View source for Cyclin-dependent kinase 2

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Redirect|CDK2|the airport with the Transport Canada identifier CDK2|Diavik Airport}}
{{Infobox_gene}}
'''Cyclin-dependent kinase 2''', also known as '''cell division protein kinase 2''', or Cdk2, is an [[enzyme]] that in humans is encoded by the ''CDK2'' [[gene]].<ref name="pmid1653904">{{cite journal | vauthors = Tsai LH, Harlow E, Meyerson M | title = Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase | journal = Nature | volume = 353 | issue = 6340 | pages = 174–7 | date = September 1991 | pmid = 1653904 | doi = 10.1038/353174a0 | bibcode = 1991Natur.353..174T | s2cid = 4358953 }}</ref><ref name="entrez2">{{Cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1017|title=Entrez Gene: CDK2 cyclin-dependent kinase 2}}</ref> The [[protein]] encoded by this gene is a member of the [[cyclin-dependent kinase]] family of [[serine/threonine-specific protein kinase|Ser/Thr protein kinases]]. This protein kinase is highly similar to the gene products of ''[[Saccharomyces cerevisiae|S. cerevisiae]]'' [[cdc28]], and ''[[Schizosaccharomyces pombe|S. pombe]]'' cdc2, also known as [[Cdk1]] in humans. It is a catalytic subunit of the [[cyclin-dependent kinase]] complex, whose activity is restricted to the G1-S phase of the [[cell cycle]], where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including [[cyclin E]] or [[cyclin A|A]]. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase.<ref name=":0">{{cite journal | vauthors = Echalier A, Endicott JA, Noble ME | title = Recent developments in cyclin-dependent kinase biochemical and structural studies | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1804 | issue = 3 | pages = 511–9 | date = March 2010 | pmid = 19822225 | doi = 10.1016/j.bbapap.2009.10.002 }}</ref> Its activity is also regulated by [[phosphorylation]]. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported.<ref name="entrez">{{cite web |url= https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1017 |title=Entrez Gene: CDK2 cyclin-dependent kinase 2 }}</ref> The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.<ref name="Cdk2 knockout mice are viable">{{cite journal | vauthors = Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P | title = Cdk2 knockout mice are viable | journal = Current Biology | volume = 13 | issue = 20 | pages = 1775–85 | date = October 2003 | pmid = 14561402 | doi = 10.1016/j.cub.2003.09.024 | s2cid = 14320937 | doi-access = free | bibcode = 2003CBio...13.1775B }}</ref>

== Dispensability in normally functioning tissue ==
Original cell-culture based experiments demonstrated cell cycle arrest at the G1-S transition resulting from the deletion of Cdk2.<ref name=":1">{{cite journal | vauthors = Satyanarayana A, Kaldis P | title = Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms | journal = Oncogene | volume = 28 | issue = 33 | pages = 2925–39 | date = August 2009 | pmid = 19561645 | doi = 10.1038/onc.2009.170 | doi-access = free }}</ref> Later experiments showed that Cdk2 deletions lengthened the [[G1 phase|G<sub>1</sub> phase]] of the cell cycle in mouse embryo fibroblasts. However, they still entered [[S phase]] after this period and were able to complete the remaining phases of the cell cycle.<ref name=":2">{{cite journal | vauthors = Su TT, Stumpff J | title = Promiscuity rules? The dispensability of cyclin E and Cdk2 | journal = Science's STKE | volume = 2004 | issue = 224 | pages = pe11 | date = March 2004 | pmid = 15026579 | pmc = 3242733 | doi = 10.1126/stke.2242004pe11 }}</ref> When Cdk2 was deleted in mice, the animals remained viable despite a reduction in body size. However, meiotic function of both male and female mice was inhibited. This suggests that Cdk2 is non-essential for the cell cycle of healthy cells, but essential for [[meiosis]] and reproduction.<ref name=":1" /> Cells in Cdk2 knockout mice likely undergo fewer divisions, contributing to the reduction in body size. Germ cells also stop dividing at prophase of meiosis, leading to reproductive sterility.<ref name=":2" />  Cdk1 is now believed to compensate for many aspects of Cdk2 deletion, except for meiotic function.<ref name=":1" />

