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[[File:Cyclin-dependent kinase structure.pdf|thumb|Tertiary structure of human Cdk2, determined by X-ray crystallography. Like other protein kinases, Cdk2 is composed of two lobes: a smaller amino-terminal lobe (top) that is composed primarily of beta sheet and the PSTAIRE helix, and a large carboxy-terminal lobe (bottom) that is primarily made up of alpha helices. The ATP substrate is shown as a ball-and-stick model, located deep within the active-site cleft between the two lobes. The phosphates are oriented outward, toward the mouth of the cleft, which is blocked in this structure by the T-loop (highlighted in green). (PDB 1hck)]]
[[File:Cyclin-dependent kinase structure.pdf|thumb|Tertiary structure of human Cdk2, determined by X-ray crystallography. Like other protein kinases, Cdk2 is composed of two lobes: a smaller amino-terminal lobe (top) that is composed primarily of beta sheet and the PSTAIRE helix, and a large carboxy-terminal lobe (bottom) that is primarily made up of alpha helices. The ATP substrate is shown as a ball-and-stick model, located deep within the active-site cleft between the two lobes. The phosphates are oriented outward, toward the mouth of the cleft, which is blocked in this structure by the T-loop (highlighted in green). (PDB 1hck)]]
[[File:Cell Cycle 3.png|alt=|thumb|Schematic of the cell cycle. outer ring: I = [[Interphase]], M = [[Mitosis]]; inner ring: M = Mitosis; G1 = [[G1 phase|Gap phase 1]]; S = [[S phase|Synthesis]]; G2 = [[G2 phase|Gap phase 2]].]]
[[File:Cell Cycle 3.png|alt=|thumb|Schematic of the cell cycle. outer ring: I = [[Interphase]], M = [[Mitosis]]; inner ring: M = Mitosis; G1 = [[G1 phase|Gap phase 1]]; S = [[S phase|Synthesis]]; G2 = [[G2 phase|Gap phase 2]].]]
'''Cyclin-dependent kinases (CDKs)''' are a predominant group of serine/threonine protein kinases involved in the regulation of the [[cell cycle]] and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals.<ref name=":0">{{cite journal |last1=Ding |first1=Lei |last2=Jiaqi |first2=Cao |last3=Wen |first3=Lin |last4=Hongijan |first4=Chen |last5=Xianhui |first5=Xiong |last6=Hongshun |first6=Ao |last7=Min |first7=Yu |last8=Jie |first8=Lin |last9=Qinghua |first9=Cui |date=2020 |title=The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer |journal=International journal of molecular sciences |volume=21 |issue=6 |doi=10.3390/ijms21061960}}</ref> <ref name=":1">{{Cite journal |last=Hives |first=Mark |last2=Jurecekova |first2=Jana |last3=Holeckova |first3=Klaudia Hives |last4=Kliment |first4=Jan |last5=Sivonova |first5=Monika Kmetova |date=2023 |title=The driving power of the cell cycle: cyclin-dependent kinases, cyclins and their inhibitors |url=https://pubmed.ncbi.nlm.nih.gov/36598318/ |journal=Bratislavske Lekarske Listy |volume=124 |issue=4 |pages=261–266 |doi=10.4149/BLL_2023_039 |issn=0006-9248 |pmid=36598318}}</ref> They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved.<ref>{{Cite journal |last=S |first=Gokul Babu |last2=Gohil |first2=Deependra Singh |last3=Roy Choudhury |first3=Swarup |date=2023-01-19 |title=Genome-wide identification, evolutionary and expression analysis of the cyclin-dependent kinase gene family in peanut |url=https://doi.org/10.1186/s12870-023-04045-w |journal=BMC Plant Biology |volume=23 |issue=1 |pages=43 |doi=10.1186/s12870-023-04045-w |issn=1471-2229 |pmc=PMC9850575 |pmid=36658501}}</ref> <ref name=":2">{{Cite book |last=O Morgan |first=David |title=The Cell Cycle: Principles of Control |publisher=New Science Press Ltd |year=2007 |isbn=978-0-9539181-2-6 |location=London |pages=2-54, 196-266}}</ref> The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. [[Cyclin|Cyclins]] have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex.<ref name=":3">{{Cite book |last=Alberts |first=Bruce |title=Essential Cell Biology |last2=Hopkin |first2=Karen |last3=Johnson |first3=Alexander |last4=Morgan |first4=David |last5=Raff |first5=Martin |last6=Roberts |first6=Keith |last7=Walter |first7=Peter |publisher=[[W. W. Norton & Company]] |year=2019 |isbn=9780393679533 |edition=5th |pages=613-627}}</ref><ref name=":4">{{Cite journal |last=Łukasik |first=Paweł |last2=Załuski |first2=Michał |last3=Gutowska |first3=Izabela |date=2021-03-13 |title=Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development–Review |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998717/ |journal=[[International Journal of Molecular Sciences]] |volume=22 |issue=6 |pages=2935 |doi=10.3390/ijms22062935 |issn=1422-0067 |pmc=7998717 |pmid=33805800}}</ref> CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions.<ref name=":5">{{Cite journal |last=Malumbres |first=Marcos |date=2014-06-30 |title=Cyclin-dependent kinases |url=https://doi.org/10.1186/gb4184 |journal=Genome Biology |volume=15 |issue=6 |pages=122 |doi=10.1186/gb4184 |issn=1474-760X}}</ref> Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke. <ref name=":4" />
'''Cyclin-dependent kinases''' ('''CDKs''') are the families of [[protein kinase]]s first discovered for their role in regulating the [[cell cycle]]. They are also involved in regulating [[transcription (genetics)|transcription]], mRNA processing, and the differentiation of nerve cells.<ref name = "Morgan2007">{{cite book | vauthors = Morgan DO | year = 2007 | title = The Cell Cycle: Principles of Control | location = London | publisher = New Science Press | edition = 1st | isbn = 978-0-87893-508-6 }}</ref> 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.<ref name = "Morgan2007" /><ref>{{cite journal | vauthors = Lee MG, Nurse P | title = Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2 | journal = Nature | volume = 327 | issue = 6117 | pages = 31–5 | year = 1987 | pmid = 3553962 | doi = 10.1038/327031a0 | bibcode = 1987Natur.327...31L | s2cid = 4300190 }}</ref> CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the [[Kinase|kinase domain]].<ref name = "Morgan2007" /> 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 [[CDKN1B|p27]]. CDKs phosphorylate their substrates on serines and threonines, so they are [[Serine/threonine-specific protein kinase|serine-threonine kinases]].<ref name = "Morgan2007" /> 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]].<ref name = "Morgan2007" />


== Evolutionary history ==
==Types==
CDKs were initially identified through studies in model organisms such as yeasts and frogs, underscoring their pivotal role in cell cycle progression. These enzymes operate by forming complexes with cyclins, whose levels fluctuate throughout the cell cycle, thereby ensuring timely cell cycle transitions. Over the years, the understanding of CDKs has expanded beyond cell division to include roles in gene transcription integration of cellular signals.<ref name=":5" /> <ref>{{Cite journal |last=Barberis |first=Matteo |date=2021-12-13 |title=Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast |url=https://www.nature.com/articles/s41540-021-00201-w |journal=npj Systems Biology and Applications |language=en |volume=7 |issue=1 |pages=1–11 |doi=10.1038/s41540-021-00201-w |issn=2056-7189}}</ref>


