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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 MembersCDK1CDK2CDK3
CDK4CDK5
Other NamesCdc2
Cyclin-dependent kinase 1		Cyclin-dependent kinase 2Cyclin-dependent kinase 3PSK-J3
Cyclin-dependent kinase 4		Cyclin-dependent kinase 5
Molecular Weight
(kDa)		34 kDa33 kDa35 kDa33 kDa33 kDa
Structural Data297 aa298 aa305 aa303 aa292 aa
IsoformsNot KnownNot Known
Not Known
Not Known
Not Known
SpeciesPresent in all speciesPresent in all speciesPresent in all speciesPresent in all speciesPresent 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		p9CKSNot Known
RacNot 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
ActivatorsCyclin A1, A2
Cyclin B1-B3
Ringo		Cyclin A1, A2
Cyclin E1, E2, E3		Ik3-1
Cyclin C		Cyclin D1-D3p35/p25 (P1371)
p39
Cyclin D1
InhibitorsOlomoucine (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
CancerNeurodegeneration
Alzheimer's disease
Parkinson's disease
Stroke
ALS
Nieman-Pick's disease
Family MembersCDK6CDK7CDK8CDK9CDK10CDK11
Other NamesTau PK II
Cyclin-dependent kinase 6		MO15
CAK
Cyclin-dependent kinase 7		Cyclin-dependent kinase 8Cyclin dependent kinase 9Cyclin-dependent kinase 10cdc2L1
cdc2L2
Cyclin-dependent kinase 11
Molecular Weight
(kDa)		36 kDa39 kDa53.3 kDa42.8 kDa41 kDa92.7 kDa
Structural Data326 aa346 aa464 aa372 aa360 aa777/795 aa
IsoformsNot Known
Not Known
Not Known
Not Known
Not Known
Not Known
SpeciesPresent in all speciesPresent in all speciesPresent in all speciesPresent in all speciesPresent in all speciesPresent 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
AllAllAllAllAll
Subcellular
Localization		Not Known
Not Known
Not Known
Not Known
Not Known
Not Known
Binding Partners/
Associated Proteins		v-CyclinMAT 1Not Known
Not Known
Ets2RNA polymerase II
CK2
RanBPM
Upstream
Activators		Not Known
Not Known
Not Known
Not Known
Not Known
Not Known
Downstream
Activation		pRbCTD RNA pol IICTD RNA pol IICTD RNA pol IINot Known
Not Known
ActivatorsCyclin D1-D3Cyclin HCyclin CCyclin K
Cyclin T1		Not Known
Cyclin L2/Ania-6
Inhibitorsp15INK4A
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		TranscriptionTranscriptionTranscription
Cell cycle		Splicing
Apoptosis
Cell cycle (G2/M)
Neuronal functions
Disease
Relevance		CancerCancerNot Known
HIVNot Known
Cancer
Related Products
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References

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2.
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3.
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5.
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9.
Krystof V, Baumli S, Furst R. 2012. Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target. CPD. 18(20):2883-2890. https://doi.org/10.2174/138161212800672750
10.
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11.
Meijer L. 2003. Cell Cycle Regulators as Therapeutic Targets.  Life in Progress.
12.
Monaco III E, Vallano M. 2003. Cyclin-Dependent Kinase Inhibitors: Cancer Killers to Neuronal Guardians. CMC. 10(5):367-379. https://doi.org/10.2174/0929867033368277
13.
Morgan DO. 1997. CYCLIN-DEPENDENT KINASES: Engines, Clocks, and Microprocessors. Annu. Rev. Cell Dev. Biol.. 13(1):261-291. https://doi.org/10.1146/annurev.cellbio.13.1.261
14.
Pavletich NP. 1999. Mechanisms of cyclin-dependent kinase regulation: structures of cdks, their cyclin activators, and cip and INK4 inhibitors. Journal of Molecular Biology. 287(5):821-828. https://doi.org/10.1006/jmbi.1999.2640
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
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