Cyclin-dependent kinase - AbsoluteAstronomy.com

Cyclin-dependent kinases (CDKs) are a family of protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

kinases first discovered for their role in regulating the cell cycle

Cell cycle

The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

. They are also involved in regulating transcription

Transcription (genetics)

Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

, mRNA processing, and the differentiation of nerve cells. They are present in all known eukaryotes, and their regulatory function in the cell cycle

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

Cyclin

Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...

. Without cyclin

Cyclin

Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...

, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases. The consensus sequence for the phosphorylation

Phosphorylation

Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

site in the amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

sequence of a CDK substrate is [S/T*]PX[K/R], where S/T* is the phosphorylated serine

Serine

Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

or threonine

Threonine

Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...

, P is proline

Proline

Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

, X is any amino acid, K is lysine

Lysine

Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

, and R is arginine

Arginine

Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

Types

Table 1: Known CDKs, their cyclin partners, and their functions in the human and consequences of deletion in mice.

CDK	Cyclin partner	Function	Deletion Phenotype in Mice
Cdk1	Cyclin B	M phase	None. ~E2.5.
Cdk2	Cyclin E	G1/S transition	Reduced size, imparted neural progenitor cell proliferation. Viable, but both males & females sterile.
Cdk2	Cyclin A	S phase, G2 phase
Cdk3	Cyclin C	G1 phase ?	No defects. Viable, fertile.
Cdk4	Cyclin D	G1 phase	Reduced size, insulin deficient diabetes. Viable, but both male & female infertile.
Cdk5	p35	Transcription	Severe neurological defects. Died immediately after birth.
Cdk6	Cyclin D	G1 phase
Cdk7	Cyclin H	CDK-activating kinase, transcription
Cdk8	Cyclin C	Transcription
Cdk11	Cyclin L	?	Mitotic defects. E3.5.
?	Cyclin F	?	Defects in extraembryonic tissues. E10.5.
?	Cyclin G	?

CDKs and Cyclins in the Cell Cycle

Most of the known cyclin-CDK complexes regulate the progression through the cell cycle

Cell cycle

. Animal cells contain at least nine CDKs, four of which, Cdk1, 2, 3, and 4, are directly involved in cell cycle regulation. In mammalian cells, CDK1, with its partners cyclin A2 and B1, alone can drive the cell cycle. Another one, Cdk5, is involved indirectly as the CDK-activating kinase. Cyclin-CDK complexes phosphorylate substrates appropriate for the particular cell cycle phase. Cyclin-CDK complexes in earlier cell-cycle phase help activate cyclin-CDK complexes in later phases.

Table 2: Cyclins and CDKs by Cell-Cycle Phase

Phase	Cyclin	CDK
G0	C	Cdk3
G1	D, E	Cdk4, Cdk2, Cdk6
S	A, E	Cdk2
G2	A	Cdk2, Cdk1
M	B	Cdk1

Table 3: Cyclin-dependent kinases that control the cell cycle in model organisms.

Species	Name	Original name	Size (amino acids)	Function
Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...	Cdk1	Cdc28	298	All cell-cycle stages
Schizosaccharomyces pombe Schizosaccharomyces pombe Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...	Cdk1	Cdc2	297	All cell-cycle stages
Drosophila melanogaster Drosophila melanogaster Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...	Cdk1	Cdc2	297	M
	Cdk2	Cdc2c	314	G1/S, S, possibly M
	Cdk4	Cdk4/6	317	G1, promotes growth
Xenopus laevis	Cdk1	Cdc2	301	M
	Cdk2		297	S, possibly M
Homo sapiens	Cdk1	Cdc2	297	M
	Cdk2		298	G1, S, possibly M
	Cdk4		301	G1
	Cdk6		326	G1

A list of CDKs with their regulator protein, cyclin or other.

CDK1
Cdk1
Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....

