Cyclin-dependent Kinases (CDKs)

Cyclin-dependent kinases (CDKs) are typical serine/threonine kinases that display the 11 subdomains shared by all kinases. The complete sequence of the Homo sapiens genome shows that among the ~30,000 predicted genes, there are 13 CDKs and 25 cyclins. Eleven CDKS and their associated cyclins have been characterized in man.

The structure of CDK2 consists of an amino-terminal lobe rich in β-sheets and a larger, mostly α-helical, carboxy-terminal lobe. The ATP binding site is located in a deep cleft between the two lobes that contain the conserved catalytic residues. Crystallographic studies have shown the importance of cyclin binding upon CDK2 as it forces the kinase subunit into an active conformation. The T-loop, which blocks substrate access in monomeric CDK2, moves to the outside of the catalytic cleft after binding cyclin A. This then permits the activating phosphorylation of Thr160 (by CDK7/cyclinH/MAT1). The second conformational change induced by cyclin binding is found within the ATP-binding site where a reorientation of the amino acid side chains induces the alignment of the triphosphate of ATP, which is necessary for phosphate transfer. The high degree of sequence homology between the catalytic domains of different CDKs suggests that their 3-dimensional structures will be similar. This has been essentially confirmed with CDK5 and CDK6.

Progression through the G1, S, G2, M phases of the cell cycle is directly controlled by CDKs. In early-mid G1, extracellular signals modulate the activation of CDK4 and CDK6, which are associated with D-type cyclins. These complexes phosphorylate and thereby inactivate the retinoblastoma protein pRb, resulting in the release of E2F and DP1 transcription factors that control the expression of genes required for the G1/S transition and S phase progression. The CDK2/cyclin E complex, which is responsible for the G1/S phase transition, also regulates centrosome duplication. During S phase, CDK2/cyclinA phosphorylates different substrates allowing DNA replication and the inactivation of G1 transcription factors. Around the S/G2 phase transition, CDK1 associates with cyclin A. Later, CDK1/cyclinB appears and triggers the G2/M phase transition by phosphorylating a large set of substrates. Phosphorylation of the anaphase promoting complex (APC) by CDK1/cyclin B is required for the transition to anaphase and completion of mitosis. These successive waves of CDK/cyclin assemblies and activations are tightly regulated by post-translational modifications and by intracellular translocations. They are coordinated and dependent on the completion of previous steps, through so-called “checkpoint” controls. Recent studies using knock out experiments performed in mice suggest that CDK2 and CDK3 may be dispensable, whereas CDK1, CDK5 and CDK11 are essential genes.

Some CDKs directly regulate transcription. CDK7/cyclin H/MAT1 is a component of the transcription factor TFIIH. Both CDK7/cyclin H and CDK8/cyclin C phosphorylate the C-terminal domain of the largest subunit of RNA polymerase II, which is required for elongation. CDK9/cyclin T is a component of the positive transcription elongation factor P-TEFb. It is responsible for the Tat-associated kinase activity involved in HIV-1 Tat transactivation.

CDK5 activity is important for outgrowth of neurites and neuronal development, for myogenesis and for somite organization in embryos. An interesting aspect of CDK5 is the nature of its associated regulatory subunits, p35 or p25, a proteolytic cleavage product. Despite their evolutionary distance from cyclins, the predicted structure of p35/p25 shows a similar fold to that of cyclins, which explains the efficient activation of CDK5. Conversion of p35 to p25 leads to constitutive activation of CDK5 and alteration of its cellular localization. CDK5/p25 expression in cultured primary neurons triggers apoptosis. A considerable amount of evidence links CDK5 activity to cytoskeletal abnormalities that can lead to neuronal death as observed in Alzheimer’s disease. CDK2, CDK5 and CDK11 have an essential function in apoptosis. CDK5 also acts as a downstream element of dopamine signaling by phosphorylating the striatum-specific DARPP-32 protein which then becomes an inhibitor of PKA.

The involvement of CDKs in many physiological functions and diseases has led to the identification of over 70 potent pharmacological inhibitors. Over 30 of these inhibitors have been co-crystallized with CDK2, CDK5 or CDK6. Pharmacological inhibitors of CDKs have been evaluated for therapeutic use against cancer, alopecia, neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke), cardiovascular disorders (restenosis), glomerulonephritis, viral infections (HCMV/HIV/HSV) and parasitic protozoa (Plasmodium).

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Related Products" section below.