== Mechanism of activation ==
Cyclin-dependent kinase 2 is structured in two lobes. The lobe beginning at the N-terminus (N-lobe) contains many beta sheets, while the C-terminus lobe (C-lobe) is rich in alpha helices.<ref name=":0" />  Cdk2 is capable of binding to many different cyclins, including cyclins A, B, E, and possibly C.<ref name=":1" /> Recent studies suggest Cdk2 binds preferentially to [[cyclin]]s A and E, while Cdk1 prefers cyclins A and B.<ref name=":3">{{cite journal | vauthors = Wood DJ, Korolchuk S, Tatum NJ, Wang LZ, Endicott JA, Noble ME, Martin MP | title = Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition | journal = Cell Chemical Biology | volume = 26 | issue = 1 | pages = 121–130.e5 | date = November 2018 | pmid = 30472117 | pmc = 6344228 | doi = 10.1016/j.chembiol.2018.10.015 }}</ref>
[[File:CDK2CyclinA Cropped.png|alt=Cdk2 (blue) and its binding partner, cyclin A (red).|thumb|Cdk2 (blue) and its binding partner, cyclin A (red).<ref name="pmid7630397">{{PDB|1FIN}}; {{cite journal | vauthors = Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP | title = Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex | journal = Nature | volume = 376 | issue = 6538 | pages = 313–20 | date = July 1995 | pmid = 7630397 | doi = 10.1038/376313a0 | bibcode = 1995Natur.376..313J | s2cid = 4361179 }}</ref>]]
Cdk2 becomes active when a cyclin protein (either A or E) binds at the active site located between the N and C lobes of the kinase. Due to the location of the active site, partner cyclins interact with both lobes of Cdk2. Cdk2 contains an important alpha helix located in the C lobe of the kinase, called the C-helix or the PSTAIRE-helix. Hydrophobic interactions cause the C-helix to associate with another helix in the activating cyclin. Activation induces a conformational change where the helix rotates and moves closer to the N-lobe.{{citation needed|date=February 2019}} This allows the glutamic acid located on the C-helix to form an ion pair with a nearby lysine side chain. The significance of this movement is that it brings the side
chain of Glu 51, which belongs to a triad of catalytic site residues
conserved in all eukaryotic kinases, into the catalytic site. This
triad (Lys 33, Glu 51 and Asp 145) is involved in ATP phosphate
orientation and magnesium coordination, and is thought to be
critical for catalysis. This conformational change also relocates the [[activation loop]] to the C-lobe, revealing the ATP binding site now available for new interactions. Finally, the Threonine-160 residue is exposed and phosphorylated as the C-lobe activation segment is displaced from the catalytic site and the threonine residue is no longer sterically hindered. The phosphorylated threonine residue creates stability in the final enzyme conformation. It is important to note that throughout this activation process, cyclins binding to Cdk2 do not undergo any conformational change.<ref>{{cite journal | vauthors = Malumbres M | title = Cyclin-dependent kinases | journal = Genome Biology | volume = 15 | issue = 6 | pages = 122 | date = 2014-06-30 | pmid = 25180339 | pmc = 4097832 | doi = 10.1186/gb4184 | doi-access = free }}</ref><ref name=":0" />
[[File:CDK2CyclinE Cropped.png|thumb|Cdk2 (blue) and its binding partner cyclin E (orange).<ref name="pmid15660127">{{PDB|1W98}}; {{cite journal | vauthors = Honda R, Lowe ED, Dubinina E, Skamnaki V, Cook A, Brown NR, Johnson LN | title = The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2-independent roles | journal = The EMBO Journal | volume = 24 | issue = 3 | pages = 452–63 | date = February 2005 | pmid = 15660127 | pmc = 548659 | doi = 10.1038/sj.emboj.7600554 }}</ref>]]

