The reference OMIM entry for this protein is 603368

Cyclin-dependent kinase 6; cdk6
Plstire cdk6/mll fusion gene, included

CLONING

The cyclin-dependent protein kinases (CDKs) regulate major cell cycle transitions in eukaryotic cells. By RT-PCR of HeLa cell mRNA with degenerate primers corresponding to conserved regions of CDC2 (116940), Meyerson et al. (1992) identified cDNAs encoding 7 novel human protein kinases. They designated 1 of these proteins PLSTIRE, following the accepted practice of naming cdc2-related kinases based on the amino acid sequence of the region corresponding to the conserved PSTAIRE motif of CDC2. The predicted 326-amino acid PLSTIRE protein shares 47% and 71% identity with CDC2 and PSK-J3 (CDK4; 123829). The in vitro transcription/translation product has an apparent molecular weight of 40 kD by SDS-PAGE. Northern blot analysis revealed that the PLSTIRE gene was expressed as 13-, 8.5-, and 6-kb mRNAs in several human tissues. Hussain et al. (2013) found expression of Cdk6 in the neuroepithelium of the cerebral cortex of the developing mouse brain. Cdk6 immunostaining was prominent at the apical ventricular surface and in the basal progenitor cells. Within the cell, Cdk6 localized to the cytosol of neurons and showed prominent staining around either side of the nucleus.

GENE FUNCTION

Meyerson and Harlow (1994) demonstrated that PLSTIRE is associated with cyclins D1 (168461), D2 (123833), and D3 (123834) in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. PLSTIRE immunoprecipitated from human cells exhibited significant kinase activity, and was able to phosphorylate RB1 (614041). Based on these findings, they renamed the protein CDK6 (cyclin-dependent kinase 6). In primary T cells that were stimulated to enter the cell cycle, cellular CDK6 kinase activity first appeared in mid-G1, prior to the activation of any previously characterized CDK. Meyerson and Harlow (1994) suggested that CDK6, and the homologous CDK4, link growth factor stimulation with the onset of cell cycle progression. Guan et al. (1994) proposed that CDK4 and CDK6 are physiologic RB1 kinases that are inhibited by the p14 (600431), p16 (600160), and p18 (603369) CDK inhibitors. This inhibition prevents the phosphorylation of RB1 and keeps RB1 in its active growth-suppressing state. See CDKN2D (600927). Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB by CDK4/CDK6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E (see 123837) is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F (189971). Veiga-Fernandes and Rocha (2003) showed that, in contrast to naive CD8 (see 186910) T cells in G0/G1 arrest, memory CD8 T cells in G0/G1 arrest have low expression of the cyclin-dependent kinase inhibitor p27(Kip1) (CDKN1B; 600778) and high CDK6 activity. They found that preactivated CDK6 is associated with cyclin D3 (CCND3) in the cytoplasm, facilitating the switch to S phase and the rapid division of ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 603368 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).