Cyclin-dependent kinase 6

Last updated
CDK6
Protein CDK6 PDB 1bi7.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CDK6 , MCPH12, PLSTIRE, cyclin-dependent kinase 6, cyclin dependent kinase 6
External IDs OMIM: 603368 MGI: 1277162 HomoloGene: 963 GeneCards: CDK6
Orthologs
SpeciesHumanMouse
Entrez

1021

12571

Ensembl

ENSG00000105810

ENSMUSG00000040274

UniProt

Q00534

Q64261

RefSeq (mRNA)

NM_001145306
NM_001259

NM_009873

RefSeq (protein)

NP_001138778
NP_001250

NP_034003

Location (UCSC) Chr 7: 92.6 – 92.84 Mb Chr 5: 3.39 – 3.58 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. [5] [6] It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. [7] The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. [8] 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. [9]

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. [10] 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. [7] 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. [10]

Structure

The CDK6 gene is conserved in eukaryotes, including the budding yeast and the nematode Caenorhabditis elegans. [11] 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. [6] The gene is overexpressed in cancers like lymphoma, leukemia, medulloblastoma and melanoma associated with chromosomal rearrangements. [6] The CDK6 protein contains a catalytic core composed of a serine/threonine domain. [12] 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. [10] After binding the Cyclin in the PSTAIRE helix, the protein changes its conformational structure to expose the phosphorylation motif. [10] 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. [10]

Function

Cell cycle

In 1994, Matthew Meyerson and Ed Harlow investigated the product of a close analogous gene of CDK4. [7] 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. [7] In mammalian cells, cell cycle is activated by CDK6 in the early G1 phase [13] through interactions with cyclins D1, D2 and D3. [7] There are many changes in gene expression that are regulated through this enzyme. [14] After the complex is formed, the C-CDK6 enzymatic complex phosphorylates the protein pRb. [15] After its phosphorylation, pRb releases its binding partner E2F, a transcriptional activator, which in turn activates DNA replication. [16] The CDK6 complex ensures a point of switch to commit to division responding to external signals, like mitogens and growth factors. [17]

CDK6 is involved in a positive feedback loop that activates transcription factors through a reaction cascade. [18] 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. [19] While doing this, the CDK6 in conjunction with CDK4, act as a switch signal that first appears in G1, [7] directing the cell towards S phase of the cell cycle. [14]

CDK6 is important for the control of G1 to S phase transition. [7] However, in recent years, new evidence proved that the presence of CDK6 is not essential for proliferation in every cell type, [20] 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. [20] [21]

Cellular development

In mutant Knockout mice of CDK6, the hematopoietic function is impaired, regardless of otherwise organism normal development. [20] This might hint additional roles of CDK6 in the development of blood components. [20] There are additional functions of CDK6 not associated with its kinase activity. [22] For example, CDK6 is involved in the differentiation of T cells, acting as an inhibitor of differentiation. [22] Even though CDK6 and CDK4 share 71% amino acid identity, this role in differentiation is unique to CDK6. [22] 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 [23] and in the development of other stem cells. [10] [16]

DNA protection

CDK6 differs from CDK4 in other important roles. [24] 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. [24]

Metabolic homeostasis

Studies in the metabolic control of cells have revealed yet another role of CDK6. [25] This new role is associated with the balance of the oxidative and non-oxidative branches of the pentose pathway in cells. [25] This pathway is a known route altered in cancer cells, when there is an aberrant overexpression of CDK6 and CDK4. [25] The overexpression of these proteins provides the cancer cells with a new hallmark capability of cancer; the deregulation of the cell metabolism. [25]

Centrosome stability

In 2013, researchers discovered yet another role of CDK6. [26] There is evidence that CDK6 associates with the centrosome and controls organized division and cell cycle phases in neuron production. [26] When the CDK6 gene is mutated in these developing lines, the centrosomes are not properly divided, this could lead to division problems such as aneuploidy, which in turns leads to health issues like primary microcephaly. [26]

Mechanisms of regulation

CDK6 is positively regulated primarily by its union to the D cyclins D1, D2 and D3. If this subunit of the complex is not available, CDK6 is not active or available to phosphorylate the Rb substrate. [9] An additional positive activator needed by CDK6 is the phosphorylation in a conserved threonine residue located in 177 position, this phosphorylation is done by the cdk-activating kinases, CAK. [27] Additionally, CDK6 can be phosphorylated and activated by the Kaposi's sarcoma-associated herpes virus, stimulating the CDK6 over activation and uncontrolled cell proliferation. [28]

CDK6 is negatively regulated by binding to certain inhibitors that can be classified in two groups; [29] CKIs or CIP/KIP family members like the protein p21 [16] and p27 act blocking and inhibiting the assembled C-CDKs binding complex enzymes [27] in their catalytic domain. [30]

Furthermore, inhibitors of the INK4 family members like p15, p16, p18 and p19 inhibit the monomer of CDK6, preventing the complex formation. [19] [31]

Clinical relevance

CDK6 is a protein kinase activating cell proliferation, it is involved in an important point of restriction in the cell cycle. [18] For this reason, CDK6 and other regulators of the G1 phase of the cell cycle are known to be unbalanced in more than 80-90% of tumors. [9] In cervical cancer cells, CDK6 function has been shown to be altered indirectly by the p16 inhibitor. [31] CDK6 is also overexpressed in tumors that exhibit drug resistance, for example glioma malignancies exhibit resistance to chemotherapy using temozolomide (TMZ) when they have a mutation overexpressing CDK6. [32] Likewise, the overexpression of CDK6 is also associated with resistance to hormone therapy using the anti oestrogen Fluvestrant in breast cancer. [33]

