Cyclin-dependent kinases (CDKs) are the families of
protein kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s first discovered for their role in regulating the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
. They are also involved in regulating
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
, 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
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constit ...
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
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
sequence of a CDK substrate is
/T*X
/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.
Types
CDKs and cyclins in the cell cycle
Most of the known cyclin-CDK complexes regulate the progression through the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
. 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, CDK7, is involved indirectly as the CDK-activating kinase.
Cyclin-CDK complexes phosphorylate substrates appropriate for the particular cell cycle phase.
Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase.
A list of CDKs with their regulator protein, cyclin or other:
*
CDK1
Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in t ...
;
cyclin A
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 ce ...
,
cyclin B
Cyclin B is a member of the cyclin family. Cyclin B is a mitotic cyclin. The amount of cyclin B (which binds to Cdk1) and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degra ...
*
CDK2
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 ...
;
cyclin A
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 ce ...
,
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 of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27K ...
*;
cyclin C
Cyclin-C is a protein that in humans is encoded by the ''CCNC'' gene.
The protein encoded by this gene is a member of the cyclin family of proteins. The encoded protein interacts with cyclin-dependent kinase 8 and induces the phosphorylation of t ...
*
CDK4;
cyclin D1,
cyclin D2
G1/S-specific cyclin-D2 is a protein that in humans is encoded by the ''CCND2'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in prot ...
,
cyclin D3
G1/S-specific cyclin-D3 is a protein that in humans is encoded by the ''CCND3'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein ...
*
CDK5
Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS).
The molecule belongs ...
;
CDK5R1
Cyclin-dependent kinase 5 activator 1 is an enzyme that in humans is encoded by the ''CDK5R1'' gene.
Function
The protein encoded by this gene (p35) is a neuron-specific activator of cyclin-dependent kinase 5 (CDK5); the activation of CDK5 is ...
,
CDK5R2
Cyclin-dependent kinase 5 activator 2 is an enzyme that in humans is encoded by the ''CDK5R2'' gene.
The protein encoded by this gene is a neuron-specific activator of CDK5 kinase. It associates with CDK5 to form an active kinase. This protein an ...
. See also
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 (STK9) that is essential for normal brain development. Mutations in the gene can cause deficiencies in t ...
.
*
CDK6
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 th ...
;
cyclin D1,
cyclin D2
G1/S-specific cyclin-D2 is a protein that in humans is encoded by the ''CCND2'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in prot ...
,
cyclin D3
G1/S-specific cyclin-D3 is a protein that in humans is encoded by the ''CCND3'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein ...
*
CDK7
Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the ''CDK7'' gene.
The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are h ...
;
cyclin H
Cyclin-H is a protein that in humans is encoded by the ''CCNH'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throu ...
*;
cyclin C
Cyclin-C is a protein that in humans is encoded by the ''CCNC'' gene.
The protein encoded by this gene is a member of the cyclin family of proteins. The encoded protein interacts with cyclin-dependent kinase 8 and induces the phosphorylation of t ...
*
CDK9
Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.
Function
The protein encoded by this gene is a member of the cyclin-dependent kinase (CDK) family. CDK family members are highly similar to the gene produc ...
;
cyclin T1
Cyclin-T1 is a protein that in humans is encoded by the ''CCNT1'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance thro ...
,
cyclin T2a,
cyclin T2b
Cyclin is a Protein family, family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle.
Etymology
Cyclins were ...
,
cyclin K
*
* CDK11 () ;
cyclin L
*
CDK12;
cyclin L
* CDK13 () ;
cyclin L
Regulation of activity
CDK levels remain 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 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
In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs ran ...
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 change 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 activity requires an activating
phosphorylation on a
threonine adjacent to the CDK's
active site.
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 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast ''Schizosaccharomyces pombe'' (''S. pombe'')Wee1has a molecular mass of 96 kDa and is a key regulator of cell cycle progression.
It influences ...
, a kinase conserved in all eukaryotes.
Fission yeast
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically m ...
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 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast ''Schizosaccharomyces pombe'' (''S. pombe'')Wee1has a molecular mass of 96 kDa and is a key regulator of cell cycle progression.
It influences ...
but can phosphorylate both the threonine and the tyrosine.
Phosphatases from the
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 or genes such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell divis ...
family dephosphorylate both the threonine and the tyrosine.
CDK inhibitors
A
cyclin-dependent kinase inhibitor
A cyclin-dependent kinase inhibitor protein is a protein which inhibits the enzyme cyclin-dependent kinase (CDK). Several function as tumor suppressor proteins. Cell cycle
The cell cycle, or cell-division cycle, is the series of events t ...
(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 family 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 inhibit S- and M-CDKs.
Based on molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms. Analysis of MD simulations and MM-PBSA studies, revealed the binding energy profiles of all the selected complexes. Selected ligands performed better than the experimental drug candidate (Roscovitine). Ligands-3 and 14 show specificity for CDK7 and Ligands-5 and 16 were specific against CDK9. These ligands are expected to possess lower risk of side effects due to their natural origin.
Interpretation of dynamic simulations and binding free energy studies unveiled that Ligand2 (Out of 17 in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds) has a stable and equivalent free energy to Flavopiridol, SU9516, and CVT-313 inhibitors. Ligand2 scrutinized as a selective inhibitor of CDK2 without off-target binding (CDK1 and CDK9) based on ligand efficiency and binding affinity.
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.
Non-cyclin activators
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
Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limit ...
), 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, crystal 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 (Lee) Hartwell (born October 30, 1939 in Los Angeles, California) 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 wit ...
,
R. Timothy Hunt, and
Paul M. Nurse
Sir Paul Maxime Nurse (born 25 January 1949) is an English geneticist, former President of the Royal Society and Chief Executive and Director of the Francis Crick Institute. He was awarded the 2001 Nobel Prize in Physiology or Medicine along ...
received the 2001
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
for their complete description of
cyclin and cyclin-dependent kinase mechanisms, which are central to the regulation of the cell cycle.
Medical significance
Diseases of CDK
As drug targets
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
A CDK (cyclin-dependent kinase) inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), ...
s such as
seliciclib
Seliciclib (roscovitine or CYC202) is an experimental drug candidate in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the gro ...
are undergoing clinical trials. Although it was originally developed as a potential anti-cancer drug, seliciclib has also proven to induce
apoptosis in
neutrophil granulocytes, which mediate
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
. This means that novel drugs for treatment of
chronic inflammation diseases such as
arthritis and
cystic fibrosis could be developed.
Flavopiridol (
alvocidib) 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. Palbociclib and abemaciclib have been approved for the management of hormone receptor (estrogen receptor/progestogen receptor) expressing metastatic breast cancer in combination with endocrine therapy.
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
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...
s, which have often serious side-effects, even a minor success would be an improvement.
Complications of developing a CDK drug include the fact that many CDKs are not involved in the cell cycle, but other processes such as transcription, neural physiology, and glucose homeostasis.
References
Further reading
*
External links
*
*
KEGG – Human Cell Cycle
{{DEFAULTSORT:Cyclin-Dependent Kinase
Cell cycle regulators
Protein families
EC 2.7.11