One of the two different human cDNAs that can complement cdc28 mutations of budding yeast Saccharomyces cerevisiae cloned by Ninomiya et al. corresponds to the CDK2 gene (Ninomiya 1991). Elledge et al. identified CDK2 as a second functional p34 homolog with the help of a human cDNA expression library to search for suppressors of cdc28 mutations in S. cerevisiae (Elledge 1991). CDK2 gene is mapped to 12q13 (Demetrick 1994) (Fig. 1). The cloning of approximately 2.4-kilobase pair genomic DNA fragment from the upstream region of the human CDK2 gene has been described (Shiffman 1996). The CDK2 gene fragment was found to contain 5 transcription initiation sites within a 72-bp stretch. A 200-bp subfragment that confers 70% of maximal basal promoter activity was shown to contain 2 synergistically acting Sp1 sites (Shiffman 1996). The intron-exon boundaries of 7 exons in this gene were also identified (Shiffman 1996). There are other reports of CDK2 gene expressed as a 2.1 kb transcript encoding a polypeptide of 298 amino acids and encodes the human homolog of the Xenopus Eg1 gene, sharing 89% amino acid identity (Elledge 1991).

The presence of CDK2 mRNA was observed late in G1 or in early S phase, slightly before CDC2 mRNA, under growth stimulation in normal human fibroblast cells (Ninomiya 1991). CDK2 mRNA has also been shown to be induced by serum in several cultured cell types (Shiffman 1996).

The CDK2 protein was found to be highly homologous to p34CDC2 kinase (65% identical) and more significantly homologous to Xenopus Eg1 kinase (89% identical), suggesting that CDK2 is the human homolog of Eg1 (Ninomiya 1991). CDK2 protein has a biological activity closely related to the CDC28 and CDK1 (Cdc2, p34CDC2) kinases (Ninomiya 1991) and the protein retains nearly all of the amino acids highly conserved among previously identified p34 homologs from other species (Elledge 1991). CDK2 is a mammalian Ser/Thr kinase that plays a critical role in controlling the progression from G1 to S phase of the cell cycle (Morgan 1997) and is functionally homologous to the well-studied cdc28a S. cerevisae protein (Zhao 2011). Monomeric CDK2 lacks regulatory activity requiring to be aroused by its positive regulators, cyclins E and A, or catalytic segment phosphorylation (Yan 2015). CDK2 activation is a two-step process; step one requires its association with the regulatory subunit cyclins A or E and step two involves phosphorylation of the residue Thr160 (Marcos 2011, Morris 2002, Pavletich 1999).
The crystal structure of the human CDK2 apoenzyme and its Mg2+ATP complex have been determined to 2.4 Å resolution (De Bondt 1993) while the crystal structure of CDK2-ATP complex has been determined at 2.3 Å resolution (Jeffrey 1995). Monomeric CDK2 is made of 298 amino acids (PDB code: 1HCL, residues 1-298), and folds into a typical bilobal structure, composed of a smaller N-terminal lobe (residues 1-85) that consists of antiparallel five-strand β-sheet and a major C-helix, together with a larger C-terminal lobe primarily composed of α-helix (De Bondt 1993). The two terminal domains are linked by a single peptide strand (residues 81-83) which acts as a hinge linker making sure that the two lobes can rotate with respect to each other without disruption of the secondary structure of this kinase (Cox 1994). Three binding sites have been reported in the monomeric CDK2 structure; the adenosine triphosphate (ATP) binding site (Site I) and two non-competitive binding sites (Site II and III). An allosteric binding site (Site IV) is generated as a result of structural changes that yield a variation of the ATP binding site when the kinase is subjected to the cyclin binding process (Yan 2015). Competitive binding site (Site I) is the most well-known ATP binding site, situated deep at the junction of the N and C domains. It includes the pivotal catalytic residues with high sensitivity and linker region (residues 81-83), and consists of 136 consecutive amino acids (10-145) on the CDK2 (Knockaert 2002). There is no association between non-competitive binding sites (site II and III) and catalytic subunits (Li 2013). Site III is also known to accommodate short peptides that partially dissociate the CDK2/cyclin E complex, thus obstructing the enzymatic activity of CDK2 (Chen 2009). The allosteric binding site (site IV) also known as ANS fluorophore 8-anilino-1-naphthalene sulfonate) binding pocket is located in a region that is adjacent to the C-helix, away from the ATP site, approximately halfway of the ATP site and the C-helix (Yan 2015).