== Role in DNA replication ==
The success of the cell division process is dependent on the precise regulation of processes at both cellular and tissue levels. Complex interactions between proteins and DNA within the cell allow genomic DNA to be passed to daughter cells. Interactions between cells and extracellular matrix proteins allow new cells to be incorporated into existing tissues. At the cellular level,  the process is controlled by different levels of [[cyclin-dependent kinase]]s (Cdks) and their partner cyclins. Cells utilize various checkpoints as a means of delaying cell cycle progression until it can repair defects.<ref>{{cite journal | vauthors = Bartek J, Lukas C, Lukas J | title = Checking on DNA damage in S phase | journal = Nature Reviews. Molecular Cell Biology | volume = 5 | issue = 10 | pages = 792–804 | date = October 2004 | pmid = 15459660 | doi = 10.1038/nrm1493 | s2cid = 33560392 }}</ref>

Cdk2 is active during G<sub>1</sub> and S phase of the cell cycle, and therefore acts as a G<sub>1</sub>-S phase checkpoint control. Prior to G<sub>1</sub> phase, levels of Cdk4 and Cdk6 increase along with cyclin D. This allows for the partial phosphorylation of Rb, and partial activation of E2F at the beginning of G<sub>1</sub> phase, which promotes cyclin E synthesis and increased Cdk2 activity. At the end of G<sub>1</sub> phase, the [[Cyclin E/Cdk2|Cdk2/Cyclin E]] complex reaches maximum activity and plays a significant role in the initiation of S phase.<ref name=":4">{{cite journal | vauthors = Caruso JA, Duong MT, Carey JP, Hunt KK, Keyomarsi K | title = Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies | journal = Cancer Research | volume = 78 | issue = 19 | pages = 5481–5491 | date = October 2018 | pmid = 30194068 | pmc = 6168358 | doi = 10.1158/0008-5472.can-18-1235 }}</ref> Other non-Cdk proteins also become active during the G<sub>1</sub>-S [[phase transition]]. For example, the [[Retinoblastoma protein|retinoblastoma]] (Rb) and p27 proteins are phosphorylated by Cdk2 – cyclin A/E complexes, fully deactivating them.<ref name=":5">{{cite journal | vauthors = Giacinti C, Giordano A | title = RB and cell cycle progression | journal = Oncogene | volume = 25 | issue = 38 | pages = 5220–7 | date = August 2006 | pmid = 16936740 | doi = 10.1038/sj.onc.1209615 | doi-access = free }}</ref> This allows E2F transcription factors to express genes that promote entry into S phase where DNA is replicated prior to division.<ref>{{cite journal | vauthors = Cobrinik D | title = Pocket proteins and cell cycle control | journal = Oncogene | volume = 24 | issue = 17 | pages = 2796–809 | date = April 2005 | pmid = 15838516 | doi = 10.1038/sj.onc.1208619 | doi-access = free }}</ref><ref>{{Cite book|title=The molecular basis of cancer|others=Mendelsohn, John, 1936-, Gray, Joe W.,, Howley, Peter M.,, Israel, Mark A.,, Thompson, Craig (Craig B.)|isbn=978-1-4557-4066-6|edition= Fourth|location=Philadelphia, PA|oclc=870870610|year=2015}}</ref><ref name=":5" /> Additionally, NPAT, a known substrate of the Cdk2-Cyclin E complex, functions to activate histone gene transcription when phosphorylated.<ref name="pmid10995386">{{cite journal | vauthors = Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E | title = NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription | journal = Genes & Development | volume = 14 | issue = 18 | pages = 2283–97 | date = September 2000 | pmid = 10995386 | pmc = 316937 | doi = 10.1101/gad.827700 }}</ref> This increases the synthesis of histone proteins (the major protein component of chromatin), and subsequently supports the DNA replication stage of the cell cycle. Finally, at the end of S phase, the ubiquitin proteasome degrades cyclin E.<ref name=":2" />

