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 "Similar 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