The evolutionary journey of CDKs has led to a diverse family with specific members dedicated to cell cycle phases or transcriptional control. For instance, budding yeast expresses six distinct CDKs, with some binding multiple cyclins for cell cycle control and others binding with a single cyclin for transcription regulation. In humans, the expansion to 20 CDKs and 29 cyclins illustrates their complex regulatory roles. Key CDKs such as CDK1 are indispensable for cell cycle control, while others like CDK2 and CDK3 are not. Moreover, transcriptional CDKs, such as CDK7 in humans, play crucial roles in initiating transcription by phosphorylating RNA polymerase II (RNAPII), indicating the intricate link between cell cycle regulation and transcriptional management. This evolutionary expansion from simple regulators to multifunctional enzymes underscores the critical importance of CDKs in the complex regulatory networks of eukaryotic cells.<ref name=":5" />
{| class="wikitable"
{| class="wikitable"
|+Table 1: '''Cyclin-dependent kinases that control the cell cycle in model organisms''' <ref name=":2" />
|+ Table 1: Known CDKs, their [[cyclin]] partners, and their functions in the human<ref name = "Morgan1997" /> and consequences of deletion in mice<ref name = "Satyanarayana2009">{{cite journal | vauthors = Satyanarayana A, Kaldis P | title = Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms | journal = Oncogene | volume = 28 | issue = 33 | pages = 2925–39 | date = August 2009 | pmid = 19561645 | doi = 10.1038/onc.2009.170 | s2cid = 3096776 | doi-access = }}</ref>

|-
|-
! Species !! Name !! Original name !! Size (amino acids) !! Function
!CDK !! Cyclin partner !! Function !! Deletion Phenotype in Mice

|-
|-
| ''[[Saccharomyces cerevisiae]]'' || CDK1 || Cdc28 || 298 || All cell-cycle stages
| Cdk1 || [[Cyclin B]] || [[M phase]] || None
|-
|-
| ''[[Schizosaccharomyces pombe]]'' || CDK1 || Cdc2 || 297 || All cell-cycle stages
| Cdk2 || [[Cyclin E]] || G1/S transition || Reduced size, imparted neural progenitor cell proliferation. Viable, but both males & females sterile.
|-
|-
| ''[[Drosophila melanogaster]]'' || CDK1 || Cdc2 || 297 || M
| Cdk2 || [[Cyclin A]] || S phase, G2 phase
|-
|-
| Cdk3 || [[Cyclin C]] || [[G1 phase]]
| || CDK2 || Cdc2c || 314 || G1/S, S, possibly M
|| No defects. Viable, fertile.
|-
|-
| || CDK4 || Cdk4/6 || 317 || G1, promotes growth
| Cdk4 || [[Cyclin D]] || G1 phase || Reduced size, insulin deficient diabetes. Viable, but both male & female infertile.

|}

== CDKs and cyclins in the cell cycle ==

Most of the known cyclin-CDK complexes regulate the progression through the [[cell cycle]]. Animal cells contain at least nine CDKs, four of which, CDK1, 2, 3, and 4, are directly involved in cell cycle regulation.<ref name = "Morgan2007" /> In mammalian cells, CDK1, with its partners cyclin A2 and B1, alone can drive the cell cycle.<ref name = "Satyanarayana2009" /> Another one, CDK7, is involved indirectly as the CDK-activating kinase.<ref name = "Morgan2007" /> Cyclin-CDK complexes phosphorylate substrates appropriate for the particular cell cycle phase.<ref name = "Morgan1997" /> Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase.<ref name = "Morgan2007" />

{| class="wikitable"
|+ Table 2: Cyclins and CDKs by Cell-Cycle Phase
|-
|-
| ''[[Xenopus laevis]]'' || CDK1 || Cdc2 || 301 || M
! Phase !! Cyclin !! CDK
|-
|-
| G0 || C || Cdk3
| || CDK2 || || 297 || S, possibly M
|-
|-
| G1 || D, E || Cdk4, Cdk2, Cdk6
| ''[[Homo sapiens]]'' || CDK1 || Cdc2 || 297 || M
|-
|-
| S || A, E || Cdk2
| || CDK2 || || 298 || G1, S, possibly M
|-
|-
| G2 || A || Cdk2, Cdk1
| || CDK4 || || 301 || G1
|-
|-
| M || B || Cdk1
| || CDK6 || || 326 || G1
|}
|}


== CDKs and cyclins in the cell cycle ==

CDK is one of the estimated 800 human [[Protein kinase|protein kinases]]. CDKs have low molecular weight, and they are known to be inactive by themselves. They are characterized by their dependency on the regulatory subunit, cyclin. The activation of CDKs also requires post-translational modifications involving phosphorylation reactions. This phosphorylation typically occurs on a specific threonine residue, leading to a conformational change in the CDK that enhances its kinase activity.<ref>{{Cite journal |last=Knockaert |first=Marie |last2=Meijer |first2=Laurent |date=2002-09-01 |title=Identifying in vivo targets of cyclin-dependent kinase inhibitors by affinity chromatography |url=https://www.sciencedirect.com/science/article/pii/S0006295202011449 |journal=Biochemical Pharmacology |series=Cell Signaling, Transcription and Translation as Therapeutic Targets |volume=64 |issue=5 |pages=819–825 |doi=10.1016/S0006-2952(02)01144-9 |issn=0006-2952}}</ref> The activation forms a cyclin-CDK complex which phosphorylates specific regulatory proteins that are required to initiate steps in the cell-cycle.<ref name=":3" />

In human cells, the CDK family comprises 20 different members that play a crucial role in the regulation of the cell cycle and transcription. These are usually separated into cell-cycle CDKs, which regulate cell-cycle transitions and cell division, and transcriptional CDKs, which mediate gene transcription. [[Cyclin-dependent kinase 1|CDK1]], [[Cyclin-dependent kinase 2|CDK2]], [[Cyclin-dependent kinase 3|CDK3]], [[Cyclin-dependent kinase 4|CDK4]], [[Cyclin-dependent kinase 6|CDK6]], and [[Cyclin-dependent kinase 7|CDK7]]<nowiki/>are directly related to the regulation of cell-cycle events, while CDK7 – 11 are associated with transcriptional regulation.<ref name=":0" /> Different cyclin-CDK complexes regulate different phases of the cell cycle, known as G0/G1, S, G2, and M phases, featuring several checkpoints to maintain genomic stability and ensure accurate DNA replication.<ref name=":0" /><ref name=":3" /> Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase.<ref name=":2" />
{| class="wikitable"
{| class="wikitable"
|+ Table 3: Cyclin-dependent kinases that control the cell cycle in model organisms<ref name = "Morgan2007" />
|+Table 2: '''Cell-cycle CDKs, their cyclin partners, and their functions in the human''' <ref name=":0" /> <ref name=":4" /> <ref name=":3" />
!CDK
!Cyclin partner
!Established functions
|-
|-
|CDK1
! Species !! Name !! Original name !! Size (amino acids) !! Function
|cyclin B
|-
|M phase transition
| ''[[Saccharomyces cerevisiae]]'' || Cdk1 || Cdc28 || 298 || All cell-cycle stages
|-
| ''[[Schizosaccharomyces pombe]]'' || Cdk1 || Cdc2 || 297 || All cell-cycle stages
|-
| ''[[Drosophila melanogaster]]'' || 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
| || Cdk2 || || 297 || S, possibly M
|cyclin A
|G1/S transition
|-
|-
|CDK2
| ''[[Homo sapiens]]'' || Cdk1 || Cdc2 || 297 || M
|cyclin E
|S/G2 transition
|-
|-
|CDK3
| || Cdk2 || || 298 || G1, S, possibly M
|cyclin C
|G0/G1 and G1/S transitions
|-
|-
|CDK4, CDK6
| || Cdk4 || || 301 || G1
|cyclin D
|G1/S transition. Phosphorylation of retinoblastoma gene product (Rb)
|-
|-
|CDK7
| || Cdk6 || || 326 || G1
|cyclin H
|CAK and RNAPII transcription
|}
|}


== CDK structure and activation ==
'''A list of CDKs with their regulator protein, cyclin or other:'''
Cyclin-dependent kinases (CDKs) mainly consist of a two-lobed configuration, which is characteristic of all kinases in general. CDKs have specific features in their structure that play a major role in their function and regulation.<ref name=":1" />
*[[CDK1]]; [[cyclin A]], [[cyclin B]]
*[[Cyclin-dependent kinase 2|CDK2]]; [[cyclin A]], [[cyclin E]]
*{{Gene|CDK3}}; [[cyclin C]]
*[[CDK4]]; [[cyclin D1]], [[cyclin D2]], [[cyclin D3]]
*[[CDK5]]; [[CDK5R1]], [[CDK5R2]]. See also [[CDKL5]].
*[[CDK6]]; [[cyclin D1]], [[cyclin D2]], [[cyclin D3]]
*[[CDK7]]; [[cyclin H]]
*{{Gene|CDK8}}; [[cyclin C]]
*[[CDK9]]; [[cyclin T1]], [[cyclin T2a]], [[cyclin T2b]], [[cyclin K]]
*{{Gene|CDK10}}
* CDK11 ({{Gene|CDC2L2}}) ; [[cyclin L]]
* [[CDK12]]; [[cyclin L]]
* CDK13 ({{Gene|CDC2L5}}) ; [[cyclin L]]