Cancer

Loss of normal cell cycle control is the first step to developing different hallmarks of cancer; alterations of CDK6 can directly or indirectly affect the following hallmarks; disregulated cell cellular energetics, sustaining of proliferative signaling, evading growth suppressors and inducing angiogenesis, [9] for example, deregulation of CDK6 has been shown to be important in lymphoid malignancies by increasing angiogenesis, a hallmark of cancer. [19] These features are reached through upregulation of CDK6 due to chromosome alterations or epigenetic dysregulations. [9] Additionally, CDK6 might be altered through genomic instability, a mechanism of downregulation of tumor suppressor genes; this represents another evolving hallmark of cancer. [34]

Medulloblastoma

Medulloblastoma is the most common cause of brain cancer in children. [35] About a third of these cancers have upregulated CDK6, representing a marker for poor prognosis for this disease. [35] Since it is so common for these cells to have alterations in CDK6, researchers are seeking for ways to downregulate CDK6 expression acting specifically in those cell lines. The MicroRNA (miR) -124 has successfully controlled cancer progression in an in-vitro setting for medulloblastoma and glioblastoma cells. [35] Furthermore, researchers have found that it successfully reduces the growth of xenograft tumors in rat models. [35]

As a drug target

The direct targeting of CDK6 and CDK4 should be used with caution in the treatment of cancer, because these enzymes are important for the cell cycle of normal cells as well. [35] Furthermore, small molecules targeting these proteins might increase drug resistance events. [35] However, these kinases have been shown to be useful as coadjuvants in breast cancer chemotherapy. [36] Another indirect mechanism for the control of CDK6 expression, is the use of a mutated D-cyclin that binds with high affinity to CDK6, but does not induce its kinase activity. [36] this mechanism was studied in the development of mammary tumorigenesis in rat cells, however, the clinical effects have not yet been shown in human patients. [36] A

Interactions

Cyclin-dependent kinase 6 interacts with:

See also

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. In fact, yeast cells can proliferate normally when their CDK gene has been replaced with the homologous human gene. CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the kinase domain. By definition, a CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase but its activity can be typically further modulated by phosphorylation and other binding proteins, like p27. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases. The consensus sequence for the phosphorylation site in the amino acid sequence of a CDK substrate is [S/T*]PX[K/R], where S/T* is the phosphorylated serine or threonine, P is proline, X is any amino acid, K is lysine, and R is arginine.

<span class="mw-page-title-main">Restriction point</span> Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

<span class="mw-page-title-main">G1/S transition</span> Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

p16 Mammalian protein found in Homo sapiens

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

INK4 is a family of cyclin-dependent kinase inhibitors (CKIs). The members of this family (p16INK4a, p15INK4b, p18INK4c, p19INK4d) are inhibitors of CDK4 (hence their name INhibitors of CDK4), and of CDK6. The other family of CKIs, CIP/KIP proteins are capable of inhibiting all CDKs. Enforced expression of INK4 proteins can lead to G1 arrest by promoting redistribution of Cip/Kip proteins and blocking cyclin E-CDK2 activity. In cycling cells, there is a resassortment of Cip/Kip proteins between CDK4/5 and CDK2 as cells progress through G1. Their function, inhibiting CDK4/6, is to block progression of the cell cycle beyond the G1 restriction point. In addition, INK4 proteins play roles in cellular senescence, apoptosis and DNA repair.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

<span class="mw-page-title-main">Cyclin-dependent kinase 2</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

<span class="mw-page-title-main">Cyclin-dependent kinase 4</span> Human protein

Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

<span class="mw-page-title-main">Cyclin-dependent kinase inhibitor protein</span> Protein which inhibits cyclin-dependent kinase

A cyclin-dependent kinase inhibitor protein(also known as CKIs, CDIs, or CDKIs) is a protein which inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the process of DNA synthesis, mitosis, and cytokines control one another. If a malfunction prevents the successful completion of DNA synthesis during the G1 phase, a signal is sent to delay or stop the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.

<span class="mw-page-title-main">Cyclin D1</span> Protein found in humans

Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.

<span class="mw-page-title-main">Cyclin D2</span> Protein-coding gene in humans

G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene.

<span class="mw-page-title-main">CDKN2B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 (MTS-2) or p15INK4b is a protein that is encoded by the CDKN2B gene in humans.

<span class="mw-page-title-main">CDKN2C</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor C is an enzyme that in humans is encoded by the CDKN2C gene.

<span class="mw-page-title-main">CDKN2D</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor D is an enzyme that in humans is encoded by the CDKN2D gene.

<span class="mw-page-title-main">Cyclin-dependent kinase 3</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 3 is an enzyme that in humans is encoded by the CDK3 gene.

The CIP/KIP family is one of two families of mammalian cyclin dependent kinase (CDK) inhibitors (CKIs) involved in regulating the cell cycle. The CIP/KIP family is made up of three proteins: p21cip1/waf1, P27kip1, p57kip2 These proteins share sequence homology at the N-terminal domain which allows them to bind to both the cyclin and CDK. Their activity primarily involves the binding and inhibition of G1/S- and S-Cdks; however, they have also been shown to play an important role in activating the G1-CDKs CDK4 and CDK6. In addition, more recent work has shown that CIP/KIP family members have a number of CDK-independent roles involving regulation of transcription, apoptosis, and the cytoskeleton.

References

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