Bartosch B., Lee G.Y., Murphy M., Sweeney C., Hergersberg M., Hunt T., Carrington M., Jaussi R. Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], ALTERNATIVE SPLICING.
[3]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CDK2-BETA). Strain: FVB/N. Tissue: Mammary gland.
[4]	"Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers." Wu C.-L., Kirley S.D., Xiao H., Chuang Y., Chung D.C., Zukerberg L.R. Cancer Res. 61:7325-7332(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT TYR-15, MUTAGENESIS OF TYR-15, IDENTIFICATION IN A COMPLEX WITH CABLES1; CCNA1 AND CCNE1, INTERACTION WITH CABLES1.
[5]	"ik3-1/Cables is a substrate for cyclin-dependent kinase 3 (cdk 3)." Yamochi T., Semba K., Tsuji K., Mizumoto K., Sato H., Matsuura Y., Nishimoto I., Matsuoka M. Eur. J. Biochem. 268:6076-6082(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS CABLES1 KINASE.
[6]	"Cdk2 knockout mice are viable." Berthet C., Aleem E., Coppola V., Tessarollo L., Kaldis P. Curr. Biol. 13:1775-1785(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[7]	"Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice." Ortega S., Prieto I., Odajima J., Martin A., Dubus P., Sotillo R., Barbero J.L., Malumbres M., Barbacid M. Nat. Genet. 35:25-31(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[8]	"p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint." Satyanarayana A., Hilton M.B., Kaldis P. Mol. Biol. Cell 19:65-77(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[9]	"Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry." Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J. Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-15, MASS SPECTROMETRY. Tissue: Embryonic fibroblast.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U63337 mRNA. Translation: AAB37128.1. AJ223732 mRNA. Translation: CAA11533.1. AJ223733 Genomic DNA. Translation: CAA11534.1. AJ223733 Genomic DNA. Translation: CAA11535.1. BC005654 mRNA. Translation: AAH05654.1.
IPI	IPI00124240. IPI00225350.
RefSeq	NP_058036.1. NM_016756.4. NP_904326.1. NM_183417.3.
UniGene	Mm.111326.
3D structure databases
ProteinModelPortal	P97377.
SMR	P97377. Positions 1-346.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-24176N.
IntAct	P97377. 4 interactions.
PTM databases
PhosphoSite	P97377.
Proteomic databases
PaxDb	P97377.
PRIDE	P97377.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000026415; ENSMUSP00000026415; ENSMUSG00000025358. ENSMUST00000026416; ENSMUSP00000026416; ENSMUSG00000025358.
GeneID	12566.
KEGG	mmu:12566.
Organism-specific databases
CTD	1017.
MGI	MGI:104772. Cdk2.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	P97377.
KO	K02206.
OMA	YLEVAAS.
OrthoDB	EOG4C5CJV.
Enzyme and pathway databases
Reactome	REACT_120463. Meiosis. REACT_27235. Meiotic Recombination (mouse). REACT_89750. Hemostasis.
Gene expression databases
ArrayExpress	P97377.
Bgee	P97377.
CleanEx	MM_CDK2.
Genevestigator	P97377.
GermOnline	ENSMUSG00000025358. Mus musculus.
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. 2 hits. [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
ChiTaRS	CDK2. mouse.
NextBio	281656.
SOURCE	Search...

Entry information

Entry name

CDK2_MOUSE

Accession

Primary (citable) accession number: P97377
Secondary accession number(s): O55105

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	May 30, 2000
Last modified:	May 1, 2013
This is version 124 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program