; cyclin A
Cyclin A
Cyclin A is a member of the cyclin family.Cyclin A binds to S phase Cdk2 and is required for the cell to progress through the S phase. Cyclin A/ Cdk2 is inhibited by the complex p21CIP.-External links:*...

, cyclin B
Cyclin B
Cyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B...
CDK2
Cyclin-dependent kinase 2
Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...

; cyclin A
Cyclin A
Cyclin A is a member of the cyclin family.Cyclin A binds to S phase Cdk2 and is required for the cell to progress through the S phase. Cyclin A/ Cdk2 is inhibited by the complex p21CIP.-External links:*...

, cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....

; cyclin C
CDK4; cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...

, cyclin D2
Cyclin D2
G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene.-Further reading:...

, cyclin D3
CDK5; CDK5R1
CDK5R1
Cyclin-dependent kinase 5 activator 1 is an enzyme that in humans is encoded by the CDK5R1 gene.-Interactions:CDK5R1 has been shown to interact with CDK5RAP2, Beta-catenin, Cyclin-dependent kinase 5, Amphiphysin, Protein SET, CAMK2A, Actinin, alpha 1 and PCTK1.-Further reading:...

, CDK5R2
CDK5R2
Cyclin-dependent kinase 5 activator 2 is an enzyme that in humans is encoded by the CDK5R2 gene.-Interactions:CDK5R2 has been shown to interact with Actinin, alpha 1.-Further reading:...

. See also CDKL5
CDKL5
CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 that is essential for normal brain development. Although little is known about the protein's function, it may play a role in regulating the activity of...

.
CDK6; cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...

, cyclin D2
Cyclin D2
G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene.-Further reading:...

, cyclin D3
CDK7; cyclin H
Cyclin H
Cyclin-H is a protein that in humans is encoded by the CCNH gene.-Interactions:Cyclin H has been shown to interact with P53, Cyclin-dependent kinase 7 and MNAT1.-Further reading:...

; cyclin C
CDK9
CDK9
CDK9 or cyclin-dependent kinase 9 is a cyclin-dependent kinase associated with P-TEFb.CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle...

; cyclin T1, cyclin T2a, cyclin T2b, cyclin K
Cyclin K
Cyclin-K is a protein that in humans is encoded by the CCNK gene.-Further reading:...
CDK11 ; cyclin L
CDK12 ; cyclin L
CDK13 ; cyclin L

Regulation of CDK activity

CDK levels remains relatively constant throughout the cell cycle and most regulation is post-translational. Most knowledge of CDK structure and function is based on CDKs of S. pombe (Cdc2), S. cerevisiae (CDC28), and vertebrates (CDC2 and CDK2). The four major mechanisms of CDK regulation are cyclin binding, CAK

CDK-activating kinase

CDK-activating kinase activates the cyclin-CDK complex by phosphorylating threonine residue 160 in the CDK activation loop....

phosphorylation, regulatory inhibitory phosphorylation, and binding of CDK inhibitory subunits (CKIs).

Cyclin binding

The active site, or ATP-binding site, of all kinases is a cleft between a small amino-terminal lobe and a larger carboxy-terminal lobe. The structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding. Phosphorylation by CDK-activating kinase (CAK) at Thr 161 on the T-loop increases the complex activity. Without cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, and the position of several key amino acid residues is not optimal for ATP-binding. With cyclin, two alpha helices change position to permit ATP binding. One of them, the L12 helix that comes just before the T-loop in the primary sequence, becomes a beta strand and helps rearrange the T-loop, so it no longer blocks the active site. The other alpha helix called the PSTAIRE helix rearranges and helps changes the position of the key amino acid residues in the active site.

There is considerable specificity in which cyclin binds with CDK. Furthermore, cyclin binding determines the specificity of the cyclin-CDK complex for particular substrates. Cyclins can directly bind the substrate or localize the Cdk to a subcellular area where the substrate is found. Substrate specificity of S cyclins is imparted by the hydrophobic batch (centered on the MRAIL sequence), which has affinity for substrate proteins that contain a hydrophobic RXL (or Cy) motif. Cyclin B1 and B2 can localize Cdk1 to the nucleus and the Golgi, respectively, through a localization sequence outside the Cdk-binding region.

