Cyclin-dependent kinases

Abstract

Cyclin-dependent kinases (CDKs) are protein kinases characterized by needing a separate subunit - a cyclin - that provides domains essential for enzymatic activity. CDKs play important roles in the control of cell division and modulate transcription in response to several extra- and intracellular cues. The evolutionary expansion of the CDK family in mammals led to the division of CDKs into three cell-cycle-related subfamilies (Cdk1, Cdk4 and Cdk5) and five transcriptional subfamilies (Cdk7, Cdk8, Cdk9, Cdk11 and Cdk20). Unlike the prototypical Cdc28 kinase of budding yeast, most of these CDKs bind one or a few cyclins, consistent with functional specialization during evolution. This review summarizes how, although CDKs are traditionally separated into cell-cycle or transcriptional CDKs, these activities are frequently combined in many family members. Not surprisingly, deregulation of this family of proteins is a hallmark of several diseases, including cancer, and drug-targeted inhibition of specific members has generated very encouraging results in clinical trials.

Figure 1

Comparison of yeast and mammalian CDKs. Cells of the budding yeast Saccharomyces cerevisiae contain two cell-cycle-related CDKs that are activated by multiple cyclins - Cdc28 and Pho85. Cdk1 is the mammalian ortholog of Cdc28, whereas Cdk5 is considered to be the Pho85 ortholog. The Cdk4/Cdk6 subfamily is not present in yeast. Kin28, Srb10, Bur1 and Ctk1 are the yeast orthologs of Cdk7, Cdk8, Cdk9 and Cdk12, respectively. The Cdk20 and Cdk11/Cdk10 subfamilies are not represented in yeast. Also indicated is the cyclin partner for the mammalian CDKs. CDK, cyclin-dependent kinase.

Figure 2

Evolutionary relationships among the mammalian CDK subfamilies. The name of the different CDK subfamilies functioning in the cell cycle (orange) or transcription (green) is shown in boldface, and the domain structure of the individual proteins is depicted. The conserved protein kinase domain (red) and some additional domains (see key) are indicated for each CDK. Human cells contain two separate genes, Cdk11A and Cdk11B, each of them encoding a long isoform, Cdk11^p110, and a shorter protein, Cdk11^p58, generated by an internal ribosome binding site. The phylogenetic tree is based on the comparison of the human kinase domains [1]. CDK, cyclin-dependent kinase.

Figure 3

A three-dimensional view of CDK structure and activation. In monomeric Cdk2 (left; [PDB:1HCL]), the major C-helix (N-lobe) and the activation domain are close, ensuring that the catalytic pocket is inaccessible. Upon binding of cyclin A (right: [PDB: 1JST]), the C-helix and the activation domain are pulled apart - a configuration that is further fixed by phosphorylation of residue T160, making the catalytic pocket accessible for enzymatic activity. The position of the inhibitory Thr14 (T14) and Tyr15 (Y15) residues in the G-loop is also shown. Color code: CDK subunit, orange; cyclin subunit, green; purple indicates specific named protein domains. CDK, cyclin-dependent kinase.

Figure 4

An overview of CDK functions in the cell. Each CDK (in orange boxes) is shown in a complex with its major partner (green) - for clarity, only a few substrates are depicted. Most CDKs function in the nucleus (orange background), whereas a few family members are attached to the cell membrane or display cytoplasmic activities (blue background). Classical cell cycle CDKs - Cdk4, Cdk6, Cdk2 and Cdk1 - regulate the transitions through the different phases of the cell-division cycle. These activities are at least partially mediated by the control of multiple transcription factors (TFs) or regulatory elements such as the retinoblastoma protein (Rb). Cdk10 and Cdk11 also control transcription by phosphorylating TFs, hormone receptors and associated regulators (HRs), or splicing factors (SPFs). Cdk7, Cdk9 and Cdk12 directly phosphorylate the C-terminal domain (CTD) of RNA polymerase II (RNAPII), thus modulating the different phases of generation of transcripts. The Mediator complex is specifically regulated by Cdk8 or the highly related Cdk19. Cdk7 functions as a CDK-activating kinase (CAK) by directly phosphorylating several of the CDKs mentioned above. Cdk5 displays many functions in the cell, but it is better known for its function in the control of neuron-specific proteins such as Tau. The members of the Cdk14 subfamily, such as Cdk14 itself or Cdk16, are activated at the membrane by cyclin Y and also participate in many different pathways, such as Wnt-dependent signaling or signal transduction in the primary cilium. It is important to note that, for clarity, many interactions between CDKs and other partners, substrates or cellular processes are not shown - for instance, Cdk1 can bind to other cyclins and can also phosphorylate more than 100 substrates during mitotic entry that are not indicated here. CAK, CDK-activating kinase; CDK, cyclin-dependent kinase; CTD, C-terminal domain; Rb, retinoblastoma protein; RNAPII, RNA polymerase II; SPF, splicing factor; TF, transcription factor.