The nuclear translocation of CDK2/cyclin E and cyclin E binding are needed for CDK2 enzymatic activation and substrate targeting because the CDK2 activating enzyme (CAK) and many of the CDK2 targets reside in the nucleus (Blanchard 2000, Dietrich 1997, Keenan 2001). Intracellular trafficking of CDK2 is unclear though some studies suggest that cyclins may play a role in the translocation of the cyclin/CDK complex via the classical importin α/β pathway (Moore 1999, Moore 2002). It is suggested that importin α binds to the nuclear localization signal on cyclins whereas importin β binds to nuclear transport machinery proteins as well as to cyclin-bound importin α. Translocation of the cyclin/CDK/importin α/β complex into the nucleus then occurs via an energy-dependent process (Flores 2010). Other studies have demonstrated consistent concentration of CDK2/cyclin E in the nucleus in both Drosophila embryos and cultured human cells (Knoblich 1994, Ohtsubo 1995), whereas CDK1 (Cdc2)/ CCNB1 (cyclin B1) is retained in the cytoplasm in interphase, entering the nucleus at the earliest stages of mitosis (Lehner and OFarrell 1990, Pines and Hunter, 1994).  Other studies using egg extracts have shown how accumulation of CDK2/cyclin E in the nucleus is needed both for initiating DNA replication (Chevalier 1996) and preventing re-replication (Hua 1997, Walter 1998). There are indications that CDK2 nuclear translocation is associated with the formation of molecular complexes containing active MAP Kinase and is dependent on MAP Kinase activation (Blanchard 2000).

CDK2 activity has been indicated to be regulated by protein CDNK1B (p27KIP1) which inhibits CDK2 kinase activity in G0 and early G1 phase and leads to cell-cycle arrest (Polyak 1994). Once combined with its positive regulatory subunits, CDK2 fosters the transition of the well-established G1/S phase boundary and drives the cell cycle through S interval (Shapiro 2006, Sherr 1994, Pines 1991). CDK2/cyclin A is a necessity for orderly S-phase progression (Sherr 1994), while phosphorylation of retinoblastoma protein ( RB1) to facilitate the G1/S transition is mediated by CDK2/cyclin E complex (Pines 1991). CDK2/cyclin E phosphorylates Rb leading to the release and activation of E2F transcription factors required to promote transcription of genes that encode proteins required for G1 to S phase progression (Dyson 1998, Nevins 1998). CDK2 associates with both inactive and activated MAP Kinase and its activation is linked to formation of CDK2/ MAP Kinase complexes (Blanchard 2000). CDK2 is one of the most essential regulators for the transition and progression in a cell-division cycle and plays a crucial role in regulating multiple events of cell division cycle including centrosome duplication, DNA synthesis, G1-S transition, and modulation of G2 progression (Chohan 2015, De Boer 2008, Fiset 2011, Omar 2010). CDK2 is a requirement for robust DNA damage checkpoint signalling and loss of CDK2 was observed to cause a marked deficiency in the G2/M arrest which is a basic response to DNA damage in cells that were also nullizygous for P53 (Chung and Bunz, 2010). CDK2 plays a critical role in facilitating robust DNA damage checkpoint control by the ATR- CHEK1- CDC25A pathway. CDK2 seems to promote the formation of active ATR complexes by ATRIP phosphorylation and by CDC6 stabilization (Chung and Bunz, 2010). There is a possibility of CDK2 also controlling checkpoint signaling via additional mechanisms such as the recently described CDK2 interacting protein ( CINP) which facilitates robust ATR signalling (Lovejoy 2009). In addition, loss of CDK2 was demonstrated to alter the regulation of several proteins that are known to regulate S-phase progression, but also control mitotic entry, including CDC25A, CHK1, CDC6 and ATRIP (Donzelli and Draetta, 2003, Borlado and Mendez 2008, Cimprich and Cortez, 2008). 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 (Sheaff 1997). At low ATP levels, the inhibitory functions of CDKN1B are enhanced, thereby arresting cell proliferation (Sheaff 1997). Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A-associated CDK2 activity (Levkau 1998).  In apoptotic cells, the carboxyl-termini of the CDK inhibitors CDKN1A and CDKN1B are truncated by specific cleavage aided by CASP3 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. CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation (Levkau 1998). Forkhead box O (FOXO) are key regulators of cell survival and CDK2 is known to specifically phosphorylate FOXO1 at ser249 in vitro and in vivo resulting into cytoplasmic localization and inhibition of FOXO1 (Huang 2006).  Functional interaction between CDK2 and FOXO1 provides a mechanism that regulates apoptotic cell death after DNA strand breakage (Huang 2006). Proto-oncogenes such as MYC and RAS promote normal cell growth, fuel tumor development when deregulated and if over-activated can trigger intrinsic tumor suppressor mechanisms leading to apoptosis and senescence (Hydbring and Larsson, 2010). Ras is known to suppress Myc-induced apoptosis while Myc was recently discovered to repress Ras-induced senescence. The ability of Myc to suppress senescence is dependent on its phosphorylation at Ser 62 by CDK2. Using CDK2 as a cofactor, Myc is able to directly control major genes involved in senescence. Selective pharmacological inhibition of CDK2 was observed to force Myc/Ras expressing cells into cellular senescence, an indication that CDK2 is a potential therapeutic target for treatment of tumors driven by Myc or Ras (Hydbring and Larsson, 2010).