Phosphorylation

Full kinase

Kinase

In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...

activity requires an activating phosphorylation

Phosphorylation

Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

on a threonine

Threonine

Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...

adjacent to the active site

Active site

In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...

. The identity of the CDK-activating kinase (CAK) that performs this phosphorylation varies across the model organisms. The timing of this phosphorylation varies as well. In mammalian cells, the activating phosphorylation occurs after cyclin binding. In yeast cells, it occurs before cyclin binding. CAK activity is not regulated by known cell-cycle pathways and cyclin binding is the limiting step for CDK activation.

Unlike activating phosphorylation, CDK inhibitory phosphorylation is vital for regulation of the cell cycle. Various kinases and phosphatases regulate their phosphorylation state. One of the kinases that place the tyrosine phosphate is Wee1

Wee1

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe . It has a molecular mass of 96 kDa and it is a key regulator of cell cycle progression....

, a kinase conserved in all eukaryotes. Fission yeast also contains a second kinase Mik1 that can phosphorylate the tyrosine. Vertebrates contain a different second kinase called Myt1 that is related to Wee1

Wee1

but can phosphorylate both the threonine and the tyrosine. Phosphatases from the Cdc25

Cdc25

Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...

family dephosphorylate both the threonine and the tyrosine.

CDK Inhibitors

A cyclin-dependent kinase inhibitor

Cyclin-dependent kinase inhibitor protein

A cyclin-dependent kinase inhibitor protein is a protein which inhibits cyclin-dependent kinase. Several function as tumor suppressor genes. Cell cycle progression is negatively controlled by cyclin-dependent kinases inhibitors . CDIs are involved in cell cycle arrest at the G1 phase.-Examples:...

(CKI) is a protein that interacts with a cyclin-CDK complex to block kinase activity, usually during G1 or in response to signals from the environment or from damaged DNA. In animal cells, there are two major CKI families: the INK4 family and the Cip/Kip family. The INK4 family proteins are strictly inhibitory and bind CDK monomers. Crystal structures of CDK6-INK4 complexes show that INK4 binding twists the CDK to distort cyclin binding and kinase activity. The Cip/Kip family proteins bind both the cyclin and the CDK of a complex and can be inhibitory or activating. Cip/Kip proteins activate cyclin D and CDK4 or CDK6 complexes by enhancing complex formation.

In yeast and Drosophila, CKIs are strong inhibitors of S- and M-CDK, but do not inhibit G1/S-CDKs. During G1, high levels of CKIs prevent cell cycle events from occurring out of order, but do not prevent transition through the Start checkpoint, which is initiated through G1/S-CDKs. Once the cell cycle is initiated, phosphorylation by early G1/S-CDKs leads to destruction of CKIs, relieving inhibition on later cell cycle transitions. In mammalian cells, the CKI regulation works differently. Mammalian protein p27 (Dacapo in Drosophila) inhibits G1/S- and S-CDKs, but does not inhibits S- and M-CDKs.

Suk1 or Cks

The CDKs directly involved in the regulation of the cell cycle associate with small, 9- to 13-kiloDalton proteins called Suk1 or Cks. These proteins are required for CDK function, but their precise role is unknown.
Cks1 binds the carboxy lobe of the Cdk, and recognizes phosphorylated residues. It may help the cyclin-CDK complex with substrates that have multiple phosphorylation sites by increasing affinity for the substrate.

Viral Cyclins

Viruses can encode proteins with sequence homology to cyclins. One much-studied example is K-cyclin (or v-cyclin) from Kaposi sarcoma herpes virus (see Kaposi’s sarcoma), which activates CDK6. Viral cyclin-CDK complexes have different substrate specificities and regulation sensitivities.

