Cyclin A:Cdk2-associated events at S phase entry

Stable Identifier
R-HSA-69656
Type
Pathway
Species
Homo sapiens
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Cyclin A:Cdk2 plays a key role in S phase entry by phosphorylation of proteins including Cdh1, Rb, p21 and p27. During G1 phase of the cell cycle, cyclin A is synthesized and associates with Cdk2. After forming in the cytoplasm, the Cyclin A:Cdk2 complexes are translocated to the nucleus (Jackman et al.,2002). Prior to S phase entry, the activity of Cyclin A:Cdk2 complexes is negatively regulated through Tyr 15 phosphorylation of Cdk2 (Gu et al., 1995) and also by the association of the cyclin kinase inhibitors (CKIs), p27 and p21. Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK2 kinase activity (Aprelikova et al., 1995). The entry into S phase is promoted by the removal of inhibitory Tyr 15 phosphates from the Cdk2 subunit of Cyclin A:Cdk2 complex by the Cdc25 phosphatases (Blomberg and Hoffmann, 1999) and by SCF(Skp2)-mediated degradation of p27/p21 (see Ganoth et al., 2001). While Cdk2 is thought to play a primary role in regulating entry into S phase, recent evidence indicates that Cdk1 is equally capable of promoting entry into S phase and the initiation of DNA replication (see Bashir and Pagano, 2005). Thus, Cdk1 complexes may also play a significant role at this point in the cell cycle.

Literature References
PubMed ID Title Journal Year
11231585 The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27

Ganoth, D, Bornstein, G, Ko, TK, Larsen, B, Tyers, M, Pagano, M, Hershko, A

Nat Cell Biol 2001
11907280 Cyclin A- and cyclin E-Cdk complexes shuttle between the nucleus and the cytoplasm

Jackman, M, Kubota, Y, Den Elzen, N, Hagting, A, Pines, J

Mol Biol Cell 2002
15014502 Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase

Bashir, T, Dorrello, NV, Amador, V, Guardavaccaro, D, Pagano, M

Nature 2004
10454565 Ectopic expression of Cdc25A accelerates the G(1)/S transition and leads to premature activation of cyclin E- and cyclin A-dependent kinases

Blomberg, I, Hoffmann, I

Mol Cell Biol 1999
1396589 Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15

Gu, Y, Rosenblatt, J, Morgan, DO

EMBO J 1992
7629134 Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase

Aprelikova, O, Xiong, Y, Liu, ET

J Biol Chem 1995
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