| Structural highlights
Function
[CDK2_HUMAN] 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Several gamma-herpesviruses encode proteins related to the mammalian cyclins, regulatory subunits of cyclin-dependent kinases (cdks) essential for cell cycle progression. We report a 2.5 A crystal structure of a full-length oncogenic viral cyclin from gamma-herpesvirus 68 complexed with cdk2. The viral cyclin binds cdk2 with an orientation different from cyclin A and makes several novel interactions at the interface, yet it activates cdk2 by triggering conformational changes similar to cyclin A. Sequences within the viral cyclin N-terminus lock part of the cdk2 T-loop within the core of the complex. These sequences and others are conserved amongst the viral and cellular D-type cyclins, suggesting that this structure has wider implications for other cyclin-cdk complexes. The observed resistance of this viral cyclin-cdk complex to inhibition by the p27(KIP:) cdk inhibitor is explained by sequence and conformational variation in the cyclin rendering the p27(KIP:)-binding site on the cyclin subunit non-functional.
Crystal structure of a gamma-herpesvirus cyclin-cdk complex.,Card GL, Knowles P, Laman H, Jones N, McDonald NQ EMBO J. 2000 Jun 15;19(12):2877-88. PMID:10856233[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999 Sep 17;98(6):859-69. PMID:10499802
- ↑ Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell. 2000 Sep 29;103(1):127-40. PMID:11051553
- ↑ Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E. NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. Genes Dev. 2000 Sep 15;14(18):2283-97. PMID:10995386
- ↑ Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. Genes Dev. 2000 Sep 15;14(18):2298-313. PMID:10995387
- ↑ Luciani MG, Hutchins JR, Zheleva D, Hupp TR. The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A. J Mol Biol. 2000 Jul 14;300(3):503-18. PMID:10884347 doi:10.1006/jmbi.2000.3830
- ↑ Garrett S, Barton WA, Knights R, Jin P, Morgan DO, Fisher RP. Reciprocal activation by cyclin-dependent kinases 2 and 7 is directed by substrate specificity determinants outside the T loop. Mol Cell Biol. 2001 Jan;21(1):88-99. PMID:11113184 doi:10.1128/MCB.21.1.88-99.2001
- ↑ Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M, West SC. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature. 2005 Mar 31;434(7033):598-604. PMID:15800615 doi:10.1038/nature03404
- ↑ De Boer L, Oakes V, Beamish H, Giles N, Stevens F, Somodevilla-Torres M, Desouza C, Gabrielli B. Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events. Oncogene. 2008 Jul 17;27(31):4261-8. doi: 10.1038/onc.2008.74. Epub 2008 Mar 31. PMID:18372919 doi:10.1038/onc.2008.74
- ↑ Flores O, Wang Z, Knudsen KE, Burnstein KL. Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition. Endocrinology. 2010 Mar;151(3):896-908. doi: 10.1210/en.2009-1116. Epub 2010 Feb , 10. PMID:20147522 doi:10.1210/en.2009-1116
- ↑ Kumar S, Barthwal MK, Dikshit M. Cdk2 nitrosylation and loss of mitochondrial potential mediate NO-dependent biphasic effect on HL-60 cell cycle. Free Radic Biol Med. 2010 Mar 15;48(6):851-61. doi:, 10.1016/j.freeradbiomed.2010.01.004. Epub 2010 Jan 15. PMID:20079829 doi:10.1016/j.freeradbiomed.2010.01.004
- ↑ Chen S, Bohrer LR, Rai AN, Pan Y, Gan L, Zhou X, Bagchi A, Simon JA, Huang H. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol. 2010 Nov;12(11):1108-14. doi: 10.1038/ncb2116. Epub 2010 Oct 10. PMID:20935635 doi:10.1038/ncb2116
- ↑ Chung JH, Bunz F. Cdk2 is required for p53-independent G2/M checkpoint control. PLoS Genet. 2010 Feb 26;6(2):e1000863. doi: 10.1371/journal.pgen.1000863. PMID:20195506 doi:10.1371/journal.pgen.1000863
- ↑ Hydbring P, Bahram F, Su Y, Tronnersjo S, Hogstrand K, von der Lehr N, Sharifi HR, Lilischkis R, Hein N, Wu S, Vervoorts J, Henriksson M, Grandien A, Luscher B, Larsson LG. Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):58-63. doi: 10.1073/pnas.0900121106. , Epub 2009 Dec 4. PMID:19966300 doi:10.1073/pnas.0900121106
- ↑ Fiset A, Xu E, Bergeron S, Marette A, Pelletier G, Siminovitch KA, Olivier M, Beauchemin N, Faure RL. Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and regulates insulin internalization. Cell Signal. 2011 May;23(5):911-9. doi: 10.1016/j.cellsig.2011.01.019. Epub 2011 , Jan 22. PMID:21262353 doi:10.1016/j.cellsig.2011.01.019
- ↑ Huang X, Summers MK, Pham V, Lill JR, Liu J, Lee G, Kirkpatrick DS, Jackson PK, Fang G, Dixit VM. Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry. Mol Cell. 2011 May 20;42(4):511-23. doi: 10.1016/j.molcel.2011.03.027. PMID:21596315 doi:10.1016/j.molcel.2011.03.027
- ↑ Neganova I, Vilella F, Atkinson SP, Lloret M, Passos JF, von Zglinicki T, O'Connor JE, Burks D, Jones R, Armstrong L, Lako M. An important role for CDK2 in G1 to S checkpoint activation and DNA damage response in human embryonic stem cells. Stem Cells. 2011 Apr;29(4):651-9. doi: 10.1002/stem.620. PMID:21319273 doi:10.1002/stem.620
- ↑ Brown NR, Lowe ED, Petri E, Skamnaki V, Antrobus R, Johnson LN. Cyclin B and cyclin A confer different substrate recognition properties on CDK2. Cell Cycle. 2007 Jun 1;6(11):1350-9. Epub 2007 Jun 11. PMID:17495531
- ↑ Card GL, Knowles P, Laman H, Jones N, McDonald NQ. Crystal structure of a gamma-herpesvirus cyclin-cdk complex. EMBO J. 2000 Jun 15;19(12):2877-88. PMID:10856233 doi:10.1093/emboj/19.12.2877
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