# '''N-terminal lobe (N-lobe):''' In this part, the inhibitory element known as the glycine-rich G-loop is located. The inhibitory element is found within the beta-sheets in this N-terminal lobe.<ref name=":2" /><ref name=":1" /> Additionally, there is a helix known as the C-helix. This helix contains the PSTAIRE sequence in CDK1. This region plays a crucial role in regulating the binding between cyclin-dependent kinases (CDKs) and cyclins.<ref name=":5" /><ref name=":1" />
==Regulation of activity==
# '''C-terminal lobe (C-lobe):''' This part contains α-helices and the activation segment, which extends from the DFG motif (D145 in CDK2) to the [[Protein kinase#Structural motifs|APE motif]] (E172 in CDK2). This segment also includes a phosphorylation-sensitive residue (T160 in CDK2) in the so-called T-loop. The activation segment in the C-lobe serves as a platform for the binding of the phospho-acceptor Ser/Thr region of substrates.<ref name=":5" /><ref name=":2" /><ref name=":1" />
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, [[CDK-activating kinase|CAK]] phosphorylation, regulatory inhibitory phosphorylation, and binding of CDK inhibitory subunits (CKIs).<ref name = "Morgan1995">{{cite journal | vauthors = Morgan DO | title = Principles of CDK regulation | journal = Nature | volume = 374 | issue = 6518 | pages = 131–4 | date = March 1995 | pmid = 7877684 | doi = 10.1038/374131a0 | bibcode = 1995Natur.374..131M | s2cid = 4323623 }}</ref>


===Cyclin binding===
===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.<ref name = "Morgan2007" /> The structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding.<ref name = "Morgan2007" /> 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.<ref name = "Morgan2007" /> 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.<ref name = "Morgan2007" /> The other alpha helix called the PSTAIRE helix rearranges and helps change the position of the key amino acid residues in the active site.<ref name = "Morgan2007" />
The active site, or [[ATP-binding cassette transporter|ATP-binding site]], in all kinases is a cleft located between a smaller amino-terminal lobe and a larger carboxy-terminal lobe. Research on the structure of human CDK2 has shown that CDKs have a specially adapted ATP-binding site that can be regulated through the binding of cyclin. Phosphorylation by [[CDK-activating kinase|CDK-activating kinase (CAK)]] at Thr160 in the T-loop helps to increase the complex's activity. Without cyclin, a flexible loop known as the activation loop or T-loop blocks the cleft, and the positioning of several key amino acids is not optimal for ATP binding. <ref name=":1" /><ref name=":6">{{Cite journal |last=Li |first=Yan |last2=Zhang |first2=Jingxiao |last3=Gao |first3=Weimin |last4=Zhang |first4=Lilei |last5=Pan |first5=Yanqiu |last6=Zhang |first6=Shuwei |last7=Wang |first7=Yonghua |date=2015 |title=Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2 |url=https://www.mdpi.com/1422-0067/16/5/9314 |journal=International Journal of Molecular Sciences |language=en |volume=16 |issue=5 |pages=9314–9340 |doi=10.3390/ijms16059314 |issn=1422-0067}}</ref> With cyclin, two alpha helices change position to enable ATP binding. One of them, the L12 helix located just before the T-loop in the primary sequence, is transformed into a beta strand and helps to reorganize the T-loop so that it no longer blocks the active site. The other alpha helix, known as the PSTAIRE helix, is reorganized and helps to change the position of the key amino acids in the active site.<ref name=":4" /><ref name=":6" />


There's considerable specificity in which cyclin binds to CDK. Furthermore, the cyclin binding determines the specificity of the cyclin-CDK complex for certain substrates, highlighting the importance of distinct activation pathways that confer cyclin-binding specificity on CDK1. This illustrates the complexity and fine-tuning in the regulation of the cell cycle through selective binding and activation of CDKs by their respective cyclins.<ref>{{Cite journal |last=Merrick |first=Karl A. |last2=Larochelle |first2=Stéphane |last3=Zhang |first3=Chao |last4=Allen |first4=Jasmina J. |last5=Shokat |first5=Kevan M. |last6=Fisher |first6=Robert P. |date=2008-12-05 |title=Distinct activation pathways confer cyclin-binding specificity on Cdk1 and Cdk2 in human cells |url=https://pubmed.ncbi.nlm.nih.gov/19061641/ |journal=Molecular Cell |volume=32 |issue=5 |pages=662–672 |doi=10.1016/j.molcel.2008.10.022 |issn=1097-4164 |pmc=2643088 |pmid=19061641}}</ref><ref name=":7">{{Cite journal |last=Massacci |first=Giorgia |last2=Perfetto |first2=Livia |last3=Sacco |first3=Francesca |date=2023 |title=The Cyclin-dependent kinase 1: more than a cell cycle regulator |url=https://www.nature.com/articles/s41416-023-02468-8 |journal=British Journal of Cancer |language=en |volume=129 |issue=11 |pages=1707–1716 |doi=10.1038/s41416-023-02468-8 |issn=1532-1827}}</ref>
There is considerable specificity in which cyclin binds with CDK.<ref name = "Morgan1997">{{cite journal | vauthors = Morgan DO | title = Cyclin-dependent kinases: engines, clocks, and microprocessors | journal = Annual Review of Cell and Developmental Biology | volume = 13 | pages = 261–91 | year = 1997 | pmid = 9442875 | doi = 10.1146/annurev.cellbio.13.1.261 }}</ref> Furthermore, cyclin binding determines the specificity of the cyclin-CDK complex for particular substrates.<ref name = "Morgan1997" /> 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.<ref name = "Morgan2007" />

Cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. The [[Leucine zipper|RXL-binding site]]  was crucial in revealing how CDKs selectively enhance activity toward specific substrates by facilitating substrate docking.<ref>{{Cite journal |last=Wood |first=Daniel J. |last2=Endicott |first2=Jane A. |date=2018 |title=Structural insights into the functional diversity of the CDK–cyclin family |url=https://royalsocietypublishing.org/doi/10.1098/rsob.180112 |journal=Open Biology |language=en |volume=8 |issue=9 |doi=10.1098/rsob.180112 |issn=2046-2441 |pmc=PMC6170502 |pmid=30185601}}</ref> Substrate specificity of S cyclins is imparted by the hydrophobic batch, which has affinity for substrate proteins that contain a hydrophobic RXL (or Cy) motif.<ref name=":2" /> [[Cyclin B1]] and [[Cyclin B2|B2]] can localize CDK1 to the nucleus and the Golgi, respectively, through a localization sequence outside the CDK-binding region.<ref name=":2" /><ref name=":7" />


===Phosphorylation===
===Phosphorylation===
[[File:Two steps in Cdk activation.pdf|thumb|240x240px|Cyclin binding alone causes partial activation of Cdks, but complete activation also requires activating phosphorylation by a CAK. In animal cells, CAK phosphorylates the Cdk subunit only after cyclin binding, as shown here. Budding yeast contains a different version of CAK that can phosphorylate the Cdk even in the absence of cyclin, and so the two activation steps can occur in either order.]]
[[File:Two steps in Cdk activation.pdf|thumb|240x240px|Cyclin binding alone causes partial activation of Cdks, but complete activation also requires activating phosphorylation by a CAK. In animal cells, CAK phosphorylates the Cdk subunit only after cyclin binding, as shown here. Budding yeast contains a different version of CAK that can phosphorylate the Cdk even in the absence of cyclin, and so the two activation steps can occur in either order.]]To achieve full kinase activity, an activating phosphorylation on a threonine adjacent to the CDK's active site is required.<ref>{{Cite journal |last=Zabihi |first=Mitra |last2=Lotfi |first2=Ramin |last3=Yousefi |first3=Amir-Mohammad |last4=Bashash |first4=Davood |date=2023-04-01 |title=Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities |url=https://doi.org/10.1007/s00432-022-04135-6 |journal=Journal of Cancer Research and Clinical Oncology |language=en |volume=149 |issue=4 |pages=1585–1606 |doi=10.1007/s00432-022-04135-6 |issn=1432-1335}}</ref> The identity of the CDK-activating kinase (CAK) that carries out this phosphorylation varies among different model organisms. The timing of this phosphorylation also varies; in mammalian cells, the activating phosphorylation occurs after cyclin binding, while in yeast cells, it occurs before cyclin binding. CAK activity is not regulated by known cell cycle pathways, and it is the cyclin binding that is the limiting step for CDK activation.<ref name=":2" />
Full [[kinase]] activity requires an activating [[phosphorylation]] on a [[threonine]] adjacent to the CDK's [[active site]].<ref name="Morgan2007" /> The identity of the CDK-activating kinase (CAK) that performs this phosphorylation varies across the model organisms.<ref name="Morgan2007" /> The timing of this phosphorylation varies as well. In mammalian cells, the activating phosphorylation occurs after cyclin binding.<ref name="Morgan2007" /> In yeast cells, it occurs before cyclin binding.<ref name="Morgan2007" /> CAK activity is not regulated by known cell-cycle pathways and cyclin binding is the limiting step for CDK activation.<ref name="Morgan2007" />