== Cancer cell proliferation ==
Although Cdk2 is mostly dispensable in the cell cycle of normally functioning cells, it is critical to the abnormal growth processes of cancer cells. The CCNE1 gene produces cyclin E, one of the two major protein binding partners of Cdk2. Overexpression of CCNE1 occurs in many tumor cells, causing the cells to become dependent on Cdk2 and cyclin E.<ref name=":3" /> Abnormal cyclin E activity is also observed in breast, lung, colorectal, gastric, and bone cancers, as well as in leukemia and lymphoma.<ref name=":4" /> Likewise, abnormal expression of cyclin A2 is associated with chromosomal instability and tumor proliferation, while inhibition leads to decreased tumor growth.<ref>{{cite journal | vauthors = Gopinathan L, Tan SL, Padmakumar VC, Coppola V, Tessarollo L, Kaldis P | title = Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis | journal = Cancer Research | volume = 74 | issue = 14 | pages = 3870–9 | date = July 2014 | pmid = 24802190 | pmc = 4102624 | doi = 10.1158/0008-5472.CAN-13-3440 }}</ref> Therefore, CDK2 and its cyclin binding partners represent possible therapeutic targets for new cancer therapeutics.<ref name=":3" /> Pre-clinical models have shown preliminary success in limiting tumor growth, and have also been observed to reduce side effects of current chemotherapy drugs.<ref>{{cite journal | vauthors = Xia P, Liu Y, Chen J, Coates S, Liu D, Cheng Z | title = Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy | journal = The Journal of Biological Chemistry | volume = 293 | issue = 51 | pages = 19672–19685 | date = October 2018 | pmid = 30361442 | pmc = 6314117 | doi = 10.1074/jbc.ra118.004673 | doi-access = free }}</ref><ref name=":6">{{cite journal | vauthors = Whittaker SR, Mallinger A, Workman P, Clarke PA | title = Inhibitors of cyclin-dependent kinases as cancer therapeutics | journal = Pharmacology & Therapeutics | volume = 173 | pages = 83–105 | date = May 2017 | pmid = 28174091 | pmc = 6141011 | doi = 10.1016/j.pharmthera.2017.02.008 }}</ref><ref>{{cite journal | vauthors = Cicenas J, Kalyan K, Sorokinas A, Stankunas E, Levy J, Meskinyte I, Stankevicius V, Kaupinis A, Valius M | title = Roscovitine in cancer and other diseases | journal = Annals of Translational Medicine | volume = 3 | issue = 10 | pages = 135 | date = June 2015 | pmid = 26207228 | pmc = 4486920 | doi = 10.3978/j.issn.2305-5839.2015.03.61 }}</ref>

Identifying selective Cdk2 inhibitors is difficult due to the extreme similarity between the active sites of Cdk2 and other Cdks, especially Cdk1.<ref name=":3" /> Cdk1 is the only essential cyclin dependent kinase in the cell cycle, and inhibition could lead to unintended side effects.<ref>{{cite journal | vauthors = Brown NR, Korolchuk S, Martin MP, Stanley WA, Moukhametzianov R, Noble ME, Endicott JA | title = CDK1 structures reveal conserved and unique features of the essential cell cycle CDK | journal = Nature Communications | volume = 6 | pages = 6769 | date = April 2015 | pmid = 25864384 | pmc = 4413027 | doi = 10.1038/ncomms7769 | bibcode = 2015NatCo...6.6769B }}</ref> Most CDK2 inhibitor candidates target the ATP binding site and can be divided into two main subclasses: type I and type II. Type I inhibitors competitively target the ATP binding site in its active state. Type II inhibitors target CDK2 in its unbound state, either occupying the ATP binding site or hydrophobic pocket within the kinase. Type II inhibitors are believed to be more selective.<ref name=":6" /> Recently, the availability of new CDK crystal structures led to the identification of a potential allosteric binding site near the C-helix. Inhibitors of this allosteric site are classified as type III inhibitors.<ref>{{cite journal | vauthors = Rastelli G, Anighoro A, Chripkova M, Carrassa L, Broggini M | title = Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2 | journal = Cell Cycle | volume = 13 | issue = 14 | pages = 2296–305 | date = 2014-06-09 | pmid = 24911186 | pmc = 4111683 | doi = 10.4161/cc.29295 }}</ref> Another possible target is the T-loop of CDK2. When cyclin A binds to CDK2, the N-terminal lobe rotates to activate the ATP binding site and switch the position of the activation loop, called the T-loop.<ref>{{cite journal | vauthors = Pellerano M, Tcherniuk S, Perals C, Ngoc Van TN, Garcin E, Mahuteau-Betzer F, Teulade-Fichou MP, Morris MC | title = Targeting Conformational Activation of CDK2 Kinase | journal = Biotechnology Journal | volume = 12 | issue = 8 | pages = 1600531 | date = August 2017 | pmid = 28430399 | doi = 10.1002/biot.201600531 }}</ref>

