Cyclin-dependent kinase 6

Cell division protein kinase 6 (CDK6) is an

CDK6
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]
Available structures
This kinase is a catalytic subunit of the protein PDB Ortholog search: PDBe RCSB
kinase complex, important for the G1 phase
List of PDB id codes
progression and G1/S transition of the cell cycle
and the complex is composed also by an 1BI7, 1BI8, 1BLX, 1G3N, 1JOW, 1XO2, 2EUF, 2F2C,
activating sub-unit; the cyclin D.[10] The activity 3NUP, 3NUX, 4AUA, 4EZ5, 4TTH
of this kinase first appears in mid-G1 phase,
which is controlled by the regulatory subunits Identifiers
including D-type cyclins and members of INK4
Aliases CDK6, MCPH12, PLSTIRE, cyclin-dependent kinase 6,
family of CDK inhibitors.[7] This kinase, as well
cyclin dependent kinase 6
as CDK4, has been shown to phosphorylate, and
External OMIM: 603368 MGI: 1277162 HomoloGene: 963
thus regulate the activity of, tumor suppressor
IDs GeneCards: CDK6
Retinoblastoma protein making CDK6 an
important protein in cancer development.[10] Gene location (Human)

Contents
Structure
Function
Cell cycle Chr. Chromosome 7 (human)[1]
Cellular development
DNA protection
Metabolic homeostasis
Centrosome stability
Band 7q21.2 Start 92,604,921 bp[1]
Mechanisms of regulation
Clinical relevance
End 92,836,594 bp[1]
Cancer
Gene location (Mouse)
Medulloblastoma
As a drug target
Interactions
See also
References
 Further reading
External links

Structure
The CDK6 gene is conserved in eukaryotes, Chr. Chromosome 5 (mouse)[2]
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 Band 5 A1|5 2.04 cM Start 3,341,485 bp[2]
amino acid protein with a kinase function.[6] The
End 3,531,008 bp[2]
gene is overexpressed in cancers like lymphoma,
leukemia, medulloblastoma and melanoma RNA expression pattern
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 More reference expression data
found in the cytoplasm and the nucleus, however
Gene ontology
most of the active complexes are found in the
nucleus of proliferating cells.[10]
Molecular • transferase activity
function • protein kinase activity
• nucleotide binding
Function • cyclin-dependent protein serine/threonine kinase
activity
Cell cycle • kinase activity
• protein serine/threonine kinase activity
In 1994, Matthew Meyerson and Ed Harlow
• protein binding
investigated the product of a close analogous
• ATP binding
gene of CDK4.[7] This gene, identified as
PLSTIRE was translated into a protein that
• cyclin binding
interacted with the cyclins CD1, CD2 and CD3
• FBXO family protein binding
(same as CDK4), but that was different from Cellular • cytoplasm
CDK4; the protein was then renamed CDK6 for component • centrosome
simplicity.[7] In mammalian cells, cell cycle is • cell projection
activated by CDK6 in the early G1 phase[13] • cyclin-dependent protein kinase holoenzyme
through interactions with cyclins D1, D2 and complex
D3.[7] There are many changes in gene • ruffle
expression that are regulated through this • microtubule organizing center
enzyme.[14] After the complex is formed, the C- • cytoskeleton
CDK6 enzymatic complex phosphorylates the • cell nucleus
protein pRb.[15] After its phosphorylation, pRb • cytosol
releases its binding partner E2F, a transcriptional
• nucleoplasm
activator, which in turn activates DNA
Biological • cell differentiation
replication.[16] The CDK6 complex ensures a process • lateral ventricle development
point of switch to commit to division responding • phosphorylation
to external signals, like mitogens and growth • positive regulation of cell-matrix adhesion
factors.[17] • positive regulation of fibroblast proliferation
CDK6 is involved in a positive feedback loop • dentate gyrus development
that activates transcription factors through a • regulation of erythrocyte differentiation
reaction cascade.[18] Importantly, these C-CDK • astrocyte development
complexes act as a kinase, phosphorylating and • negative regulation of cell differentiation
inactivating the protein of Rb and p-Rb related • response to virus
“pocket proteins” p107 and p130.[19] While • negative regulation of cell cycle
doing this, the CDK6 in conjunction with CDK4, • negative regulation of osteoblast differentiation
act as a switch signal that first appears in G1,[7] • generation of neurons
directing the cell towards S phase of the cell • cell division
cycle.[14] • regulation of cell motility
• protein phosphorylation
CDK6 is important for the control of G1 to S
• cell cycle arrest
phase transition.[7] However, in recent years, new
evidence proved that the presence of CDK6 is not
• negative regulation of epithelial cell proliferation
essential for proliferation in every cell type,[20]
• regulation of gene expression
the cell cycle has a complex circuitry of • cell cycle
regulation and the role of CDK6 might be more • type B pancreatic cell development
important in certain cell types than in others, • negative regulation of myeloid cell differentiation
where CDK4 or CDK2 can act as protein kinases • negative regulation of cellular senescence
compensating its role.[20][21] • gliogenesis
• negative regulation of cell proliferation
• negative regulation of monocyte differentiation
Cellular development
• signal transduction
In mutant Knockout mice of CDK6, the • regulation of G2/M transition of mitotic cell cycle
hematopoietic function is impaired, regardless of • regulation of cell proliferation
otherwise organism normal development.[20] • cell dedifferentiation
This might hint additional roles of CDK6 in the
• G1/S transition of mitotic cell cycle
development of blood components.[20] There are
• negative regulation of cyclin-dependent protein
additional functions of CDK6 not associated with
serine/threonine kinase activity involved in G1/S
its kinase activity.[22] For example, CDK6 is
transition of mitotic cell cycle
involved in the differentiation of T cells, acting
Sources:Amigo / QuickGO
as an inhibitor of differentiation.[22] Even though
CDK6 and CDK4 share 71% amino acid identity, Orthologs
this role in differentiation is unique to CDK6.[22] Species Human Mouse
CDK6 has also been found to be important in the
Entrez
development of other cell lines, for example, 1021 12571
CDK6 has a role in the alteration of the
morphology of astrocytes[23] and in the Ensembl
ENSG00000105810 ENSMUSG00000040274
development of other stem cells.[10][16]

