P97377 (CDK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 124. History...
Names and origin
|Protein names||Recommended name:|
Cyclin-dependent kinase 2
Cell division protein kinase 2
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||346 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
ATP + a protein = ADP + a phosphoprotein.
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.
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
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.
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.
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
Contains 1 protein kinase domain.
|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:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 346||346||Cyclin-dependent kinase 2||PRO_0000085771|
|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|
|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|
|Alternative sequence||197 – 244||48||Missing in isoform CDK2-alpha.||VSP_004800|
|Mutagenesis||15||1||Y → F: Loss of thyrosine phosphorylation by WEE1 and CABLES1. Ref.4|
|||"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).
|||"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.
|||"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).
Tissue: Mammary gland.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|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.
|RefSeq||NP_058036.1. NM_016756.4. |
3D structure databases
|SMR||P97377. Positions 1-346. |
Protein-protein interaction databases
|IntAct||P97377. 4 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000026415; ENSMUSP00000026415; ENSMUSG00000025358. |
ENSMUST00000026416; ENSMUSP00000026416; ENSMUSG00000025358.
|MGI||MGI:104772. Cdk2. |
Enzyme and pathway databases
|Reactome||REACT_120463. Meiosis. |
REACT_27235. Meiotic Recombination (mouse).
Gene expression databases
|GermOnline||ENSMUSG00000025358. Mus musculus. |
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 2 hits. |
|SMART||SM00220. S_TKc. 1 hit. |
|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.
|ChiTaRS||CDK2. mouse. |
|Accession||Primary (citable) accession number: P97377|
Secondary accession number(s): O55105
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|