Cyclin-dependent kinase 6

1BI7, 1BI8, 1BLX, 1G3N, 1JOW, 1XO2, 2EUF, 2F2C, 3NUP, 3NUX, 4AUA, 4EZ5, 4TTH102112571ENSG00000105810ENSMUSG00000040274Q00534Q64261NM_001145306NM_001259NM_009873NP_001138778NP_001250NP_034003Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.1bi7: MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX1bi8: MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURES CDK6-P19INK4D INHIBITOR COMPLEX1blx: P19INK4D/CDK6 COMPLEX1g3n: STRUCTURE OF A P18(INK4C)-CDK6-K-CYCLIN TERNARY COMPLEX1jow: Crystal structure of a complex of human CDK6 and a viral cyclin1xo2: Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin2euf: X-ray structure of human CDK6-Vcyclin in complex with the inhibitor PD03329912f2c: X-ray structure of human CDK6-Vcyclinwith the inhibitor aminopurvalanol Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point. This kinase is a catalytic subunit of the protein kinase complex, important for the G1 phase progression and G1/S transition of the cell cycle and the complex is composed also by an activating sub-unit; the cyclin D. The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor Retinoblastoma protein making CDK6 an important protein in cancer development. The CDK6 gene is conserved in eukaryotes, including the budding yeast and the nematode Caenorhabditis elegans. The CDK6 gene is located on chromosome 7 in humans. The gene spans 231,706 base pairs and encodes a 326 amino acid protein with a kinase function. The gene is overexpressed in cancers like lymphoma, leukemia, medulloblastoma and melanoma associated with chromosomal rearrangements. The CDK6 protein contains a catalytic core composed of a serine/threonine domain. This protein also contains an ATP-binding pocket, inhibitory and activating phosphorylation sites, a PSTAIRE-like cyclin-binding domain and an activating T-loop motif. After binding the Cyclin in the PSTAIRE helix, the protein changes its conformational structure to expose the phosphorylation motif. The protein can be found in the cytoplasm and the nucleus, however most of the active complexes are found in the nucleus of proliferating cells. In 1994, Matthew Meyerson and Ed Harlow investigated the product of a close analogous gene of CDK4. This gene, identified as PLSTIRE was translated into a protein that interacted with the cyclins CD1, CD2 and CD3 (same as CDK4), but that was different from CDK4; the protein was then renamed CDK6 for simplicity. In mammalian cells, cell cycle is activated by CDK6 in the early G1 phase through interactions with cyclins D1, D2 and D3. There are many changes in gene expression that are regulated through this enzyme. After the complex is formed, the C-CDK6 enzymatic complex phosphorylates the protein pRb. After its phosphorylation, pRb releases its binding partner E2F, a transcriptional activator, which in turn activates DNA replication. The CDK6 complex ensures a point of switch to commit to division responding to external signals, like mitogens and growth factors. CDK6 is involved in a positive feedback loop that activates transcription factors through a reaction cascade. Importantly, these C-CDK complexes act as a kinase, phosphorylating and inactivating the protein of Rb and p-Rb related “pocket proteins” p107 and p130. While doing this, the CDK6 in conjunction with CDK4, act as a switch signal that first appears in G1, directing the cell towards S phase of the cell cycle. CDK6 is important for the control of G1 to S phase transition. However, in recent years, new evidence proved that the presence of CDK6 is not essential for proliferation in every cell type, the cell cycle has a complex circuitry of regulation and the role of CDK6 might be more important in certain cell types than in others, where CDK4 or CDK2 can act as protein kinases compensating its role. In mutant Knockout mice of CDK6, the hematopoietic function is impaired, regardless of otherwise organism normal development. This might hint additional roles of CDK6 in the development of blood components. There are additional functions of CDK6 not associated with its kinase activity. For example, CDK6 is involved in the differentiation of T cells, acting as an inhibitor of differentiation. Even though CDK6 and CDK4 share 71% amino acid identity, this role in differentiation is unique to CDK6. CDK6 has also been found to be important in the development of other cell lines, for example, CDK6 has a role in the alteration of the morphology of astrocytes and in the development of other stem cells. CDK6 differs from CDK4 in other important roles. For example, CDK6 plays a role in the accumulation of the apoptosis proteins p53 and p130, this accumulation keeps cells from entering cell division if there is DNA damage, activating pro- apoptotic pathways. Studies in the metabolic control of cells have revealed yet another role of CDK6. This new role is associated with the balance of the oxidative and non-oxidative branches of the pentose pathway in cells. This pathway is a known route altered in cancer cells, when there is an aberrant overexpression of CDK6 and CDK4. The overepression of these proteins provides the cancer cells with a new hallmark capability of cancer; the deregulation of the cell metabolism.