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]], a kinase conserved in all eukaryotes.<ref name = "Morgan2007" /> [[Fission yeast]] also contains a second kinase Mik1 that can phosphorylate the tyrosine.<ref name = "Morgan2007" /> Vertebrates contain a different second kinase called Myt1 that is related to Wee1 but can phosphorylate both the threonine and the tyrosine.<ref name = "Morgan2007" /> Phosphatases from the [[Cdc25]] family dephosphorylate both the threonine and the tyrosine.<ref name = "Morgan2007" />
Unlike activating phosphorylation, CDK inhibitory phosphorylation is crucial for cell cycle regulation. Various kinases and phosphatases control their phosphorylation state. For instance, the activity of CDK1 is controlled by the balance between  [[WEE1|WEE1 kinases]], [[MYT1|Myt1 kinases]], and the phosphorylation of  [[CDC25|Cdc25c phosphatases]]. Wee1, a kinase preserved across all eukaryotes, phosphorylates CDK1 at Tyr 15. Myt1 can phosphorylate both the threonine (Thr 14) and the tyrosine (Tyr 15). The phosphorylation is performed by Cdc25c phosphatases, by removing the phosphate groups from both the threonine and the tyrosine.<ref name=":0" /><ref name=":5" />  This inhibitory phosphorylation helps preventing cell-cycle progression in response to events like DNA damage. The phosphorylation does not significantly alter the CDK structure, but reduces its affinity to the substrate, thereby inhibiting its activity. For the cell cycle to progress, these inhibitory phosphates must be removed by the Cdc25 phosphatases to reactivate the CDKs.<ref name=":5" />


===CDK inhibitors===
===CDK inhibitors===


A [[Cyclin-dependent kinase inhibitor protein|cyclin-dependent kinase inhibitor]] (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.<ref name = "Morgan2007" /> In animal cells, there are two major CKI families: the [[Ink4|INK4]] family and the [[CIP/KIP]] family.<ref name = "Morgan2007" /> 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.<ref name = "Morgan2007" />
A cyclin-dependent kinase inhibitor (CKI) is a protein that interacts with a cyclin-CDK complex to inhibit kinase activity, often during G1 phase or in response to external signals or DNA damage. In animal cells, two primary CKI families exist: the [[INK4]] family (p16, p15, p18, p19) and the [[CIP/KIP]] family  (p21, p27, p57). The INK4 family proteins specifically bind to and inhibit CDK4 and CDK6 by D-type cyclins or by CAK, while the CIP/KIP family prevent the activation of CDK-cyclin heterodimers, disrupting both cyclin binding and kinase activity.<ref name=":4" /><ref name=":5" /> These inhibitors have a KID (kinase inhibitory domain) at the N-terminus, facilitating their attachment to cyclins and CDKs. Their primary function occurs in the nucleus, supported by a C-terminal sequence that enables their nuclear translocation.<ref name=":1" />


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.<ref name = "Morgan2007" />
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.<ref name=":2" /> 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.<ref name=":1" />


Ligand-based inhibition methods involve the use of small molecules or ligands that specifically bind to [[Cyclin-dependent kinase 2|CDK2]], which is a crucial regulator of the cell cycle. The ligands bind to the active site of CDK2, thereby blocking its activity. These inhibitors can either mimic the structure of ATP, competing for the active site and preventing protein phosphorylation needed for cell cycle progression, or bind to allosteric sites, altering the structure of CDK2 to decrease its efficiency.<ref name=":6" />[[File:CDK2-Selective inhibitor.png|thumb|
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.<ref name="pmid3176087">{{cite journal | vauthors = Singh R, Bhardwaj VK, Das P, Purohit R | title = Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective | journal = Journal of Biomolecular Structure and Dynamics | volume = 38 | issue = 17 |date= November 2019 | pages = 5126–5135 | pmid = 3176087 | doi = 10.1080/07391102.2019.1696709 | s2cid = 208276454 }}</ref>
Graphical abstract of CDK2<ref name="pmid33749525">{{cite journal |vauthors=Singh R, Bhardwaj VK, Sharma J, Das P, Purohit R |date=March 2021 |title=Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration |url=https://figshare.com/articles/journal_contribution/14259911 |journal=Journal of Biomolecular Structure and Dynamics |volume=40 |issue=17 |pages=7693–7701 |doi=10.1080/07391102.2021.1900918 |pmid=33749525 |s2cid=232309609}}</ref>]]


=== CDK subunits (CKS) ===
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.<ref name="pmid33749525">{{cite journal | vauthors = Singh R, Bhardwaj VK, Sharma J, Das P, Purohit R | title = Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration | journal = Journal of Biomolecular Structure and Dynamics |date= March 2021 | volume = 40 | issue = 17 | pages = 7693–7701 | pmid = 33749525 | doi = 10.1080/07391102.2021.1900918 | s2cid = 232309609 | url = https://figshare.com/articles/journal_contribution/14259911 }}</ref> [[File:CDK2-Selective inhibitor.png|thumb|
Graphical abstract of CDK2<ref name="pmid33749525"/>]]


CDKs are essential for the control and regulation of the cell cycle. They are associated with small regulatory subunits regulatory subunits ([[Cyclin-dependent kinase regulatory subunit family|CKSs]]). In mammalian cells, two CKSs are known: [[CKS1B|CKS1]] and [[CKS2]]. These proteins are necessary for the proper functioning of CDKs, although their exact functions are not yet fully known. An interaction occurs between CKS1 and the carboxy-terminal lobe of CDKs, where they bind together. This binding increases the affinity of the cyclin-CDK complex for its substrates, especially those with multiple phosphorylation sites, thus contributing the promotion of cell proliferation.<ref>{{Cite journal |last=Liu |first=Chun-Yan |last2=Zhao |first2=Wen-Li |last3=Wang |first3=Jin-Xing |last4=Zhao |first4=Xiao-Fan |date=2015-07-22 |title=Cyclin-dependent kinase regulatory subunit 1 promotes cell proliferation by insulin regulation |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825559/ |journal=Cell Cycle |volume=14 |issue=19 |pages=3045–3057 |doi=10.1080/15384101.2015.1053664 |issn=1538-4101 |pmc=4825559 |pmid=26199131}}</ref>
===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 [[CKS1B|Cks]].<ref name = "Morgan1997" /> These proteins are required for CDK function, but their precise role is unknown.<ref name = "Morgan1997" />
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.<ref name = "Morgan1997" />


===Non-cyclin activators===
===Non-cyclin activators===


==== Viral cyclins ====
==== 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.<ref name = "noncyclin">{{cite journal | vauthors = Nebreda AR | title = CDK activation by non-cyclin proteins | journal = Current Opinion in Cell Biology | volume = 18 | issue = 2 | pages = 192–8 | date = April 2006 | pmid = 16488127 | doi = 10.1016/j.ceb.2006.01.001 }}</ref>
Viruses can encode proteins with [[sequence homology]] to cyclins. One much-studied example is [[Cyclin K|K-cyclin]] (or v-cyclin) from Kaposi sarcoma herpes virus (see [[Kaposi’s sarcoma]]), which activates CDK6. The vCyclin-CDK6 complex promotes an accelerated transition from G1 to S phase in the cell by phosphorylating pRb and releasing E2F. This leads to the removal of inhibition on Cyclin E–CDK2's enzymatic activity. It is shown that vCyclin contributes to promoting transformation and tumorigenesis, mainly through its effect on p27 pSer10 phosphorylation and cytoplasmic sequestration'''.'''<ref>{{Cite journal |last=Jones |first=Tiffany |last2=Ramos da Silva |first2=Suzane |last3=Bedolla |first3=Roble |last4=Ye |first4=Fengchun |last5=Zhou |first5=Fuchun |last6=Gao |first6=Shou-jiang |date=2014-03-01 |title=Viral Cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979920/ |journal=Cell Cycle |volume=13 |issue=5 |pages=845–858 |doi=10.4161/cc.27758 |issn=1538-4101 |pmc=3979920 |pmid=24419204}}</ref>