==Inhibitors==
Interpretation of dynamic simulations and binding free energy studies unveiled that Ligand2 (Out of 17 in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds) has a stable and equivalent free energy to Flavopiridol, SU9516, and CVT-313 inhibitors. Ligand2 scrutinized as a selective inhibitor of CDK2 without off-target binding (CDK1 and CDK9) based on ligand efficiency and binding affinity. <ref name="pmid33749525">{{cite journal | vauthors = Singh R, Bhardwaj VK, Sharma J, Das P, Purohit R | title = Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration | journal = Journal of Biomolecular Structure and Dynamics |date= March 2021 | volume = 40 | issue = 17 | pages = 7693–7701 | pmid = 33749525 | doi = 10.1080/07391102.2021.1900918 | s2cid = 232309609 | url = https://figshare.com/articles/journal_contribution/14259911 }}</ref> [[File:CDK2-Selective inhibitor.png|thumb|
Graphical abstract of CDK2 <ref name="pmid33749525">{{cite journal | vauthors = Singh R, Bhardwaj VK, Sharma J, Das P, Purohit R | title = Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration | journal = Journal of Biomolecular Structure and Dynamics |date= March 2021 | volume = 40 | issue = 17 | pages = 7693–7701 | pmid = 33749525 | doi = 10.1080/07391102.2021.1900918 | s2cid = 232309609 | url = https://figshare.com/articles/journal_contribution/14259911 }}</ref>]]


Known CDK inhibitors are p21Cip1 ([[p21|CDKN1A]]) and p27<sup>Kip1</sup> ([[CDKN1B]]).<ref name="pmid9660939">{{cite journal | vauthors = Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R | title = Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade | journal = Molecular Cell | volume = 1 | issue = 4 | pages = 553–63 | date = March 1998 | pmid = 9660939 | doi = 10.1016/S1097-2765(00)80055-6 | doi-access = free }}</ref>

Rosmarinic acid methyl ester is a plant-derived Cdk2 inhibitor, which was shown to suppress proliferation of vascular smooth muscle cells and to reduce [[neointima]] formation in mouse [[restenosis]] model.<ref name="Liu_2018">{{cite journal | vauthors = Liu R, Heiss EH, Waltenberger B, Blažević T, Schachner D, Jiang B, Krystof V, Liu W, Schwaiger S, Peña-Rodríguez LM, Breuss JM, Stuppner H, Dirsch VM, Atanasov AG | title = Constituents of Mediterranean Spices Counteracting Vascular Smooth Muscle Cell Proliferation: Identification and Characterization of Rosmarinic Acid Methyl Ester as a Novel Inhibitor | journal = Molecular Nutrition & Food Research | volume = 62 | issue = 7 | pages = e1700860 | date = April 2018 | pmid = 29405576 | doi = 10.1002/mnfr.201700860 | s2cid = 4634007 }}</ref>

See also the PDB gallery below showing interactions with many inhibitors (inc Purvalanol B)

==Gene regulation==
In [[melanocyte|melanocytic]] cell types, expression of the CDK2 gene is regulated by the [[Microphthalmia-associated transcription factor]].<ref name="pmid15607961">{{cite journal | vauthors = Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK, Golub TR, Fisher DE | title = Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF | journal = Cancer Cell | volume = 6 | issue = 6 | pages = 565–76 | date = December 2004 | pmid = 15607961 | doi = 10.1016/j.ccr.2004.10.014 | doi-access = free }}</ref><ref name="pmidunknown">{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 665–76 | date = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x | s2cid = 24698373 | doi-access = free }}</ref>

