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CDKs

Thursday 27 November 2003

Cyclin-dependent kinases (CDKs) belong to a group of protein kinases originally discovered as being involved in the regulation of the cell cycle (CDK9, however, is an exception, as it plays no role in cell cycle regulation).

CDKs are also involved in the regulation of transcription and mRNA processing. CDKs phosphorylate proteins on Serine and Threonine amino acid residues: they are Serine/Threonine kinases.

A cyclin-dependent kinase is activated by association with a cyclin forming a cyclin-dependent kinase complex.

Members

CDK1 CDK2 CDK3 CDK4 CDK5 CDK6 CDK7 CDK8 CDK9

A list of CDKs with their regulator protein, cyclin or other.

- CDK1; cyclin A, cyclin B
- CDK2; cyclin A, cyclin E
- CDK3
- CDK4; cyclin D1, D2, D3
- CDK5; p35 (p35 would be another type of regulator that looks only marginally similar to cyclins)
- CDK6; cyclin D1, D2, D3
- CDK7; cyclin H
- CDK8; cyclin C
- CDK9; cyclin T1, T2a, T2b, cyclin K
- CDK10
- CDK11; cyclin L

A cyclin-CDK complex can be regulated by several kinases and phosphatases, including Wee, and CDK-activating kinase (CAK), and Cdc.

CAK adds an activating phosphate to the complex, while Wee adds an inhibitory complex; the presence of both activating and inhibitory phosphates renders the complex inactive.

Cdc is a phosphatase that removes the inhibitor phosphate added by Wee, rendering the complex active. Cdk feeds back on Wee and Cdc to inhibit and enhance their respective activities.

Some CDKs family members that do not regulate the cell cycle directly but instead influence transcription (CDK7, CDK8, and CDK9) and neuronal and secretory cell function (CDK5).

CDKs in transcription and RNA splicing

The production of mRNAs in all living organisms is an extremely complex process that includes multiple catalytic activities such as transcription, capping, splicing, polyadenylation, cleavage and export.

All of these processes are controlled by a large group of proteins which form very dynamic complexes interacting with DNA and pre-mRNAs to coordinate these activities. Phosphorylations play a central role in regulating formation, activation and inactivation of these complexes.

A growing number of protein kinases have been identified that are capable of phosphorylating proteins involved in mRNA production. Among them, Cyclin-dependent Kinases (CDKs) represent a family of serine/threonine protein kinases that become active upon binding to a cyclin regulatory partner.

CDK/cyclin complexes were first identified as crucial regulators of cell cycle progression. More recently, CDK/cyclin complexes have also been implicated in transcription and mRNA processing leading to the concept of an intricate network of CDK/cyclin complexes regulating cell cycle, transcription and mRNA processing via cross-talk between multiple CDKs.

References

- Bloom J, Cross FR. Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol Cell Biol. 2007 Feb;8(2):149-60. PMID: 17245415

- Loyer P, Trembley JH, Katona R, Kidd VJ, Lahti JM. (2005) Role of CDK/cyclin complexes in transcription and RNA splicing. Cellular Signalling Sep;17(9):1033-51.

- Smith PD, O’Hare MJ, Park DS. CDKs: taking on a role as mediators of dopaminergic loss in Parkinson’s disease. Trends Mol Med. 2004 Sep;10(9):445-51. PMID: 15350897

- Sausville EA. Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol Med. 2002;8(4 Suppl):S32-7. PMID: 11927285

- Blow JJ, Hodgson B. Replication licensing—defining the proliferative state? Trends Cell Biol. 2002 Feb;12(2):72-8. PMID: 11849970