==== CDK5 activators ====
==== CDK5 activators ====
Two protein types, [[CDK5R1|p35]] and [[CDK5R2|p39]], responsible for increasing the activity of CDK5 during neuronal differentiation in postnatal development.<ref name=":8">{{Cite journal |last=Li |first=Wenqi |last2=Allen |first2=Megan E. |last3=Rui |first3=Yanfang |last4=Ku |first4=Li |last5=Liu |first5=Guanglu |last6=Bankston |first6=Andrew N. |last7=Zheng |first7=James Q. |last8=Feng |first8=Yue |date=2016-11-02 |title=p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses |url=https://pubmed.ncbi.nlm.nih.gov/27807169/ |journal=The Journal of Neuroscience: The Official Journal of the Society for Neuroscience |volume=36 |issue=44 |pages=11283–11294 |doi=10.1523/JNEUROSCI.1155-16.2016 |issn=1529-2401 |pmc=5148244 |pmid=27807169}}</ref> p35 and p39 play a crucial role in a unique mechanism for regulating CDK5 activity in neuronal development and network formation. The activation of CDK with these cofactors (p35 and p39) does not require phosphorylation of the activation loop, which is different from the traditional activation of many other kinases. This highlights the importance of activating CDK5 activity, which is critical for proper neuronal development, dendritic spine and synapse formation, as well as in response to epileptic events.<ref name=":8" /><ref>{{Cite journal |last=Bao |first=Li |last2=Lan |first2=Xiao-Mei |last3=Zhang |first3=Guo-Qing |last4=Bao |first4=Xi |last5=Li |first5=Bo |last6=Ma |first6=Dan-Na |last7=Luo |first7=Hong-Yan |last8=Cao |first8=Shi-Lu |last9=Liu |first9=Shun-Yao |last10=Jing |first10=E. |last11=Zhang |first11=Jian-Zhong |last12=Zheng |first12=Ya-Li |date=2023-01-01 |title=Cdk5 activation promotes Cos-7 cells transition towards neuronal-like cells |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10612488/ |journal=Translational Neuroscience |language=en |volume=14 |issue=1 |doi=10.1515/tnsci-2022-0318 |pmid=37901140}}</ref>
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.<ref name = "noncyclin" />


==== RINGO/Speedy ====
==== RINGO/Speedy ====
Proteins in the RINGO/Speedy group represent a standout bunch among proteins that don't share amino acid sequence homology with the cyclin family. They play a crucial role in activating CDKs. Originally identified in Xenopus, these proteins primarily bind to and activate CDK1 and CDK2, despite lacking homology to cyclins. What is particularly interesting, is that CDKs activated by RINGO/Speedy can phosphorylate different sites than those targeted by cyclin-activated CDKs, indicating a unique mode of action for these non-cyclin CDK activators.<ref>{{Cite journal |last=Gonzalez |first=Laura |last2=Nebreda |first2=Angel R. |date=2020-11-01 |title=RINGO/Speedy proteins, a family of non-canonical activators of CDK1 and CDK2 |url=https://www.sciencedirect.com/science/article/pii/S108495211930206X |journal=Seminars in Cell & Developmental Biology |series=1. Cyclins edited by Josep Clotet |volume=107 |pages=21–27 |doi=10.1016/j.semcdb.2020.03.010 |issn=1084-9521}}</ref>
Proteins with no homology to the cyclin family can be direct activators of CDKs.<ref name = "ringo">{{cite journal | vauthors = Mourón S, de Cárcer G, Seco E, Fernández-Miranda G, Malumbres M, Nebreda AR | title = RINGO C is required to sustain the spindle-assembly checkpoint | journal = Journal of Cell Science | volume = 123 | issue = Pt 15 | pages = 2586–95 | date = August 2010 | pmid = 20605920 | doi = 10.1242/jcs.059964 | s2cid = 21361240 | doi-access = }}</ref> One family of such activators is the RINGO/Speedy family,<ref name = "ringo" /> 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.<ref name = "noncyclin" />

==History==
[[Leland H. Hartwell]], [[R. Timothy Hunt]], and [[Paul M. Nurse]] received the 2001 [[Nobel Prize in Physiology or Medicine]] for their complete description of [[cyclin]] and cyclin-dependent kinase mechanisms, which are central to the regulation of the cell cycle.


==Medical significance==
==Medical significance==
===Diseases of CDK===
===CDKs and cancer ===
The dysregulation of CDKs and cyclins disrupts the cell cycle coordination, which makes them involved in the pathogenesis of several diseases, mainly cancers. Thus, studies of cyclins and cyclin-dependent kinases (CDK) are essential for advancing the understanding of cancer characteristics.<ref name=":1" /><ref name=":9">{{Cite journal |last=Ghafouri-Fard |first=Soudeh |last2=Khoshbakht |first2=Tayyebeh |last3=Hussen |first3=Bashdar Mahmud |last4=Dong |first4=Peixin |last5=Gassler |first5=Nikolaus |last6=Taheri |first6=Mohammad |last7=Baniahmad |first7=Aria |last8=Dilmaghani |first8=Nader Akbari |date=2022-10-20 |title=A review on the role of cyclin dependent kinases in cancers |url=https://doi.org/10.1186/s12935-022-02747-z |journal=Cancer Cell International |volume=22 |issue=1 |pages=325 |doi=10.1186/s12935-022-02747-z |issn=1475-2867 |pmc=PMC9583502 |pmid=36266723}}</ref> Research has shown that alterations in cyclins, CDKs, and CDK inhibitors (CKIs) are common in most cancers, involving chromosomal translocations, point mutations, insertions, deletions, gene overexpression, frame-shift mutations, missense mutations, or splicing errors.<ref name=":1" />
{{empty section|date=September 2021}}


The dysregulation of the CDK4/6-RB pathway is a common feature in many cancers, often resulting from various mechanisms that inactivate the cyclin D-CDK4/6 complex. Several signals can lead to overexpression of cyclin D and enhance CDK4/6 activity, contributing toward tumorigenesis.<ref name=":0" /><ref name=":1" /> Additionally, the CDK4/6-RB pathway interacts with the p53 signaling pathway via p21CIP1 transcription, which can inhibit both cyclin D-CDK4/6 and cyclin E-CDK2 complexes. Mutations in p53 can deactivate the G1 checkpoint, further promoting uncontrolled proliferation.<ref name=":0" /><ref name=":1" />
===As drug targets===
{{main|CDK inhibitor}}
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]]s such as [[seliciclib]] 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]].<ref>{{cite journal | vauthors = Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C | display-authors = 6 | title = Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis | journal = Nature Medicine | volume = 12 | issue = 9 | pages = 1056–64 | date = September 2006 | pmid = 16951685 | doi = 10.1038/nm1468 | s2cid = 5875865 }}</ref> This means that novel drugs for treatment of [[chronic (medicine)|chronic]] inflammation diseases such as [[arthritis]] and [[cystic fibrosis]] could be developed.


=== CDK inhibitors and therapeutic potential ===
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.<ref>{{cite journal | vauthors = Senderowicz AM | title = Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials | journal = Investigational New Drugs | volume = 17 | issue = 3 | pages = 313–20 | year = 1999 | pmid = 10665481 | doi = 10.1023/a:1006353008903 | s2cid = 23551260 }}</ref> 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.<ref name="cancer.gov">{{Cite web|url=https://www.cancer.gov/news-events/cancer-currents-blog/2015/palbociclib-breast-cancer|title=FDA Grants Palbociclib Accelerated Approval for Advanced Breast Cancer|website=National Cancer Institute|date=11 February 2015|language=en|access-date=2017-11-30}}</ref><ref>{{Cite web|url=https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm578081.htm|title=Approved Drugs - FDA approves abemaciclib for HR-positive, HER2-negative breast cancer | work = Center for Drug Evaluation and Research | publisher = U.S Food and Drug Administration |language=en |access-date=2017-11-30}}</ref>
Due to their central role in regulating cell cycle progression and cell proliferation, CDKs are considered ideal therapeutic targets for cancer.<ref name=":9" /> The following CDK4/6 inhibitors mark a significant advancement in cancer treatment, offering targeted therapies that are effective and have a manageable side effect profile.


