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Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''CDK2''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. The
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
encoded by this gene is a member of the
cyclin-dependent kinase 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 a ...
family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of ''
S. cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have bee ...
''
cdc28 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 th ...
, and ''
S. pombe ''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 meas ...
'' cdc2, also known as
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 th ...
in humans. It is a catalytic subunit of the
cyclin-dependent kinase 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 a ...
complex, whose activity is restricted to the G1-S phase of 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 subs ...
, 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 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 p27 ...
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 In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
. 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.


Dispensability in normally functioning tissue

Original cell-culture based experiments demonstrated cell cycle arrest at the G1-S transition resulting from the deletion of Cdk2. Later experiments showed that Cdk2 deletions lengthened the G1 phase of the cell cycle in mouse embryo fibroblasts. However, they still entered
S phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
after this period and were able to complete the remaining phases of the cell cycle. When Cdk2 was deleted in mice, the animals remained viable despite a reduction in body size. However, meiotic function of both male and female mice was inhibited. This suggests that Cdk2 is non-essential for the cell cycle of healthy cells, but essential for
meiosis Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
and reproduction. Cells in Cdk2 knockout mice likely undergo fewer divisions, contributing to the reduction in body size. Germ cells also stop dividing at prophase of meiosis, leading to reproductive sterility. Cdk1 is now believed to compensate for many aspects of Cdk2 deletion, except for meiotic function.


Mechanism of activation

Cyclin-dependent kinase 2 is structured in two lobes. The lobe beginning at the N-terminus (N-lobe) contains many beta sheets, while the C-terminus lobe (C-lobe) is rich in alpha helices. Cdk2 is capable of binding to many different cyclins, including cyclins A, B, E, and possibly C. Recent studies suggest Cdk2 binds preferentially to cyclins A and E, while Cdk1 prefers cyclins A and B. Cdk2 becomes active when a cyclin protein (either A or E) binds at the active site located between the N and C lobes of the kinase. Due to the location of the active site, partner cyclins interact with both lobes of Cdk2. Cdk2 contains an important alpha helix located in the C lobe of the kinase, called the C-helix or the PSTAIRE-helix. Hydrophobic interactions cause the C-helix to associate with another helix in the activating cyclin. Activation induces a conformational change where the helix rotates and moves closer to the N-lobe. This allows the glutamic acid located on the C-helix to form an ion pair with a nearby lysine side chain. The significance of this movement is that it brings the side chain of Glu 51, which belongs to a triad of catalytic site residues conserved in all eukaryotic kinases, into the catalytic site. This triad (Lys 33, Glu 51 and Asp 145) is involved in ATP phosphate orientation and magnesium coordination, and is thought to be critical for catalysis. This conformational change also relocates 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 rang ...
to the C-lobe, revealing the ATP binding site now available for new interactions. Finally, the Threonine-160 residue is exposed and phosphorylated as the C-lobe activation segment is displaced from the catalytic site and the threonine residue is no longer sterically hindered. The phosphorylated threonine residue creates stability in the final enzyme conformation. It is important to note that throughout this activation process, cyclins binding to Cdk2 do not undergo any conformational change.


Role in DNA replication

The success of the cell division process is dependent on the precise regulation of processes at both cellular and tissue levels. Complex interactions between proteins and DNA within the cell allow genomic DNA to be passed to daughter cells. Interactions between cells and extracellular matrix proteins allow new cells to be incorporated into existing tissues. At the cellular level, the process is controlled by different levels of
cyclin-dependent kinase 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 a ...
s (Cdks) and their partner cyclins. Cells utilize various checkpoints as a means of delaying cell cycle progression until it can repair defects. Cdk2 is active during G1 and S phase of the cell cycle, and therefore acts as a G1-S phase checkpoint control. Prior to G1 phase, levels of Cdk4 and Cdk6 increase along with cyclin D. This allows for the partial phosphorylation of Rb, and partial activation of E2F at the beginning of G1 phase, which promotes cyclin E synthesis and increased Cdk2 activity. At the end of G1 phase, the Cdk2/Cyclin E complex reaches maximum activity and plays a significant role in the initiation of S phase. Other non-Cdk proteins also become active during the G1-S phase transition. For example, the
retinoblastoma Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively fo ...
(Rb) and p27 proteins are phosphorylated by Cdk2 – cyclin A/E complexes, fully deactivating them. This allows E2F transcription factors to express genes that promote entry into S phase where DNA is replicated prior to division. Additionally, NPAT, a known substrate of the Cdk2-Cyclin E complex, functions to activate histone gene transcription when phosphorylated. This increases the synthesis of histone proteins (the major protein component of chromatin), and subsequently supports the DNA replication stage of the cell cycle. Finally, at the end of S phase, the ubiquitin proteasome degrades cyclin E.