Family Members	CDK1	CDK2	CDK3	CDK4	CDK5
Other Names	Cdc2 Cyclin-dependent kinase 1	Cyclin-dependent kinase 2	Cyclin-dependent kinase 3	PSK-J3 Cyclin-dependent kinase 4	Cyclin-dependent kinase 5
Molecular Weight (kDa)	34 kDa	33 kDa	35 kDa	33 kDa	33 kDa
Structural Data	297 aa	298 aa	305 aa	303 aa	292 aa
Isoforms	Not Known	Not Known	Not Known	Not Known	Not Known
Species	Present in all species	Present in all species	Present in all species	Present in all species	Present in all species
Domain Organization	Kinase scaffold	Kinase scaffold	Kinase scaffold	Kinase scaffold	Kinase scaffold
Phosphorylation Sites	Thr14 Tyr15 Thr161	Thr14 Tyr15 Thr160	Not Known	Not Known	Not Known
Tissue Distribution	Dividing Cells	Dividing Cells	Not Known	Dividing Cells	Mostly (but not only) neuronal cells
Subcellular Localization	Cytoplasmic Nuclear	Cytoplasmic Nuclear	Not Known	Not Known	Membrane Cytoplasmic
Binding Partners/ Associated Proteins	p9CKS RanBPM CK2 Cyclin F	p9CKS	Not Known	Rac	Not Known
Upstream Activators	CDC25 CDK7	CDC25 CDK7	Not Known	Not Known	Not Known
Downstream Activation	Histone H1 (H5505) Cyclin B Lamins Cdc25C (SRP5007) Vimentin (V4383) APC Nucleolin Plk1 Separase	pRb Nucleophosmin Cdc6 NPAT Smad3 p27Kip1	Not Known	pRb Smad3	Tau MAP-2B DARPP-32 Pak1 Huntingtin Cables
Activators	Cyclin A1, A2 Cyclin B1-B3 Ringo	Cyclin A1, A2 Cyclin E1, E2, E3	Ik3-1 Cyclin C	Cyclin D1-D3	p35/p25 (P1371) p39 Cyclin D1
Inhibitors	Olomoucine (O0886) Roscovitine (R7772) Purvalanol A (P4484) Kenpaullone (K3888) Indirubins (I0404) Aloisines Flavopiridol (F3055) Staurosporine (S4400)	p21cip1/WAF p27kip1 p57kip2 Olomoucine (O0886) Roscovitine (R7772) Purvalanol A (P4484) Kenpaullone (K3888) Alsterpaullone (A4847) Indirubins (I0404) Aloisines Flavopiridol (F3055) Staurosporine (S4400)	Roscovitine (R7772)	p15INK4A p18INK4C p19INK4D Flavopiridol (F3055) Fascaplysin	Olomoucine (O0886) Roscovitine (R7772) Purvalanol A (P4484) Kenpaullone (K3888) Indirubins (I0404) Aloisines Flavopiridol (F3055) Staurosporine (S4400)
Selective Activators	Not Known	Not Known	Not Known	Not Known	Not Known
Physiological Function	Cell cycle (G2/M)	Cell cycle (G1/S, S, G2) Apoptosis	Cell cycle (G0/G1)	Cell cycle (G1 and G2/M)	Neurite outgrowth Rac signaling Apoptosis Exocytosis
Disease Relevance	Cancer Alzheimer's disease	Cancer Glomerulonephritis Viral infections (herpes cytomegalovirus)	Not Known	Cancer	Neurodegeneration Alzheimer's disease Parkinson's disease Stroke ALS Nieman-Pick's disease

Family Members	CDK6	CDK7	CDK8	CDK9	CDK10	CDK11
Other Names	Tau PK II Cyclin-dependent kinase 6	MO15 CAK Cyclin-dependent kinase 7	Cyclin-dependent kinase 8	Cyclin dependent kinase 9	Cyclin-dependent kinase 10	cdc2L1 cdc2L2 Cyclin-dependent kinase 11
Molecular Weight (kDa)	36 kDa	39 kDa	53.3 kDa	42.8 kDa	41 kDa	92.7 kDa
Structural Data	326 aa	346 aa	464 aa	372 aa	360 aa	777/795 aa
Isoforms	Not Known	Not Known	Not Known	Not Known	Not Known	Not Known
Species	Present in all species	Present in all species	Present in all species	Present in all species	Present in all species	Present in all species
Domain Organization	Kinase scaffold	Kinase scaffold	Kinase scaffold	Kinase scaffold	Kinase scaffold	Kinase scaffold
Phosphorylation Sites	Not Known	Not Known	Not Known	Not Known	Not Known	Not Known
Tissue Distribution	Dividing Cells	All	All	All	All	All
Subcellular Localization	Not Known	Not Known	Not Known	Not Known	Not Known	Not Known
Binding Partners/ Associated Proteins	v-Cyclin	MAT 1	Not Known	Not Known	Ets2	RNA polymerase II CK2 RanBPM
Upstream Activators	Not Known	Not Known	Not Known	Not Known	Not Known	Not Known
Downstream Activation	pRb	CTD RNA pol II	CTD RNA pol II	CTD RNA pol II	Not Known	Not Known
Activators	Cyclin D1-D3	Cyclin H	Cyclin C	Cyclin K Cyclin T1	Not Known	Cyclin L2/Ania-6
Inhibitors	p15INK4A p18INK4C p19INK4D	Roscovitine (R7772)	Not Known	Roscovitine (R7772) Flavopiridol	Not Known	Not Known
Selective Activators	Not Known	Not Known	Not Known	Not Known	Not Known	Not Known
Physiological Function	Cell cycle (G1)	Transcription Cell cycle	Transcription	Transcription	Transcription Cell cycle	Splicing Apoptosis Cell cycle (G2/M) Neuronal functions
Disease Relevance	Cancer	Cancer	Not Known	HIV	Not Known	Cancer

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References

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15. Smith PD, O'Hare MJ, Park DS. 2004. CDKs: taking on a role as mediators of dopaminergic loss in Parkinson's disease. Trends in Molecular Medicine. 10(9):445-451. https://doi.org/10.1016/j.molmed.2004.07.003

16. Tarricone C, Dhavan R, Peng J, Areces LB, Tsai L, Musacchio A. 2001. Structure and Regulation of the CDK5-p25nck5a Complex. Molecular Cell. 8(3):657-669. https://doi.org/10.1016/s1097-2765(01)00343-4

17. Trembley JH, Loyer P, Hu D, Li T, Grenet J, Lahti JM, Kidd VJ. 2004. Cyclin Dependent Kinase 11 in RNA Transcription and Splicing.263-288. https://doi.org/10.1016/s0079-6603(04)77007-5

18. Wang Q, Su L, Liu N, Zhang L, Xu W, Fang H. 2011. Cyclin Dependent Kinase 1 Inhibitors: A Review of Recent Progress. CMC. 18(13):2025-2043. https://doi.org/10.2174/092986711795590110