# [[Palbociclib]], one of the first CDK4/6 inhibitors approved by the FDA, has become essential in the treatment of HR+/HER2- advanced or metastatic breast cancer, often in combination with endocrine therapy.<ref>{{Cite journal |last=Xiao |first=Yi |last2=Dong |first2=Jixin |date=2023-08-11 |title=Coming of Age: Targeting Cyclin K in Cancers |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10453554/ |journal=Cells |volume=12 |issue=16 |pages=2044 |doi=10.3390/cells12162044 |issn=2073-4409 |pmid=37626854}}</ref>
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]]s, which have often serious side-effects, even a minor success would be an improvement.<ref name="cancer.gov"/>
# [[Ribociclib]], demonstrating similar efficacy to palbociclib, is also approved for HR+/HER2- advanced breast cancer and offers benefits for a younger patient demographic.<ref name=":10">{{Cite journal |last=Mughal |first=Muhammad Jameel |last2=Bhadresha |first2=Kinjal |last3=Kwok |first3=Hang Fai |date=2023-01-01 |title=CDK inhibitors from past to present: A new wave of cancer therapy |url=https://www.sciencedirect.com/science/article/pii/S1044579X22002607 |journal=Seminars in Cancer Biology |volume=88 |pages=106–122 |doi=10.1016/j.semcancer.2022.12.006 |issn=1044-579X}}</ref>

# [[Abemaciclib]] stands out by being usable as monotherapy, in addition to combination treatment, for certain HR+/HER2- breast cancer patients. It has also shown effectiveness in treating patients with brain metastases.<ref name=":10" />
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.<ref name = "Sausville">{{cite journal | vauthors = Sausville EA | title = Complexities in the development of cyclin-dependent kinase inhibitor drugs | journal = Trends in Molecular Medicine | volume = 8 | issue = 4 Suppl | pages = S32-7 | year = 2002 | pmid = 11927285 | doi = 10.1016/s1471-4914(02)02308-0 }}</ref>
# [[Trilaciclib]] has proven its value by improving patients' quality of life during cancer treatment by reducing the risk of chemotherapy-induced myelosuppression, a common side effect that can lead to treatment delays and dose reductions.<ref name=":10" />


=== Challenges and future potensial ===
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.<ref>{{Cite journal |last=Solaki |first=Maria |last2=Ewald |first2=Jennifer C. |date=2018-08-17 |title=Fueling the Cycle: CDKs in Carbon and Energy Metabolism |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107797/ |journal=Frontiers in Cell and Developmental Biology |volume=6 |pages=93 |doi=10.3389/fcell.2018.00093 |issn=2296-634X |pmc=6107797 |pmid=30175098}}</ref> 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]].<ref>{{Cite journal |last=Stanciu |first=Ioana-Miruna |last2=Parosanu |first2=Andreea Ioana |last3=Nitipir |first3=Cornelia |date=2023-09-20 |title=An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer—A Systematic Review of Randomized Phase II and III Clinical Trials |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526227/ |journal=Biomolecules |volume=13 |issue=9 |pages=1422 |doi=10.3390/biom13091422 |issn=2218-273X |pmid=37759823}}</ref> The comparison with glucocorticoids serves to illustrate the potential benefits of CDK inhibitors, assuming their side effects can be more narrowly targeted or minimized.<ref>{{Cite journal |last=Lesovaya |first=Ekaterina A. |last2=Chudakova |first2=Daria |last3=Baida |first3=Gleb |last4=Zhidkova |first4=Ekaterina M. |last5=Kirsanov |first5=Kirill I. |last6=Yakubovskaya |first6=Marianna G. |last7=Budunova |first7=Irina V. |date=2022-02-18 |title=The long winding road to the safer glucocorticoid receptor (GR) targeting therapies |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8858080/ |journal=Oncotarget |volume=13 |pages=408–424 |doi=10.18632/oncotarget.28191 |issn=1949-2553 |pmc=8858080 |pmid=35198100}}</ref>
{| class="wikitable"
{| class="wikitable"
|+Table 3: Cyclin-dependent kinase inhibitor drugs<ref>{{Cite journal |last=Łukasik |first=Paweł |last2=Baranowska-Bosiacka |first2=Irena |last3=Kulczycka |first3=Katarzyna |last4=Gutowska |first4=Izabela |date=2021-03-10 |title=Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001317/ |journal=International Journal of Molecular Sciences |volume=22 |issue=6 |pages=2806 |doi=10.3390/ijms22062806 |issn=1422-0067 |pmc=8001317 |pmid=33802080}}</ref><ref>{{Cite journal |last=Sánchez-Martínez |first=Concepción |last2=Lallena |first2=María José |last3=Sanfeliciano |first3=Sonia Gutiérrez |last4=de Dios |first4=Alfonso |date=2019-10-15 |title=Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019) |url=https://www.sciencedirect.com/science/article/pii/S0960894X19305827 |journal=Bioorganic & Medicinal Chemistry Letters |volume=29 |issue=20 |pages=126637 |doi=10.1016/j.bmcl.2019.126637 |issn=0960-894X}}</ref>
|+ Cyclin-dependent kinase inhibitor drugs<ref name = "Sausville" />{{rp|Table 4}}
!Drug
!CDKs Inhibited
!Condition or disease
|-
|-
|Flavopiridol (alvocidib)
! Drug !! CDKs Inhibited
|1, 2, 4, 6, 9
|Acute Myeloid Leukemia (AML)
|-
|-
|Roscovitine (Seliciclib)
| Flavopiridol ([[alvocidib]]) || 1, 2, 4, 6, 7, 9
|2, 7, 9
|Pituitary Cushing Disease
Cystic Fibrosis, Advanced Solid Tumors

Lung Cancer
|-
|-
|Dinaclib
| [[Olomoucine]] || 1, 2, 5
|1, 2, 5, 9
|Chronic Lymphocytic Leukemia (CLL)
Breast and Lung Cancers
|-
|-
|Milciclib
| Roscovitine ([[Seliciclib]]) || 1, 2, 5, 7, 9<ref>Kolodziej M, Goetz C, Di Fazio P, Montalbano R, Ocker M, Strik H, Quint K. Roscovitine has anti-proliferative and pro-apoptotic effects on glioblastoma cell lines: A pilot study. Oncology reports. 2015 Sep 1;34(3):1549-56.</ref><ref>Otyepka M, Bártová I, Kříž Z, Koča J. Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25 and CDK2/cyclin A dynamics. Journal of Biological Chemistry. 2006 Mar 17;281(11):7271-81.</ref><ref name="pmid3176087"/>
|1, 2, 4, 7
|Hepatocellular Carcinoma (HCC)
Thymic Carcinoma
|-
|-
|Palbociclib
| [[Purvalanol]] || 1, 2, 5
|4, 6
|Breast Cancer
Head and Neck, Brain, Colon, and other Solid Cancers
|-
|-
|Ribociclib
| [[Paullone]]s || 1, 2, 5
|4, 6
|HR+/HER2- Breast Cancer
Prostate, and other Solid Cancers
|-
|-
|Abemaciclib
| [[Butryolactone]] || 1, 2, 5
|4, 6
|HR+/HER2- Breast Cancer
Lung, Brain, Colon, and other Solid Cancers
|-
|-
|Meriolin
| [[Palbociclib]] || 4, 6
|1, 2, 5, 9
|Neuroblastoma, Glioma, Myeloma, Colon Cancer
|-
|-
|Variolin B
| Thio/[[oxoflavopiridol]]s || 1
|1, 2, 5, 9
|Murine Leukemia
|-
|-
|Roniciclib
| [[Oxindoles]] || 2
|1, 2, 4, 7, 9
|Lung and Advanced Solid Cancers
|-
|-
|Meridianin E
| [[Fadraciclib]] || 2, 9<ref>[https://www.clinicalleader.com/doc/an-oral-cancer-therapy-hopes-to-treat-multiple-tumors-and-lymphomas-0001 Oral fadraciclib starts clinical trials. Sep 2021]</ref>
|1, 5, 9
|Larynx Carcinoma
Myeloid Leukemia
|-
|-
|Nortopsentins
| [[Aminothiazoles]] || 4
|-
|1
|Malignant Pleural Mesothelioma (MPM)
| [[Benzocarbazole]]s || 4
|-
| [[Pyrimidine]]s || 4
|}
|}


== References ==
== References ==
{{Reflist|32em}}
{{Reflist|32em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Loyer P, Trembley JH, Katona R, Kidd VJ, Lahti JM | title = Role of CDK/cyclin complexes in transcription and RNA splicing | journal = Cellular Signalling | volume = 17 | issue = 9 | pages = 1033–51 | date = September 2005 | pmid = 15935619 | doi = 10.1016/j.cellsig.2005.02.005 }}
{{refend}}


