CDK1 Subfamily (CDK1, CDK2 & CDK3)

The CDK1 subfamily of cyclin-dependent kinases includes CDK1, CDK2 and CDK3. All three members of this family can bind cyclin A, cyclin B, cyclin E and possibly cyclin C, and are fundamentally involved in regulation of the cell cycle.

CDK1

CDK1 is a 34kDa protein that is highly conserved and is essential for cell cycle progression in mammals. The roles of CDK2 and CDK3 in the cell cycle are dispensable as CDK1 can interact with multiple different cyclins to compensate if CDK2 and/or CDK3 are not present. Following DNA replication in S phase of the cell cycle, CDK1 is activated by binding to cyclin A or B, promoting chromosome condensation and centrosome maturation required for mitotic progression. Ablation of CDK1 in mouse models results in early embryonic lethality, indicating the vital role for CDK1 in embryonic development.

CDK1 activity is inhibited by WEE1-mediated inhibitory phosphorylation, while the Cdc25 family of phosphatases catalyzes phosphate group removal. Inhibition of Cdc25 maintains inhibition of CDK1; NSC 663284 (Cat. No. 1867) is a potent and selective Cdc25 inhibitor, which prevents activation of CDK1 and arrests the cell cycle at G₁ and G₂/M phase. Ro 3006 (Cat. No. 4181) is a potent CDK1 inhibitor that suppresses the activity for CDK1/cyclin B1 and CDK1/cyclin A, and induces G₂/M phase cell cycle arrest and apoptosis in vitro.

CDK2

CDK2 is involved in the inactivation of retinoblastoma protein (Rb) during the cell cycle, and de-repression of cell cycle related genes, but it also has additional functions within DNA repair and replication. The activity of CDK2 is restricted to G₁/S phase of the cell cycle and it is known as a checkpoint control protein. CDK2 bound to cyclin E plays the same role as CDK4/6 bound to cyclin A in the cell cycle, although CDK2 is thought to activate a wider range of proteins than CDK4/6.

Due to the similarities between the active sites of CDK1 and CDK2, selective CDK2 inhibitors are hard to develop. Some success has been achieved by targeting CDK2 in its unbound state, or by targeting an allosteric binding site on CDK2, near the C-terminal helices. K 03861 (Cat. No. 6789), also known as AUZ 454, is a potent CDK2 inhibitor that inhibits both wild type and mutated CDK2. It competes with cyclin binding to inhibit CDK2 kinase activity in vitro.

Figure 1: 3D structure of CDK2 (green) bound to Cyclin A (orange). Taken from Wood et al (2019) Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition. Cell Chem Biol. 26, 121. PMID: 30472117

CDK3

CDK3 is involved in G₀ to G₁ and G₁/S phases of the cell cycle, where it interacts with cyclin C to phosphorylate targets including histone H1 and the transcription factor ATF1. ATF1 phosphorylation triggers its translocation and activation of transcription and promotes cell proliferation and translocation. Endogenous inactivating mutations in CDK3 identified in mice suggest that the role of CDK3 in the cell cycle is not essential, and that loss of CDK3 can be compensated for by other CDKs.