Introduction of Cyclin-Dependent Kinases (CDKs)
CDKs constitute a family of 20 members that regulate cell cycle, transcription, and splicing. They ensure accurate DNA replication and equal segregation during cell division. Dysregulation leads to diseases like cancer, Alzheimer's, Parkinson's, and stroke. CDK activity relies on association with cyclins, without them, enzymatic activity is significantly reduced. Cyclins, varying cyclically during the cell cycle, form a complex with CDKs, inducing conformational rearrangements. CDKs are also influenced by kinases and phosphatases, such as CDK activating kinase (CAK) and endogenous CDK inhibitors (CKIs), controlling cell cycle progression and transcription. Phosphorylation of specific residues and ubiquitin-mediated proteolysis further regulate CDK function.
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Fig. 1 A three-dimensional view of CDK structure (Malumbres M. 2014).
| Type of CDKs |
Description |
| CDK1 |
CDK1, also known as Cdc2, collaborates with cyclin B1 to facilitate the G2 to mitosis transition, regulated by checkpoint kinases like WEE1 and CHK1, ensuring proper DNA distribution to daughter cells by CDC25-mediated dephosphorylation of inhibitory phosphorylation on Thr14 and Tyr15. |
| CDK2 |
CDK2 is a crucial cell cycle regulator, orchestrating G1/S and S/G2 transitions, phosphorylating Rb for S phase entry, and influencing various transcription factors to drive the cell cycle, and controlling diverse cellular processes. |
| CDK4/6 |
Inhibiting cyclin D-CDK4/6 dimer stops G1 to S phase progression. CDK4/6, regulated by D-type cyclins and p16INK4a, phosphorylates Rb, activating E2F target genes for cell cycle advancement. |
| CDK5 |
CDK5, distinct from other CDKs, activates nervous system functions by binding p35/p39 proteins. It regulates neuronal processes, and neurogenesis, and has diverse roles in cell functions and insulin secretion. |
| CDK7 |
CDK7 phosphorylates CDK2/cyclin E for G1 to S transition and activates CDK1/cyclin B for mitotic entry. CDK7, cyclin H, and MAT1 form CAK in TFIIH, facilitating transcription initiation and DNA repair. |
| CDK8, CDK19 |
CDK8 and CDK19, part of the mediator complex, negatively regulate transcription. Their aberrations are linked to disorders, especially in cancer. Inhibitors targeting CDK8 or CDK19 show promising therapeutic potential. |
| CDK9 |
CDK9, a crucial regulator of RNA transcription elongation, exists in two isoforms (CDK942 and CDK955). CDK9's involvement in transcription makes it a potential target for treating conditions like cancer, AIDS, cardiac hypertrophy, and inflammation. |
| CDK10 |
CDK10, initially overlooked, emerged as vital for tamoxifen-resistant breast cancer treatment. Partnering with cyclin M, it regulates transcription and influences cell cycle and growth. |
| CDK11 |
CDK11, with cyclin L, regulates RNA processing and transcription. It has three isoforms: CDK11p110, CDK11p58, and CDK11p46, with distinct roles in transcription, mitosis, and apoptosis. |
| CDK12, CDK13 |
CDK12, with cyclin K, phosphorylates RNA polymerase II, influencing transcription and DNA damage response. Implicated in cancer, it's a potential therapeutic target. CDK13 shares sequence similarity with CDK12. |
CDK Activation and Inhibition
CDK activation involves the binding of cyclin to Cdk2, leading to hydrophobic interactions. This association induces a rotation in the C-helix axis, creating new interactions in the ATP-binding site. Cyclins facilitate the exposure of threonine for activating phosphorylation by CAK, stabilizing the kinase heterodimer. The CDK-cyclin interface varies among CDKs, with unique contact patterns. Some CDKs, like Cdk5, don't require activation segment phosphorylation. Additional domains in certain CDKs, like Cdk12 and Cdk13, have functional relevance in splicing regulation.
CDK inhibition occurs via phosphorylation of Thr14 and Tyr15 in the N-lobe's glycine-rich region, inhibiting kinase activity. Wee1 and Myt1 kinases phosphorylate these residues, preventing cell-cycle progression. INK4 and Cip/Kip inhibitors distort the cyclin interface, inhibiting CDK activation and providing additional regulatory levels.
In conclusion, CDKs play a crucial role in regulating cell cycle, transcription, and splicing. Dysregulation leads to diseases. CDK activity relies on cyclin association, and their complex interactions are influenced by kinases, phosphatases, and additional domains. Understanding CDK activation and inhibition mechanisms is essential for developing targeted therapeutic interventions in various conditions, including cancer and neurodegenerative diseases.
References
- Malumbres M. Cyclin-dependent kinases. Genome Biology. 2014, 15(6): 1-10.
- Łukasik P., et al. Cyclin-dependent kinases (CDK) and their role in diseases development–review. International Journal of Molecular Sciences. 2021, 22(6): 2935.
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