Q63699 (CDK2_RAT) 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

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

Protein attributes

Sequence length	298 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 By similarity. Ref.3
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 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 By similarity. Binds to RB1. Interacts with CACUL1 By similarity. May interact with CEP63 By similarity. Ref.3
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.
Induction	Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis. Ref.3
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. Nitrosylated after treatment with nitric oxide (DETA-NO) 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	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 cell division Inferred from electronic annotation. Source: UniProtKB-KW cellular response to insulin stimulus Inferred from direct assay PubMed 15994754. Source: RGD meiosis Inferred from electronic annotation. Source: UniProtKB-KW mitosis Inferred from electronic annotation. Source: UniProtKB-KW organ regeneration Inferred from expression pattern PubMed 16534847. Source: RGD response to cAMP Inferred from direct assay PubMed 15994754. Source: RGD response to cadmium ion Inferred from expression pattern PubMed 16730872. Source: RGD response to drug Inferred from expression pattern PubMed 17706465. Source: RGD response to electrical stimulus Inferred from direct assay PubMed 15607308. Source: RGD response to estradiol stimulus Inferred from expression pattern PubMed 16019103. Source: RGD response to ethanol Inferred from expression pattern PubMed 16689928. Source: RGD response to toxic substance Inferred from expression pattern PubMed 17343987. Source: RGD
Cellular_component	Cajal body Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Inferred from direct assay PubMed 15994754. Source: RGD endosome Inferred from electronic annotation. Source: UniProtKB-SubCell microtubule organizing center Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay PubMed 15994754. Source: RGD
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cyclin-dependent protein serine/threonine kinase activity Inferred from direct assay PubMed 11823715. Source: RGD metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

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

Isoform CDK2-alpha (identifier: Q63699-1)

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-beta (identifier: Q63699-2)

The sequence of this isoform is not available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 298	298	Cyclin-dependent kinase 2		PRO_0000085772
Regions
	Domain	4 – 286	283	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 By similarity
	Modified residue	19	1	Phosphotyrosine By similarity
	Modified residue	160	1	Phosphothreonine; by CAK and CCRK By similarity
Experimental info
	Sequence conflict	79	1	V → C in BAA09638. Ref.2
	Sequence conflict	99	1	L → I in BAA09638. Ref.2
	Sequence conflict	124	1	L → C in BAA09638. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform CDK2-alpha [UniParc]. Last modified November 1, 1996. Version 1. Checksum: C8CB3ADCE9B97F88	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 MDASALTGLP 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
	Isoform CDK2-beta (Sequence not available).		–	–

References

[1]	"A variant form of cyclin-dependent kinase 2 (Cdk2) in a malignantly transformed rat thyroid (FRTL-Tc) cell line." Kotani S., Endo T., Kitagawa M., Higashi H., Onaya T. Oncogene 10:663-669(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Thyroid.
[2]	"Synergistic gene expressions of cyclin E, cdk2, cdk5 and E2F-1 during the prolactin-induced G1/S transition in rat Nb2 pre-T lymphoma cells." Hosokawa Y., Yang M., Kaneko S., Tanaka M., Nakashima K. Biochem. Mol. Biol. Int. 37:393-399(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 19-124.
[3]	"Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma cells." Choi K.S., Eom Y.W., Kang Y., Ha M.J., Rhee H., Yoon J.-W., Kim S.-J. J. Biol. Chem. 274:31775-31783(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS RB1 KINASE, INDUCTION BY TGFB1, INTERACTION WITH RB1.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	D28753 mRNA. Translation: BAA05947.1. D63162 mRNA. Translation: BAA09638.1.
IPI	IPI00778415.
UniGene	Rn.104460.
3D structure databases
ProteinModelPortal	Q63699.
SMR	Q63699. Positions 1-298.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q63699. 1 interaction.
PTM databases
PhosphoSite	Q63699.
Proteomic databases
PaxDb	Q63699.
PRIDE	Q63699.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
UCSC	RGD:70486. rat.
Organism-specific databases
RGD	70486. Cdk2.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
Enzyme and pathway databases
BRENDA	2.7.11.22. 5301.
Gene expression databases
ArrayExpress	Q63699.
Genevestigator	Q63699.
GermOnline	ENSRNOG00000006469. Rattus norvegicus.
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...

Entry information

Entry name

CDK2_RAT

Accession

Primary (citable) accession number: Q63699
Secondary accession number(s): O09136

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	November 1, 1996
Last modified:	May 29, 2013
This is version 109 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program