Cyclin-dependent kinase 2 (CDK2)
The protein contains 298 amino acids for an estimated molecular weight of 33930 Da.
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. 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 phosphorylatio (updated: Dec. 20, 2017)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Anaphase-promoting complex-dependent catabolic process
Blood coagulation
Cell division
Cellular response to nitric oxide
Centriole replication
Centrosome duplication
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
DNA repair
DNA replication
DNA replication initiation
G1/S transition of mitotic cell cycle
G2/M transition of mitotic cell cycle
Granulocyte differentiation
Histone phosphorylation
Meiotic cell cycle
Meiotic nuclear division
Mitotic cell cycle
Mitotic G1 DNA damage checkpoint signaling
Mitotic nuclear division
Multicellular organism development
Negative regulation of transcription by RNA polymerase II
Obsolete negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle
Obsolete regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle
Peptidyl-serine phosphorylation
Positive regulation of cell population proliferation
Positive regulation of DNA-dependent DNA replication initiation
Positive regulation of transcription, DNA-templated
Potassium ion transport
Protein phosphorylation
Ras protein signal transduction
Regulation of G2/M transition of mitotic cell cycle
Regulation of gene expression
Regulation of gene silencing
Regulation of signal transduction by p53 class mediator
Response to organic substance
Signal transduction
Telomere maintenance via telomerase
Cellular Component
Cajal body
Centrosome
Chromosome, telomeric region
Condensed chromosome
Cyclin A1-CDK2 complex
Cyclin A2-CDK2 complex
Cyclin E1-CDK2 complex
Cyclin E2-CDK2 complex
Cyclin-dependent protein kinase holoenzyme complex
Cytoplasm
Cytosol
Endosome
Nucleoplasm
Nucleus
Transcription regulator complex
X chromosome
Y chromosome
Molecular Function
ATP binding
Cyclin binding
Cyclin-dependent protein kinase activity
Cyclin-dependent protein serine/threonine kinase activity
Kinase activity
Magnesium ion binding
Metal ion binding
Protein domain specific binding
Protein serine kinase activity
Protein serine/threonine kinase activity
Protein threonine kinase activity
The reference OMIM entry for this protein is 116953
Cyclin-dependent kinase 2; cdk2
Cell division kinase 2
P33(cdk2)
CLONING
Ninomiya-Tsuji et al. (1991) cloned 2 different cDNAs that can complement cdc28 mutations of budding yeast Saccharomyces cerevisiae. One corresponded to a gene encoding human p34(CDC2) kinase (116940), and the other to a gene that had not been characterized previously, CDK2 (cell division kinase-2). The CDK2 protein was highly homologous to p34(CDC2) kinase and more significantly homologous to Xenopus Eg1 kinase, suggesting that CDK2 is the human homolog of Eg1. The human CDC2 and CDK2 genes were both able to complement the inviability of a null allele of S. cerevisiae, CDC28. However, CDK2 was unable to complement cdc2 mutants in fission yeast Schizosaccharomyces pombe under the condition where the human CDC2 gene could complement them. CDK2 mRNA appeared late in G1 or in early S phase, slightly before CDC2 mRNA, after growth stimulation in the normal human fibroblast cells. Thus, 2 different CDC2-like kinases appear to regulate the human cell cycle at different stages.GENE FUNCTION
The complex formed of p34(cdc2) (116940) and cyclin B (176740) is required for the G2-to-M transition in cell division. Human cyclin A (123835) binds independently to 2 kinases, p34(cdc2) or p33. In adenovirus-transformed cells, the viral E1A oncoprotein seems to associate with p33/cyclin A but not with p34(cdc2)/cyclin A. Tsai et al. (1991) isolated the gene for p33, which shares 65% sequence identity with p34(cdc2). They suggested that p33(cdk2) plays a unique role in cell cycle regulation of vertebrate cells. CDK (e.g., CDK2) activation requires association with cyclins (e.g., CCNE1; 123837) and phosphorylation by CAK (CCNH; 601953), and leads to cell proliferation. Inhibition of cellular proliferation occurs upon association of CDK inhibitor (e.g., CDKN1B; 600778) with a cyclin-CDK complex. Sheaff et al. (1997) showed that expression of CCNE1-CDK2 at physiologic levels of ATP results in phosphorylation of CDKN1B at thr187, leading to elimination of CDKN1B from the cell and progression of the cell cycle from G1 to S phase. At low ATP levels, the inhibitory functions of CDKN1B are enhanced, thereby arresting cell proliferation. Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A-associated CDK2 activity. Levkau et al. (1998) showed that in apoptotic cells the carboxyl-termini of the CDK inhibitors CDKN1A (116899) and CDKN1B are truncated by specific cleavage. The enzyme involved in this cleavage is CASP3 (600636) and/or a CASP3-like caspase. After cleavage, CDKN1A loses its nuclear localization sequence and exits the nucleus. Cleavage of CDKN1A and CDKN1B resulted in a substantial reduction in their association with nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2 activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant to caspase cleavage, partially suppressed apoptosis. These data suggested that CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation. Hinchcliffe et al. (1999) developed a Xenopus egg extract arrested in S phase that supported repeated assembly of daughter centrosomes. Multiple rounds of centrosome reproduction were blocked by selective inactivation of CDK2-cyclin E (123837) and were restored by addition of purified CDK2-cyclin E. Confocal microscopy revealed that cyclin E was localized at the centroso ... More on the omim web site
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 116953 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed