CPLM-005332

Genbank Nucleotide ID

Cyclin-dependent kinase 2

Protein Synonyms/Alias

Cell division protein kinase 2; p33 protein kinase

Homo sapiens (Human)

Position	Peptide	Type	References
6	**MENFQKVEKIGEG	acetylation	[1]
6	**MENFQKVEKIGEG	ubiquitination	[2]
9	ENFQKVEKIGEGTYG	ubiquitination	[3, 4]
20	GTYGVVYKARNKLTG	ubiquitination	[4]
24	VVYKARNKLTGEVVA	ubiquitination	[4]
33	TGEVVALKKIRLDTE	acetylation	[5]
33	TGEVVALKKIRLDTE	ubiquitination	[4]
56	IREISLLKELNHPNI	ubiquitination	[3, 4]
129	RVLHRDLKPQNLLIN	ubiquitination	[3, 4]
142	INTEGAIKLADFGLA	ubiquitination	[4]
237	VTSMPDYKPSFPKWA	ubiquitination	[4, 6]
250	WARQDFSKVVPPLDE	ubiquitination	[4]
273	MLHYDPNKRISAKAA	ubiquitination	[4]
278	PNKRISAKAALAHPF	ubiquitination	[4]
291	PFFQDVTKPVPHLRL	ubiquitination	[3]

[1] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
[2] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
[3] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
[4] Systematic and quantitative assessment of the ubiquitin-modified proteome.
Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
[5] The transcriptional co-activator PCAF regulates cdk2 activity.
Mateo F, Vidal-Laliena M, Canela N, Zecchin A, Martínez-Balbás M, Agell N, Giacca M, Pujol MJ, Bachs O.
Nucleic Acids Res. 2009 Nov;37(21):7072-84. [PMID: 19773423]
[6] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661]

Functional Description

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.

DOMAIN 4 286 Protein kinase.
NP_BIND 10 18 ATP.
NP_BIND 81 83 ATP.
NP_BIND 129 132 ATP.
ACT_SITE 127 127 Proton acceptor.
METAL 132 132 Magnesium; catalytic.
METAL 145 145 Magnesium; catalytic.
BINDING 33 33 ATP.
BINDING 86 86 ATP.
BINDING 145 145 ATP.
MOD_RES 1 1 N-acetylmethionine.
MOD_RES 6 6 N6-acetyllysine.
MOD_RES 14 14 Phosphothreonine.
MOD_RES 15 15 Phosphotyrosine; by WEE1.
MOD_RES 19 19 Phosphotyrosine.
MOD_RES 160 160 Phosphothreonine; by CAK and CCRK.

3D-structure; Acetylation; Alternative splicing; ATP-binding; Cell cycle; Cell division; Complete proteome; Cytoplasm; Cytoskeleton; DNA damage; DNA repair; Endosome; Kinase; Magnesium; Meiosis; Metal-binding; Mitosis; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Serine/threonine-protein kinase; Transferase.

UniProt (SWISSPROT/TrEMBL); GenBank; EMBL

GO:0015030; C:Cajal body; IDA:UniProtKB.
GO:0005813; C:centrosome; TAS:UniProtKB.
GO:0000781; C:chromosome, telomeric region; IEA:Compara.
GO:0000793; C:condensed chromosome; IEA:Compara.
GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; IDA:UniProtKB.
GO:0005829; C:cytosol; TAS:Reactome.
GO:0005768; C:endosome; IDA:UniProtKB.
GO:0005667; C:transcription factor complex; IEA:Compara.
GO:0000805; C:X chromosome; IEA:Compara.
GO:0000806; C:Y chromosome; IEA:Compara.
GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO:0030332; F:cyclin binding; IDA:UniProtKB.
GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IDA:UniProtKB.
GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO:0031145; P:anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; TAS:Reactome.
GO:0007596; P:blood coagulation; TAS:Reactome.
GO:0051301; P:cell division; IEA:UniProtKB-KW.
GO:0071732; P:cellular response to nitric oxide; TAS:UniProtKB.
GO:0051298; P:centrosome duplication; TAS:UniProtKB.
GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome.
GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
GO:0006260; P:DNA replication; TAS:UniProtKB.
GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:Reactome.
GO:0000085; P:G2 phase of mitotic cell cycle; TAS:Reactome.
GO:0000086; P:G2/M transition of mitotic cell cycle; NAS:UniProtKB.
GO:0016572; P:histone phosphorylation; IDA:GOC.
GO:0007126; P:meiosis; TAS:UniProtKB.
GO:0007067; P:mitosis; IEA:UniProtKB-KW.
GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB.
GO:0032298; P:positive regulation of DNA-dependent DNA replication initiation; IEA:Compara.
GO:0045893; P:positive regulation of transcription, DNA-dependent; IEA:Compara.
GO:0006813; P:potassium ion transport; IEA:Compara.
GO:0007265; P:Ras protein signal transduction; IEP:BHF-UCL.
GO:0060968; P:regulation of gene silencing; IDA:UniProtKB.
GO:0051439; P:regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; TAS:Reactome.

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.

PS00107; PROTEIN_KINASE_ATP
PS50011; PROTEIN_KINASE_DOM
PS00108; PROTEIN_KINASE_ST