UniProt
Q00534 Q64261
DNA protection
CDK6 differs from CDK4 in other important RefSeq
roles.[24] For example, CDK6 plays a role in the NM_001145306 NM_009873
(mRNA)
accumulation of the apoptosis proteins p53 and NM_001259
p130, this accumulation keeps cells from entering RefSeq
NP_001138778 NP_034003
cell division if there is DNA damage, activating (protein)
NP_001250
pro- apoptotic pathways.[24]

Location Chr 7: 92.6 – 92.84 Mb Chr 5: 3.34 – 3.53 Mb

Metabolic homeostasis (UCSC)
Studies in the metabolic control of cells have PubMed [3] [4]

revealed yet another role of CDK6.[25] This new search

role is associated with the balance of the Wikidata
oxidative and non-oxidative branches of the
View/Edit Human View/Edit Mouse
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 overepression of these proteins provides the cancer cells with a new
[25]
hallmark capability of cancer; the deregulation of the cell metabolism.

Centrosome stability
In 2013 researches 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 primarymicrocephaly.[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 pRb 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
[28]
CDK6 over activation and uncontrolled cell proliferation.

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 inbreast 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
.[34]
mechanism of downregulation oftumor suppressor genes; this represents another evolving hallmark of cancer

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 ofxenograft tumors in rat models.[35]

As a drug target
Palbociclib and Ribociclib are FDA approved inhibitors of CDK4 and CDK6. Ribociclib is approved in combination with letrozole
for treatment of breast cancer in patients with an hormone receptor positive, HER2 negative advanced metastatic breast cancer.[36] A
phase three clinical trial found that Ribocyclib administered in combination with letrozole increased the likelihood of progression
free survival to 63% in the first 18 months of therapy versus 42% for letrozole alone.[37] Subsequent analysis demonstrated that
[36] Inhibitors of CDK6 have
patients treated with Ribociclib and letrozole showed a median progression-free survival of 25.3 months.
shown the disadvantage of having low specificity for CDK6 over other CDKs, and as a consequence they might act inhibiting other
CDKs that are crucial in other tissues and at other points of cell cycle.[38] The compound PD-0332991, is currently under more than
20 clinical trials acting either as single agent or as coadjuvant of other therapies in clinical trial phase I-III showing promising results
in the control of breast cancerin-vitro.[39]

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.[40] 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.[40] this mechanism was studied in the development of mammary tumorigenesis in rat cells, however, the
clinical effects have not yet been shown in humanpatients.[40] A

Interactions
Cyclin-dependent kinase 6interacts with:

CDKN2C,[41][42][43] P16,[47][48][49]
Cyclin D1,[44][45] PPM1B,[50] and
Cyclin D3,[44][46] PPP2CA.[50]

See also
Cell cycle, Mitosis, CDK, CDK4, Hallmarks of cancer Genecards Uniprot NCI