== Interactions ==
Cyclin-dependent kinase 2 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[BRCA1]],<ref name = pmid8764100>{{cite journal | vauthors = Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH | title = BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner | journal = Cancer Research | volume = 56 | issue = 14 | pages = 3168–72 | date = July 1996 | pmid = 8764100 }}</ref><ref name = pmid10373534>{{cite journal | vauthors = Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM | title = BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site | journal = Molecular and Cellular Biology | volume = 19 | issue = 7 | pages = 4843–54 | date = July 1999 | pmid = 10373534 | pmc = 84283 | doi =  10.1128/MCB.19.7.4843}}</ref><ref name = pmid9244350>{{cite journal | vauthors = Wang H, Shao N, Ding QM, Cui J, Reddy ES, Rao VN | title = BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases | journal = Oncogene | volume = 15 | issue = 2 | pages = 143–57 | date = July 1997 | pmid = 9244350 | doi = 10.1038/sj.onc.1201252 | doi-access = free }}</ref> 
* [[CDK2AP1]],<ref name = pmid10938106>{{cite journal | vauthors = Shintani S, Ohyama H, Zhang X, McBride J, Matsuo K, Tsuji T, Hu MG, Hu G, Kohno Y, Lerman M, Todd R, Wong DT | title = p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein | journal = Molecular and Cellular Biology | volume = 20 | issue = 17 | pages = 6300–7 | date = September 2000 | pmid = 10938106 | pmc = 86104 | doi = 10.1128/MCB.20.17.6300-6307.2000 }}</ref> 
* [[CDKN1B]]<ref name = pmid12529437/><ref name = pmid15355997/><ref name = pmid15619620>{{cite journal | vauthors = Youn CK, Cho HJ, Kim SH, Kim HB, Kim MH, Chang IY, Lee JS, Chung MH, Hahm KS, You HJ | title = Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity | journal = Nature Cell Biology | volume = 7 | issue = 2 | pages = 137–47 | date = February 2005 | pmid = 15619620 | doi = 10.1038/ncb1215 | s2cid = 42766325 }}</ref><ref name = pmid12972555>{{cite journal | vauthors = Porter LA, Kong-Beltran M, Donoghue DJ | title = Spy1 interacts with p27Kip1 to allow G1/S progression | journal = Molecular Biology of the Cell | volume = 14 | issue = 9 | pages = 3664–74 | date = September 2003 | pmid = 12972555 | pmc = 196558 | doi = 10.1091/mbc.E02-12-0820 }}</ref><ref name = pmid12417722>{{cite journal | vauthors = Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL | title = Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells | journal = Molecular and Cellular Biology | volume = 22 | issue = 23 | pages = 8184–98 | date = December 2002 | pmid = 12417722 | pmc = 134072 | doi = 10.1128/mcb.22.23.8184-8198.2002 }}</ref> 
* [[CDKN3]],<ref name = pmid12745075>{{cite journal | vauthors = Yeh CT, Lu SC, Chao CH, Chao ML | title = Abolishment of the interaction between cyclin-dependent kinase 2 and Cdk-associated protein phosphatase by a truncated KAP mutant | journal = Biochemical and Biophysical Research Communications | volume = 305 | issue = 2 | pages = 311–4 | date = May 2003 | pmid = 12745075 | doi = 10.1016/s0006-291x(03)00757-5 }}</ref><ref name = pmid8127873>{{cite journal | vauthors = Hannon GJ, Casso D, Beach D | title = KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 5 | pages = 1731–5 | date = March 1994 | pmid = 8127873 | pmc = 43237 | doi = 10.1073/pnas.91.5.1731 | bibcode = 1994PNAS...91.1731H | doi-access = free }}</ref><ref name = pmid8242751>{{cite journal | vauthors = Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ | title = The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases | journal = Cell | volume = 75 | issue = 4 | pages = 805–16 | date = November 1993 | pmid = 8242751 | doi = 10.1016/0092-8674(93)90499-g | doi-access = free }}</ref> 
* [[CEBPA]],<ref name = pmid11684017>{{cite journal | vauthors = Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA | title = C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 | journal = Molecular Cell | volume = 8 | issue = 4 | pages = 817–28 | date = October 2001 | pmid = 11684017 | doi = 10.1016/s1097-2765(01)00366-5 | doi-access = free }}</ref> 