CDK5 Activators

The proteins p35 and p39 activate CDK5. Although they lack cyclin sequence homology, crystals structures show that p35 folds in a similar way as the cyclins. However, activation of CDK5 does not require activation loop phosphorylation.

RINGO/Speedy

Proteins with no homology to the cyclin family can be direct activators of CDKs. One family of such activators is the RINGO/Speedy family, which was originally discovered in Xenopus. All five members discovered so far directly activate Cdk1 and Cdk2, but the RINGO/Speedy-CDK2 complex recognizes different substrates than cyclin A-CDK2 complex.

History

Leland H. Hartwell

Leland Harrison Hartwell is former president and director of the Fred Hutchinson Cancer Research Center in Seattle, Washington. He shared the 2001 Nobel Prize in Physiology or Medicine with Paul Nurse and R...

, R. Timothy Hunt, and Paul M. Nurse received the 2001 Nobel Prize in Physiology or Medicine

Nobel Prize in Physiology or Medicine

The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

for their complete description of cyclin

Cyclin

Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...

and cyclin-dependent kinase mechanisms, which are central to the regulation of the cell cycle.

Medical significance

CDKs are considered a potential target for anti-cancer medication. If it is possible to selectively interrupt the cell cycle regulation in cancer cells by interfering with CDK action, the cell will die. At present, some CDK inhibitor

CDK inhibitor

A CDK inhibitor is a chemical that inhibits the function of CDKs. It is used to treat cancers by preventing overproliferation of cancer cells...

s such as Seliciclib

Seliciclib

R-roscovitine is a trial drug in the family of pharmacological cyclin-dependent kinase inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells...

are undergoing clinical trials. Although it was originally developed as a potential anti-cancer drug, in recent laboratory tests Seliciclib has also proven to induce apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

in neutrophil granulocytes, which mediate inflammation

Inflammation

Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

. This means that novel drugs for treatment of chronic

Chronic (medicine)

A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...

inflammation diseases such as arthritis

Arthritis

Arthritis is a form of joint disorder that involves inflammation of one or more joints....

and cystic fibrosis

Cystic fibrosis

Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...

could be developed.

Flavopiridol (Alvocidib

Alvocidib

Alvocidib is a cyclin-dependent kinase inhibitor under clinical development for the treatment of chronic lymphocytic leukemia. It has been studied also for the treatment of arthritis and atherosclerotic plaque formation...

) is the first CDK inhibitor to be tested in clinical trials after being identified in an anti-cancer agent screen in 1992. It competes for the ATP site of the CDKs.

More research is required, however, because disruption of the CDK-mediated pathway has potentially serious consequences; while CDK inhibitors seem promising, it has to be determined how side-effects can be limited so that only target cells are affected. As such diseases are currently treated with glucocorticoid

Glucocorticoid

Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...

s, which have often serious side-effects, even a minor success would mean an improvement.

Complications of developing a CDK drug include the fact that many CDKs are not involved in the cell cycle such as transcription, viral infection, neural physiology, and glucose homeostatsis.

Table 4: Cyclin-dependent kinase inhibitor drugs

Drug	CDKs Inhibited
Flavopiridol (Alvocidib Alvocidib Alvocidib is a cyclin-dependent kinase inhibitor under clinical development for the treatment of chronic lymphocytic leukemia. It has been studied also for the treatment of arthritis and atherosclerotic plaque formation... )	1, 2, 4, 6, 7, 9
Olomoucine	1, 2, 5
Roscovitine	1, 2, 5
Purvalanol	1, 2, 5
Paullones	1, 2, 5
Butryolactone	1, 2, 5
Thio/oxoflavopiridols	1
Oxindoles	2
Aminothiazoles	4
Benzocarbazoles	4
Pyrimidines	4
Seliciclib Seliciclib R-roscovitine is a trial drug in the family of pharmacological cyclin-dependent kinase inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells...	?

External links

KEGG - Human Cell Cycle

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