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Further reading
Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF , Weinstock KG, Gocayne
JD, White O (Sep 1995)."Initial assessment of human gene diversity and expression patterns based upon 83 million
nucleotides of cDNA sequence"(PDF). Nature. 377 (6547 Suppl): 3–174. PMID 7566098.
Aprelikova O, Xiong Y, Liu ET (Aug 1995). "Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors
block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase".
The Journal of Biological
Chemistry. 270 (31): 18195–7. doi:10.1074/jbc.270.31.18195. PMID 7629134.
Lucas JJ, Szepesi A, Modiano JF, Domenico J, Gelfand EW (Jun 1995). "Regulation of synthesis and activity of the
PLSTIRE protein (cyclin-dependent kinase 6 (cdk6)), a major cyclin D-associated cdk4 homologue in normal human
T lymphocytes". Journal of Immunology. 154 (12): 6275–84. PMID 7759865.
Bullrich F, MacLachlan TK, Sang N, Druck T, Veronese ML, Allen SL, Chiorazzi N, Koff A, Heubner K, Croce CM
(Mar 1995). "Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and
PITALRE, and a cdk inhibitor, p27Kip1, to regions involved in human cancer".Cancer Research. 55 (6): 1199–205.
PMID 7882308.
Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y (Dec 1994). "Growth suppression
by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor , correlates with wild-type pRb function".
Genes & Development. 8 (24): 2939–52. doi:10.1101/gad.8.24.2939. PMID 8001816.
Meyerson M, Harlow E (Mar 1994)."Identification of G1 kinase activity for cdk6, a novel cyclin D partner"
. Molecular
and Cellular Biology. 14 (3): 2077–86. PMC 358568 . PMID 8114739.
Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP (Jan 1996). "Inhibition of pRb phosphorylation and cell-cycle
progression by a 20-residue peptide derived from p16CDKN2/INK4A".Current Biology. 6 (1): 84–91.
doi:10.1016/S0960-9822(02)00425-6. PMID 8805225.
Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene
discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J (Apr 1997). "Interaction between
Cdc37 and Cdk4 in human cells".Oncogene. 14 (16): 1999–2004. doi:10.1038/sj.onc.1201036. PMID 9150368.
Nagasawa M, Melamed I, Kupfer A, Gelfand EW , Lucas JJ (Jun 1997). "Rapid nuclear translocation and increased
activity of cyclin-dependent kinase 6 after T cell activation".Journal of Immunology. 158 (11): 5146–54.
PMID 9164930.
Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF (Sep 1997)."Hypo-phosphorylation of
the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb"
. Proceedings of the National
Academy of Sciences of the United States of America . 94 (20): 10699–704. doi:10.1073/pnas.94.20.10699.
PMC 23451 . PMID 9380698.
Fåhraeus R, Laín S, Ball KL, Lane DP (Feb 1998). "Characterization of the cyclin-dependent kinase inhibitory
domain of the INK4 family as a model for a synthetic tumour suppressor molecule".Oncogene. 16 (5): 587–96.
doi:10.1038/sj.onc.1201580. PMID 9482104.
 Gonzales AJ, Goldsworthy TL, Fox TR (Jun 1998). "Chemical transformation of mouse liver cells results in altered
cyclin D-CDK protein complexes".Carcinogenesis. 19 (6): 1093–102. doi:10.1093/carcin/19.6.1093. PMID 9667749.
Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP (Sep 1998). "Structural basis for inhibition of the cyclin-
dependent kinase Cdk6 by the tumour suppressor p16INK4a".Nature. 395 (6699): 237–43. doi:10.1038/26155.
PMID 9751050.
Brotherton DH, Dhanaraj V, Wick S, Brizuela L, Domaille PJ, Volyanik E, Xu X, Parisini E, Smith BO, Archer SJ,
Serrano M, Brenner SL, Blundell TL, Laue ED (Sep 1998). "Crystal structure of the complex of the cyclin D-
dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d".Nature. 395 (6699): 244–50. doi:10.1038/26164.
PMID 9751051.
Jiang W, Wells NJ, Hunter T (May 1999)."Multistep regulation of DNA replication by Cdk phosphorylation of
HsCdc6". Proceedings of the National Academy of Sciences of the United States of America. 96 (11): 6193–8.
doi:10.1073/pnas.96.11.6193. PMC 26858 . PMID 10339564.
Yarbrough WG, Buckmire RA, Bessho M, LiuET (Sep 1999). "Biologic and biochemical analyses of p16(INK4a)
mutations from primary tumors".Journal of the National Cancer Institute. 91 (18): 1569–74.
doi:10.1093/jnci/91.18.1569. PMID 10491434.
Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC (Sep 1999). "Cdk phosphorylation triggers sequential
intramolecular interactions that progressively block Rb functions as cells move through G1".
Cell. 98 (6): 859–69.
doi:10.1016/S0092-8674(00)81519-6. PMID 10499802.
Grossel MJ, Baker GL, Hinds PW (Oct 1999). "cdk6 can shorten G(1) phase dependent upon the N-terminal INK4
interaction domain". The Journal of Biological Chemistry. 274 (42): 29960–7. doi:10.1074/jbc.274.42.29960.
PMID 10514479.

External links
Cyclin-Dependent+Kinase+6at the US National Library of MedicineMedical Subject Headings(MeSH)
CDK6 human gene location in theUCSC Genome Browser.
CDK6 human gene details in theUCSC Genome Browser.

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