* [[Cyclin A1]],<ref name = pmid8565853>{{cite journal | vauthors = Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF, Wolgemuth DJ, Carrington M | title = A distinct cyclin A is expressed in germ cells in the mouse | journal = Development | volume = 122 | issue = 1 | pages = 53–64 | date = January 1996 | doi = 10.1242/dev.122.1.53 | pmid = 8565853 }}</ref><ref name = pmid9041194>{{cite journal | vauthors = Yang R, Morosetti R, Koeffler HP | title = Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines | journal = Cancer Research | volume = 57 | issue = 5 | pages = 913–20 | date = March 1997 | pmid = 9041194 }}</ref><ref name = pmid11264176>{{cite journal | vauthors = Müller-Tidow C, Wang W, Idos GE, Diederichs S, Yang R, Readhead C, Berdel WE, Serve H, Saville M, Watson R, Koeffler HP | title = Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function | journal = Blood | volume = 97 | issue = 7 | pages = 2091–7 | date = April 2001 | pmid = 11264176 | doi = 10.1182/blood.v97.7.2091 | doi-access = free }}</ref><ref name = pmid10559988>{{cite journal | vauthors = Brown NR, Noble ME, Endicott JA, Johnson LN | title = The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases | journal = Nature Cell Biology | volume = 1 | issue = 7 | pages = 438–43 | date = November 1999 | pmid = 10559988 | doi = 10.1038/15674 | s2cid = 17988582 }}</ref> 
* [[Cyclin E1]],<ref name = pmid12529437>{{cite journal | vauthors = Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM | title = CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis | journal = Molecular Biology of the Cell | volume = 14 | issue = 1 | pages = 201–13 | date = January 2003 | pmid = 12529437 | pmc = 140238 | doi = 10.1091/mbc.E02-06-0319 }}</ref><ref name = pmid9891079/><ref name = pmid12839982>{{cite journal | vauthors = McKenzie PP, Danks MK, Kriwacki RW, Harris LC | title = P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest | journal = Cancer Research | volume = 63 | issue = 13 | pages = 3840–4 | date = July 2003 | pmid = 12839982 }}</ref><ref name = pmid1388288>{{cite journal | vauthors = Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM | title = Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle | journal = Science | volume = 257 | issue = 5077 | pages = 1689–94 | date = September 1992 | pmid = 1388288 | doi = 10.1126/science.1388288 | bibcode = 1992Sci...257.1689K }}</ref><ref name = pmid15004009>{{cite journal | vauthors = Mayer C, Zhao J, Yuan X, Grummt I | title = mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability | journal = Genes & Development | volume = 18 | issue = 4 | pages = 423–34 | date = February 2004 | pmid = 15004009 | pmc = 359396 | doi = 10.1101/gad.285504 }}</ref><ref name = pmid10827081>{{cite journal | vauthors = Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M | title = NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25411–7 | date = August 2000 | pmid = 10827081 | doi = 10.1074/jbc.M001676200 | doi-access = free }}</ref> 
* [[Flap structure-specific endonuclease 1]],<ref name = pmid12853968>{{cite journal | vauthors = Henneke G, Koundrioukoff S, Hübscher U | title = Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation | journal = Oncogene | volume = 22 | issue = 28 | pages = 4301–13 | date = July 2003 | pmid = 12853968 | doi = 10.1038/sj.onc.1206606 | doi-access = free }}</ref> 
* [[ORC1L]],<ref name = pmid11931757>{{cite journal | vauthors = Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B | title = Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication | journal = Molecular Cell | volume = 9 | issue = 3 | pages = 481–91 | date = March 2002 | pmid = 11931757 | doi = 10.1016/s1097-2765(02)00467-7 | doi-access = free }}</ref> 