Cancer cell proliferation

Although Cdk2 is mostly dispensable in the cell cycle of normally functioning cells, it is critical to the abnormal growth processes of cancer cells. The CCNE1 gene produces cyclin E, one of the two major protein binding partners of Cdk2. Overexpression of CCNE1 occurs in many tumor cells, causing the cells to become dependent on Cdk2 and cyclin E. Abnormal cyclin E activity is also observed in breast, lung, colorectal, gastric, and bone cancers, as well as in leukemia and lymphoma. Likewise, abnormal expression of cyclin A2 is associated with chromosomal instability and tumor proliferation, while inhibition leads to decreased tumor growth. Therefore, CDK2 and its cyclin binding partners represent possible therapeutic targets for new cancer therapeutics. Pre-clinical models have shown preliminary success in limiting tumor growth, and have also been observed to reduce side effects of current chemotherapy drugs. Identifying selective Cdk2 inhibitors is difficult due to the extreme similarity between the active sites of Cdk2 and other Cdks, especially Cdk1. Cdk1 is the only essential cyclin dependent kinase in the cell cycle, and inhibition could lead to unintended side effects. Most CDK2 inhibitor candidates target the ATP binding site and can be divided into two main subclasses: type I and type II. Type I inhibitors competitively target the ATP binding site in its active state. Type II inhibitors target CDK2 in its unbound state, either occupying the ATP binding site or hydrophobic pocket within the kinase. Type II inhibitors are believed to be more selective. Recently, the availability of new CDK crystal structures led to the identification of a potential allosteric binding site near the C-helix. Inhibitors of this allosteric site are classified as type III inhibitors. Another possible target is the T-loop of CDK2. When cyclin A binds to CDK2, the N-terminal lobe rotates to activate the ATP binding site and switch the position of the activation loop, called the T-loop.


Inhibitors

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. Known CDK inhibitors are p21Cip1 (
CDKN1A p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
) and p27Kip1 (
CDKN1B Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the ''Cip/Kip'' family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded prot ...
). Drugs that inhibit Cdk2 and arrest the cell cycle, such as GW8510 and the experimental cancer drug
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 ...
, may reduce the sensitivity of the epithelium to many cell cycle-active antitumor agents and, therefore, represent a strategy for prevention of chemotherapy-induced
alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarri ...
. Rosmarinic acid methyl ester is a plant-derived Cdk2 inhibitor, which was shown to suppress proliferation of vascular smooth muscle cells and to reduce
neointima Neointima typically refers to scar tissue that forms within tubular anatomical structures such as blood vessels, as the intima is the innermost lining of these structures. Neointima can form as a result of vascular surgery such as angioplasty ...
formation in mouse
restenosis Restenosis is the recurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and s ...
model. See also the PDB gallery below showing interactions with many inhibitors (inc Purvalanol B)


Gene regulation

In
melanocytic Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and heart. ...
cell types, expression of the CDK2 gene is regulated by the
Microphthalmia-associated transcription factor Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene. MITF is a basic helix-loop-helix leucine zipper transcription factor ...
.


Interactions

Cyclin-dependent kinase 2 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
, *
CDK2AP1 Cyclin-dependent kinase 2-associated protein 1 is an enzyme that in humans is encoded by the ''CDK2AP1'' gene. Function The protein encoded by this gene is a specific CDK2-associated protein, which is thought to negatively regulate CDK2 activit ...
, *
CDKN1B Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the ''Cip/Kip'' family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded prot ...
*
CDKN3 Cyclin-dependent kinase inhibitor 3 is an enzyme that in humans is encoded by the ''CDKN3'' gene. The protein encoded by this gene belongs to the dual specificity protein phosphatase family. It was identified as a cyclin-dependent kinase inhibito ...
, * CEBPA, *
Cyclin A1 Cyclin-A1 is a protein that in humans is encoded by the ''CCNA1'' 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 E1 G1/S-specific cyclin-E1 is a protein that in humans is encoded by the ''CCNE1'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protei ...
, *
Flap structure-specific endonuclease 1 Flap endonuclease 1 is an enzyme that in humans is encoded by the ''FEN1'' gene. Function The protein encoded by this gene removes 5' overhanging "flaps" (or short sections of single stranded DNA that "hang off" because their nucleotide bases a ...
, *
ORC1L Origin recognition complex subunit 1 is a protein that in humans is encoded by the ORC1 gene. It is closely related to CDC6, and both are the same protein in archaea. Function The origin recognition complex (ORC) is a highly conserved six sub ...
, *
P21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
, * PPM1B, *
PPP2CA Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform is an enzyme that (in humans) is encoded by the ''PPP2CA'' gene. Function This gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is one of the fou ...
, *
Retinoblastoma-like protein 1 Retinoblastoma-like 1 (p107), also known as RBL1, is a protein that in humans is encoded by the ''RBL1'' gene. Function The protein encoded by this gene is similar in sequence and possibly function to the product of the retinoblastoma 1 ( RB1 ...
, *
Retinoblastoma-like protein 2 Retinoblastoma-like protein 2 is a protein that in humans is encoded by the ''RBL2'' gene. Interactions Retinoblastoma-like protein 2 has been shown to interact with: * BRCA1, * BRF1 * C-Raf, * Cyclin E1, * Cyclin-dependent kinase 2, ...
, and *
SKP2 S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the ''SKP2'' gene. Structure and function Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-1 ...
.


References


Further reading

* *


External links

* * * {{DEFAULTSORT:Cyclin-dependent kinase 02 Cell cycle Proteins EC 2.7.11 Cell cycle regulators