thumb|Tertiary structure of human Cdk2, determined by X-ray crystallography. Like other protein kinases, Cdk2 is composed of two lobes: a smaller amino-terminal lobe (top) that is composed primarily of beta sheet and the PSTAIRE helix, and a large carboxy-terminal lobe (bottom) that is primarily made up of alpha helices. The ATP substrate is shown as a ball-and-stick model, located deep within the active-site cleft between the two lobes. The phosphates are oriented outward, toward the mouth of the cleft, which is blocked in this structure by the T-loop (highlighted in green). (PDB 1hck)
Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases involved in the regulation of the cell cycle. These enzymes function as upstream regulators of cellular processes such as transcription, DNA repair, metabolism, and epigenetic regulation, in response to extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved.
CDKs are named for the cyclins, protein activators of CDKs that become mobilized at different points in the cell cycle. Dysregulation of CDK activity is linked to diseases including cancer, neurodegenerative diseases, and stroke. The activation forms a cyclin-CDK complex which phosphorylates specific regulatory proteins that are required to initiate steps in the cell-cycle. When cyclin is bound, two alpha helices change position to enable ATP binding, in addition to the movement of the activation loop. In addition to activating the CDKs, cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. For example, cyclin B1 and B2 can localize CDK1 to the nucleus and the Golgi, respectively, through a localization sequence outside the CDK-binding region. The identity of the CDK-activating kinase (CAK) that carries out this phosphorylation varies among different model organisms. The timing of this phosphorylation also varies; in mammalian cells, the activating phosphorylation occurs after cyclin binding, while in yeast cells, it occurs before cyclin binding. CAK activity is not regulated by known cell cycle pathways, and it is the cyclin binding that is the limiting step for CDK activation.
Non-cyclin activators
Several proteins other than cyclins can activate CDKs. For instance, certain viruses encode proteins with sequence homology to cyclins. One much-studied example is K-cyclin (or v-cyclin) from Kaposi sarcoma herpes virus, which activates CDK6. The vCyclin-CDK6 complex promotes an accelerated transition from G1 to S phase. This leads to the removal of inhibition on Cyclin E–CDK2's enzymatic activity and promotes transformation and tumorigenesis. During neuronal differentiation, CDK5 is activated by the p35 and p39 proteins. This activation is important in growth of the dendritic spine and in synapse formation. The RINGO/Speedy proteins can also activate CDKs (primarily CDK1 and 2), despite lacking homology to cyclins. These proteins alter the substrate specificity of the CDKs in addition to regulating activity.
Medical significance
CDKs and cancer
Because of their roles in cell cycle regulation, CDKs are of great interest in cancer. Research has shown that alterations in cyclins, CDKs, and CDK inhibitors are common in cancers.]]
Numerous synthetic inhibitors of CDKs have been explored for potential therapeutic benefit in cancer. Ribociclib, demonstrating similar efficacy to palbociclib, is also approved for HR+/HER2- advanced breast cancer. Abemaciclib may be used in monotherapy, in addition to combination treatment, for certain HR+/HER2- breast cancer patients, including patients with brain metastases.
!Drug
!CDKs Inhibited
!Condition or disease
|-
|Flavopiridol (alvocidib)
|1, 2, 4, 6, 9
|Acute Myeloid Leukemia (AML)
|-
|Roscovitine (Seliciclib)
|2, 7, 9
|Pituitary Cushing Disease
Cystic Fibrosis, Advanced Solid Tumors
Lung Cancer
|-
|Dinaclib
|1, 2, 5, 9
|Chronic Lymphocytic Leukemia (CLL)
Breast and Lung Cancers
|-
|Milciclib
|1, 2, 4, 7
|Hepatocellular Carcinoma (HCC)
Thymic Carcinoma
|-
|Palbociclib
|4, 6
|Breast Cancer
Head and Neck, Brain, Colon, and other Solid Cancers
|-
|Ribociclib
|4, 6
|HR+/HER2- Breast Cancer
Prostate, and other Solid Cancers
|-
|Abemaciclib
|4, 6
|HR+/HER2- Breast Cancer
Lung, Brain, Colon, and other Solid Cancers
|-
|Meriolin
|1, 2, 5, 9
|Neuroblastoma, Glioma, Myeloma, Colon Cancer
|-
|Variolin B
|1, 2, 5, 9
|Murine Leukemia
|-
|Roniciclib
|1, 2, 4, 7, 9
|Lung and Advanced Solid Cancers
|-
|Meridianin E
|1, 5, 9
|Larynx Carcinoma
Myeloid Leukemia
|-
|Nortopsentins
|1
|Malignant Pleural Mesothelioma (MPM)
|}
Off-target effects are a significant concern with CDK-inhibiting drugs, as CDKs have roles in non-cancer processes including transcription, neural physiology, and glucose homeostasis.
See also
- Cell cycle
- Protein kinase
- Enzyme catalysis
- Enzyme inhibitor