* [[P21]],<ref name = pmid12417722/><ref name = pmid8242751/><ref name = pmid12839982/><ref name = pmid9858587/><ref name = pmid10878006>{{cite journal | vauthors = Ono T, Kitaura H, Ugai H, Murata T, Yokoyama KK, Iguchi-Ariga SM, Ariga H | title = TOK-1, a novel p21Cip1-binding protein that cooperatively enhances p21-dependent inhibitory activity toward CDK2 kinase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 40 | pages = 31145–54 | date = October 2000 | pmid = 10878006 | doi = 10.1074/jbc.M003031200 | doi-access = free }}</ref>
* [[PPM1B]],<ref name = pmid10934208>{{cite journal | vauthors = Cheng A, Kaldis P, Solomon MJ | title = Dephosphorylation of human cyclin-dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms | journal = The Journal of Biological Chemistry | volume = 275 | issue = 44 | pages = 34744–9 | date = November 2000 | pmid = 10934208 | doi = 10.1074/jbc.M006210200 | doi-access = free }}</ref> 
* [[PPP2CA]],<ref name = pmid10934208/> 
* [[Retinoblastoma-like protein 1]],<ref name = pmid9891079/><ref name = pmid11884610>{{cite journal | vauthors = Leng X, Noble M, Adams PD, Qin J, Harper JW | title = Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4 | journal = Molecular and Cellular Biology | volume = 22 | issue = 7 | pages = 2242–54 | date = April 2002 | pmid = 11884610 | pmc = 133692 | doi = 10.1128/mcb.22.7.2242-2254.2002 }}</ref> 
* [[Retinoblastoma-like protein 2]],<ref name = pmid9891079>{{cite journal | vauthors = Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E | title = Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest | journal = Molecular and Cellular Biology | volume = 19 | issue = 2 | pages = 1460–9 | date = February 1999 | pmid = 9891079 | pmc = 116074 | doi = 10.1128/mcb.19.2.1460 }}</ref><ref name = pmid9188854>{{cite journal | vauthors = Lacy S, Whyte P | title = Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes | journal = Oncogene | volume = 14 | issue = 20 | pages = 2395–406 | date = May 1997 | pmid = 9188854 | doi = 10.1038/sj.onc.1201085 | doi-access = free }}</ref>  and
* [[SKP2]].<ref name = pmid15355997>{{cite journal | vauthors = Rosner M, Hengstschläger M | title = Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 47 | pages = 48707–15 | date = November 2004 | pmid = 15355997 | doi = 10.1074/jbc.M405528200 | doi-access = free }}</ref><ref name = pmid9858587>{{cite journal | vauthors = Yam CH, Ng RW, Siu WY, Lau AW, Poon RY | title = Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2 | journal = Molecular and Cellular Biology | volume = 19 | issue = 1 | pages = 635–45 | date = January 1999 | pmid = 9858587 | pmc = 83921 | doi = 10.1128/mcb.19.1.635 }}</ref><ref name = pmid10559858>{{cite journal | vauthors = Marti A, Wirbelauer C, Scheffner M, Krek W | title = Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation | journal = Nature Cell Biology | volume = 1 | issue = 1 | pages = 14–9 | date = May 1999 | pmid = 10559858 | doi = 10.1038/8984 | s2cid = 8884226 }}</ref> 
{{Div col end}}
[[Image:Signal transduction pathways.svg|300px|thumb|center|Overview of signal transduction pathways involved in [[apoptosis]].]]

== References ==
{{Reflist|35em}}

== Further reading ==
{{Refbegin}}
* {{cite journal | vauthors = Kaldis P, Aleem E | title = Cell cycle sibling rivalry: Cdc2 vs. Cdk2 | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1491–4 | date = November 2005 | pmid = 16258277 | doi = 10.4161/cc.4.11.2124 | doi-access = free }}
* {{cite journal | vauthors = Moore NL, Narayanan R, Weigel NL | title = Cyclin dependent kinase 2 and the regulation of human progesterone receptor activity | journal = Steroids | volume = 72 | issue = 2 | pages = 202–9 | date = February 2007 | pmid = 17207508 | pmc = 1950255 | doi = 10.1016/j.steroids.2006.11.025 }}
{{Refend}}

== External links ==
* {{MeshName|Cyclin-Dependent+Kinase+2}}
* {{UCSC genome browser|CDK2}}
* {{UCSC gene details|CDK2}}

{{PDB Gallery|geneid=1017}}
{{Cell cycle proteins}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:Cyclin-dependent kinase 02}}
[[Category:Cell cycle]]
[[Category:Proteins]]
[[Category:EC 2.7.11]]
[[Category:Cell cycle regulators]]