== External links ==
== External links ==
* {{MeshName|Cyclin-Dependent+Kinases}}
* {{MeshName|Cyclin-Dependent+Kinases}}
* {{EC number|2.7.11.22}}
*[http://www.genome.ad.jp/kegg/pathway/hsa/hsa04110.html KEGG – Human Cell Cycle] {{Webarchive|url=https://web.archive.org/web/20081103221626/http://www.genome.ad.jp/kegg/pathway/hsa/hsa04110.html |date=2008-11-03 }}
*[http://www.genome.ad.jp/kegg/pathway/hsa/hsa04110.html KEGG – Human Cell Cycle] {{Webarchive|url=https://web.archive.org/web/20081103221626/http://www.genome.ad.jp/kegg/pathway/hsa/hsa04110.html |date=2008-11-03 }}


Revision as of 21:52, 14 February 2024

Cyclin-dependent kinase
Identifiers
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Tertiary structure of human Cdk2, determined by X-ray crystallography. Like other protein kinases, Cdk2 is composed of two lobes: a smaller amino-terminal lobe (top) that is composed primarily of beta sheet and the PSTAIRE helix, and a large carboxy-terminal lobe (bottom) that is primarily made up of alpha helices. The ATP substrate is shown as a ball-and-stick model, located deep within the active-site cleft between the two lobes. The phosphates are oriented outward, toward the mouth of the cleft, which is blocked in this structure by the T-loop (highlighted in green). (PDB 1hck)
Schematic of the cell cycle. outer ring: I = Interphase, M = Mitosis; inner ring: M = Mitosis; G1 = Gap phase 1; S = Synthesis; G2 = Gap phase 2.

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals.[1] [2] They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved.[3] [4] The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex.[5][6] CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions.[7] Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke. [6]

Evolutionary history

CDKs were initially identified through studies in model organisms such as yeasts and frogs, underscoring their pivotal role in cell cycle progression. These enzymes operate by forming complexes with cyclins, whose levels fluctuate throughout the cell cycle, thereby ensuring timely cell cycle transitions. Over the years, the understanding of CDKs has expanded beyond cell division to include roles in gene transcription integration of cellular signals.[7] [8]

The evolutionary journey of CDKs has led to a diverse family with specific members dedicated to cell cycle phases or transcriptional control. For instance, budding yeast expresses six distinct CDKs, with some binding multiple cyclins for cell cycle control and others binding with a single cyclin for transcription regulation. In humans, the expansion to 20 CDKs and 29 cyclins illustrates their complex regulatory roles. Key CDKs such as CDK1 are indispensable for cell cycle control, while others like CDK2 and CDK3 are not. Moreover, transcriptional CDKs, such as CDK7 in humans, play crucial roles in initiating transcription by phosphorylating RNA polymerase II (RNAPII), indicating the intricate link between cell cycle regulation and transcriptional management. This evolutionary expansion from simple regulators to multifunctional enzymes underscores the critical importance of CDKs in the complex regulatory networks of eukaryotic cells.[7]

Table 1: Cyclin-dependent kinases that control the cell cycle in model organisms [4]
Species Name Original name Size (amino acids) Function
Saccharomyces cerevisiae CDK1 Cdc28 298 All cell-cycle stages
Schizosaccharomyces pombe CDK1 Cdc2 297 All cell-cycle stages
Drosophila melanogaster 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

CDKs and cyclins in the cell cycle

CDK is one of the estimated 800 human protein kinases. CDKs have low molecular weight, and they are known to be inactive by themselves. They are characterized by their dependency on the regulatory subunit, cyclin. The activation of CDKs also requires post-translational modifications involving phosphorylation reactions. This phosphorylation typically occurs on a specific threonine residue, leading to a conformational change in the CDK that enhances its kinase activity.[9] The activation forms a cyclin-CDK complex which phosphorylates specific regulatory proteins that are required to initiate steps in the cell-cycle.[5]

In human cells, the CDK family comprises 20 different members that play a crucial role in the regulation of the cell cycle and transcription. These are usually separated into cell-cycle CDKs, which regulate cell-cycle transitions and cell division, and transcriptional CDKs, which mediate gene transcription. CDK1, CDK2, CDK3, CDK4, CDK6, and CDK7are directly related to the regulation of cell-cycle events, while CDK7 – 11 are associated with transcriptional regulation.[1] Different cyclin-CDK complexes regulate different phases of the cell cycle, known as G0/G1, S, G2, and M phases, featuring several checkpoints to maintain genomic stability and ensure accurate DNA replication.[1][5] Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase.[4]

Table 2: Cell-cycle CDKs, their cyclin partners, and their functions in the human [1] [6] [5]
CDK Cyclin partner Established functions
CDK1 cyclin B M phase transition
CDK2 cyclin A G1/S transition
CDK2 cyclin E S/G2 transition
CDK3 cyclin C G0/G1 and G1/S transitions
CDK4, CDK6 cyclin D G1/S transition. Phosphorylation of retinoblastoma gene product (Rb)
CDK7 cyclin H CAK and RNAPII transcription

CDK structure and activation

Cyclin-dependent kinases (CDKs) mainly consist of a two-lobed configuration, which is characteristic of all kinases in general. CDKs have specific features in their structure that play a major role in their function and regulation.[2]

  1. N-terminal lobe (N-lobe): In this part, the inhibitory element known as the glycine-rich G-loop is located. The inhibitory element is found within the beta-sheets in this N-terminal lobe.[4][2] Additionally, there is a helix known as the C-helix. This helix contains the PSTAIRE sequence in CDK1. This region plays a crucial role in regulating the binding between cyclin-dependent kinases (CDKs) and cyclins.[7][2]
  2. C-terminal lobe (C-lobe): This part contains α-helices and the activation segment, which extends from the DFG motif (D145 in CDK2) to the APE motif (E172 in CDK2). This segment also includes a phosphorylation-sensitive residue (T160 in CDK2) in the so-called T-loop. The activation segment in the C-lobe serves as a platform for the binding of the phospho-acceptor Ser/Thr region of substrates.[7][4][2]

Cyclin binding

The active site, or ATP-binding site, in all kinases is a cleft located between a smaller amino-terminal lobe and a larger carboxy-terminal lobe. Research on the structure of human CDK2 has shown that CDKs have a specially adapted ATP-binding site that can be regulated through the binding of cyclin. Phosphorylation by CDK-activating kinase (CAK) at Thr160 in the T-loop helps to increase the complex's activity. Without cyclin, a flexible loop known as the activation loop or T-loop blocks the cleft, and the positioning of several key amino acids is not optimal for ATP binding. [2][10] With cyclin, two alpha helices change position to enable ATP binding. One of them, the L12 helix located just before the T-loop in the primary sequence, is transformed into a beta strand and helps to reorganize the T-loop so that it no longer blocks the active site. The other alpha helix, known as the PSTAIRE helix, is reorganized and helps to change the position of the key amino acids in the active site.[6][10]

There's considerable specificity in which cyclin binds to CDK. Furthermore, the cyclin binding determines the specificity of the cyclin-CDK complex for certain substrates, highlighting the importance of distinct activation pathways that confer cyclin-binding specificity on CDK1. This illustrates the complexity and fine-tuning in the regulation of the cell cycle through selective binding and activation of CDKs by their respective cyclins.[11][12]

Cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. The RXL-binding site  was crucial in revealing how CDKs selectively enhance activity toward specific substrates by facilitating substrate docking.[13] Substrate specificity of S cyclins is imparted by the hydrophobic batch, which has affinity for substrate proteins that contain a hydrophobic RXL (or Cy) motif.[4] Cyclin B1 and B2 can localize CDK1 to the nucleus and the Golgi, respectively, through a localization sequence outside the CDK-binding region.[4][12]

Phosphorylation

Cyclin binding alone causes partial activation of Cdks, but complete activation also requires activating phosphorylation by a CAK. In animal cells, CAK phosphorylates the Cdk subunit only after cyclin binding, as shown here. Budding yeast contains a different version of CAK that can phosphorylate the Cdk even in the absence of cyclin, and so the two activation steps can occur in either order.

