Cyclin-dependent kinase

The activation of CDKs requires binding to cyclins and phosphorylation. This phosphorylation typically occurs on a specific threonine residue, leading to a conformational change in the CDK that enhances its kinase activity. The activation forms a cyclin-CDK complex which phosphorylates specific regulatory proteins that are required to initiate steps in the cell-cycle.In human cells, the CDK family comprises 20 different members that play a crucial role in the regulation of the cell cycle and transcription. These are usually separated into cell-cycle CDKs, which regulate cell-cycle transitions and cell division, and transcriptional CDKs, which mediate gene transcription. CDK1, CDK2, CDK3, CDK4 and CDK6 are directly related to the regulation of cell-cycle events, while CDK7 – 13 are associated with transcriptional regulation. Different cyclin-CDK complexes regulate different phases of the cell cycle, known as G0/G1, S, G2, and M phases, featuring several checkpoints to maintain genomic stability and ensure accurate DNA replication. Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phases. == CDK structure and activation ==

CDKs mainly consist of an N-terminal and a C-terminal lobe with distinct functions. The N-terminal lobe (N-lobe) contains a glycine-rich inhibitory loop and a so-called C helix that binds cyclins. 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. == See also ==