To achieve full kinase activity, an activating phosphorylation on a threonine adjacent to the CDK's active site is required.[14] The identity of the CDK-activating kinase (CAK) that carries out this phosphorylation varies among different model organisms. The timing of this phosphorylation also varies; in mammalian cells, the activating phosphorylation occurs after cyclin binding, while in yeast cells, it occurs before cyclin binding. CAK activity is not regulated by known cell cycle pathways, and it is the cyclin binding that is the limiting step for CDK activation.[4]

Unlike activating phosphorylation, CDK inhibitory phosphorylation is crucial for cell cycle regulation. Various kinases and phosphatases control their phosphorylation state. For instance, the activity of CDK1 is controlled by the balance between  WEE1 kinases, Myt1 kinases, and the phosphorylation of  Cdc25c phosphatases. Wee1, a kinase preserved across all eukaryotes, phosphorylates CDK1 at Tyr 15. Myt1 can phosphorylate both the threonine (Thr 14) and the tyrosine (Tyr 15). The phosphorylation is performed by Cdc25c phosphatases, by removing the phosphate groups from both the threonine and the tyrosine.[1][7]  This inhibitory phosphorylation helps preventing cell-cycle progression in response to events like DNA damage. The phosphorylation does not significantly alter the CDK structure, but reduces its affinity to the substrate, thereby inhibiting its activity. For the cell cycle to progress, these inhibitory phosphates must be removed by the Cdc25 phosphatases to reactivate the CDKs.[7]

CDK inhibitors

A cyclin-dependent kinase inhibitor (CKI) is a protein that interacts with a cyclin-CDK complex to inhibit kinase activity, often during G1 phase or in response to external signals or DNA damage. In animal cells, two primary CKI families exist: the INK4 family (p16, p15, p18, p19) and the CIP/KIP family  (p21, p27, p57). The INK4 family proteins specifically bind to and inhibit CDK4 and CDK6 by D-type cyclins or by CAK, while the CIP/KIP family prevent the activation of CDK-cyclin heterodimers, disrupting both cyclin binding and kinase activity.[6][7] These inhibitors have a KID (kinase inhibitory domain) at the N-terminus, facilitating their attachment to cyclins and CDKs. Their primary function occurs in the nucleus, supported by a C-terminal sequence that enables their nuclear translocation.[2]

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.[4] 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.[2]

Ligand-based inhibition methods involve the use of small molecules or ligands that specifically bind to CDK2, which is a crucial regulator of the cell cycle. The ligands bind to the active site of CDK2, thereby blocking its activity. These inhibitors can either mimic the structure of ATP, competing for the active site and preventing protein phosphorylation needed for cell cycle progression, or bind to allosteric sites, altering the structure of CDK2 to decrease its efficiency.[10]

Graphical abstract of CDK2[15]

CDK subunits (CKS)

CDKs are essential for the control and regulation of the cell cycle. They are associated with small regulatory subunits regulatory subunits (CKSs). In mammalian cells, two CKSs are known: CKS1 and CKS2. These proteins are necessary for the proper functioning of CDKs, although their exact functions are not yet fully known. An interaction occurs between CKS1 and the carboxy-terminal lobe of CDKs, where they bind together. This binding increases the affinity of the cyclin-CDK complex for its substrates, especially those with multiple phosphorylation sites, thus contributing the promotion of cell proliferation.[16]

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), which activates CDK6. The vCyclin-CDK6 complex promotes an accelerated transition from G1 to S phase in the cell by phosphorylating pRb and releasing E2F. This leads to the removal of inhibition on Cyclin E–CDK2's enzymatic activity. It is shown that vCyclin contributes to promoting transformation and tumorigenesis, mainly through its effect on p27 pSer10 phosphorylation and cytoplasmic sequestration.[17]

CDK5 activators

Two protein types, p35 and p39, responsible for increasing the activity of CDK5 during neuronal differentiation in postnatal development.[18] p35 and p39 play a crucial role in a unique mechanism for regulating CDK5 activity in neuronal development and network formation. The activation of CDK with these cofactors (p35 and p39) does not require phosphorylation of the activation loop, which is different from the traditional activation of many other kinases. This highlights the importance of activating CDK5 activity, which is critical for proper neuronal development, dendritic spine and synapse formation, as well as in response to epileptic events.[18][19]

RINGO/Speedy

Proteins in the RINGO/Speedy group represent a standout bunch among proteins that don't share amino acid sequence homology with the cyclin family. They play a crucial role in activating CDKs. Originally identified in Xenopus, these proteins primarily bind to and activate CDK1 and CDK2, despite lacking homology to cyclins. What is particularly interesting, is that CDKs activated by RINGO/Speedy can phosphorylate different sites than those targeted by cyclin-activated CDKs, indicating a unique mode of action for these non-cyclin CDK activators.[20]

Medical significance

CDKs and cancer

The dysregulation of CDKs and cyclins disrupts the cell cycle coordination, which makes them involved in the pathogenesis of several diseases, mainly cancers. Thus, studies of cyclins and cyclin-dependent kinases (CDK) are essential for advancing the understanding of cancer characteristics.[2][21] Research has shown that alterations in cyclins, CDKs, and CDK inhibitors (CKIs) are common in most cancers, involving chromosomal translocations, point mutations, insertions, deletions, gene overexpression, frame-shift mutations, missense mutations, or splicing errors.[2]

The dysregulation of the CDK4/6-RB pathway is a common feature in many cancers, often resulting from various mechanisms that inactivate the cyclin D-CDK4/6 complex. Several signals can lead to overexpression of cyclin D and enhance CDK4/6 activity, contributing toward tumorigenesis.[1][2] Additionally, the CDK4/6-RB pathway interacts with the p53 signaling pathway via p21CIP1 transcription, which can inhibit both cyclin D-CDK4/6 and cyclin E-CDK2 complexes. Mutations in p53 can deactivate the G1 checkpoint, further promoting uncontrolled proliferation.[1][2]

CDK inhibitors and therapeutic potential

Due to their central role in regulating cell cycle progression and cell proliferation, CDKs are considered ideal therapeutic targets for cancer.[21] The following CDK4/6 inhibitors mark a significant advancement in cancer treatment, offering targeted therapies that are effective and have a manageable side effect profile.

  1. Palbociclib, one of the first CDK4/6 inhibitors approved by the FDA, has become essential in the treatment of HR+/HER2- advanced or metastatic breast cancer, often in combination with endocrine therapy.[22]
  2. Ribociclib, demonstrating similar efficacy to palbociclib, is also approved for HR+/HER2- advanced breast cancer and offers benefits for a younger patient demographic.[23]
  3. Abemaciclib stands out by being usable as monotherapy, in addition to combination treatment, for certain HR+/HER2- breast cancer patients. It has also shown effectiveness in treating patients with brain metastases.[23]
  4. Trilaciclib has proven its value by improving patients' quality of life during cancer treatment by reducing the risk of chemotherapy-induced myelosuppression, a common side effect that can lead to treatment delays and dose reductions.[23]

Challenges and future potensial

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.[24] 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 glucocorticoids.[25] The comparison with glucocorticoids serves to illustrate the potential benefits of CDK inhibitors, assuming their side effects can be more narrowly targeted or minimized.[26]

Table 3: Cyclin-dependent kinase inhibitor drugs[27][28]
Drug CDKs Inhibited Condition or disease
Flavopiridol (alvocidib) 1, 2, 4, 6, 9 Acute Myeloid Leukemia (AML)
Roscovitine (Seliciclib) 2, 7, 9 Pituitary Cushing Disease

Cystic Fibrosis, Advanced Solid Tumors

Lung Cancer

Dinaclib 1, 2, 5, 9 Chronic Lymphocytic Leukemia (CLL)

Breast and Lung Cancers

Milciclib 1, 2, 4, 7 Hepatocellular Carcinoma (HCC)

Thymic Carcinoma

Palbociclib 4, 6 Breast Cancer

Head and Neck, Brain, Colon, and other Solid Cancers

Ribociclib 4, 6 HR+/HER2- Breast Cancer

Prostate, and other Solid Cancers

Abemaciclib 4, 6 HR+/HER2- Breast Cancer

Lung, Brain, Colon, and other Solid Cancers

Meriolin 1, 2, 5, 9 Neuroblastoma, Glioma, Myeloma, Colon Cancer
Variolin B 1, 2, 5, 9 Murine Leukemia
Roniciclib 1, 2, 4, 7, 9 Lung and Advanced Solid Cancers
Meridianin E 1, 5, 9 Larynx Carcinoma

Myeloid Leukemia

Nortopsentins 1 Malignant Pleural Mesothelioma (MPM)

References

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