Class of enzymes

Cyclin-dependent kinase
Identifiers
EC no.	2.7.11.22
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases involved in the regulation of the cell cycle. These enzymes function as upstream regulators of cellular processes such as transcription, DNA repair, metabolism, and epigenetic regulation, in response to 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]

CDKs are named for the cyclins, protein activators of CDKs that become mobilized at different points in the cell cycle.[5][6] Dysregulation of CDK activity is linked to diseases including cancer, neurodegenerative diseases, and stroke.[6]

CDKs and cyclins in the cell cycle

[edit]

The activation of CDKs requires binding to cyclins and phosphorylation. This phosphorylation typically occurs on a specific threonine residue, leading to a conformational change in the CDK that enhances its kinase activity.[7][better source needed] 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 and CDK6 are directly related to the regulation of cell-cycle events, while CDK7 – 13 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 phases.[4]

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	S/G2 transition
CDK2	cyclin E	G1/S 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

[edit]

CDKs mainly consist of an N-terminal and a C-terminal lobe with distinct functions. The N-terminal lobe (N-lobe) contains a glycine-rich inhibitory loop and a so-called C helix that binds cyclins.[8][2] The C-terminal lobe (C-lobe) contains the phosphorylation site (T160 in CDK2) and serves as a binding platform for substrate proteins.[8][4][2]

Cyclin and substrate binding

[edit]

The active site of a CDK catalyzes transfer of phosphate from ATP to a Ser or Thr residue on a substrate protein. When cyclin is not bound, the activation loop covers the cleft containing the active site, preventing substrate binding.[2][9] When cyclin is bound, two alpha helices change position to enable ATP binding, in addition to the movement of the activation loop.[6][9]

There is considerable specificity in the binding of cyclins to CDKs.[10][11] In addition to activating the CDKs, cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. For example, cyclin B1 and B2 can localize CDK1 to the nucleus and the Golgi, respectively, through a localization sequence outside the CDK-binding region.[4][11]

Phosphorylation

[edit]

CDKs may be either activated or inhibited by phosphorylation. Activation involves phosphorylation on a threonine adjacent to the CDK's active site.[12] 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 by inhibiting cell cycle progression in response to events like DNA damage. The phosphorylation state of CDKs is controlled by kinases and phosphatases such as WEE1 kinases, Myt1 kinases, and Cdc25c phosphatases for CDK1. Inhibitory phosphorylation does not significantly alter the CDK structure, but reduces its affinity for the substrate protein.[8]

CDK inhibitors

[edit]

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][8] 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]

CDK subunits (CKS)

[edit]

CDKs can additionally be regulated by the cyclin-dependent kinase regulatory subunit (CKSs) proteins (contrary to the name, CKSs are individual proteins, not subunits of a larger protein). 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.[13]

Non-cyclin activators

[edit]

Several proteins other than cyclins can activate CDKs. For instance, certain viruses encode proteins with sequence homology to cyclins. One much-studied example is K-cyclin (or v-cyclin) from Kaposi sarcoma herpes virus, which activates CDK6. The vCyclin-CDK6 complex promotes an accelerated transition from G1 to S phase. This leads to the removal of inhibition on Cyclin E–CDK2's enzymatic activity and promotes transformation and tumorigenesis.[14] During neuronal differentiation, CDK5 is activated by the p35 and p39 proteins. This activation is important in growth of the dendritic spine and in synapse formation.[15][16] The RINGO/Speedy proteins can also activate CDKs (primarily CDK1 and 2), despite lacking homology to cyclins. These proteins alter the substrate specificity of the CDKs in addition to regulating activity.[17]

Medical significance

[edit]

CDKs and cancer

[edit]

Because of their roles in cell cycle regulation, CDKs are of great interest in cancer.[2][18] Research has shown that alterations in cyclins, CDKs, and CDK inhibitors are common in cancers.[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

[edit]

Numerous synthetic inhibitors of CDKs have been explored for potential therapeutic benefit in cancer.[18] 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.[20] Ribociclib, demonstrating similar efficacy to palbociclib, is also approved for HR+/HER2- advanced breast cancer.[21] Abemaciclib may be used in monotherapy, in addition to combination treatment, for certain HR+/HER2- breast cancer patients, including patients with brain metastases.[21] Trilaciclib is used to decrease myelosuppression associated with chemotherapy with other drugs.[21]

Cyclin-dependent kinase inhibitor drugs[22][23]

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)

Off-target effects are a significant concern with CDK-inhibiting drugs, as CDKs have roles in non-cancer processes including transcription, neural physiology, and glucose homeostasis.[24]

See also

[edit]

• Cell cycle
• Protein kinase
• Enzyme catalysis
• Enzyme inhibitor

References

[edit]

1. ^ a b c d e f Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, et al. (March 2020). "The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer". International Journal of Molecular Sciences. 21 (6): 1960. doi:10.3390/ijms21061960. PMC 7139603. PMID 32183020.
2. ^ a b c d e f g h i j Hives M, Jurecekova J, Holeckova KH, Kliment J, Sivonova MK (2023). "The driving power of the cell cycle: cyclin-dependent kinases, cyclins and their inhibitors". Bratislavske Lekarske Listy. 124 (4): 261–266. doi:10.4149/BLL_2023_039. PMID 36598318.
3. ^ S GB, Gohil DS, Roy Choudhury S (January 2023). "Genome-wide identification, evolutionary and expression analysis of the cyclin-dependent kinase gene family in peanut". BMC Plant Biology. 23 (1) 43. Bibcode:2023BMCPB..23...43S. doi:10.1186/s12870-023-04045-w. PMC 9850575. PMID 36658501.
4. ^ a b c d e f Morgan D (2007). The Cell Cycle: Principles of Control. London: New Science Press Ltd. pp. 2–54, 196–266. ISBN 978-0-9539181-2-6.
5. ^ a b c d Alberts B, Hopkin K, Johnson A, Morgan D, Raff M, Roberts K, Walter P (2019). Essential Cell Biology (5th ed.). W. W. Norton & Company. pp. 613–627. ISBN 9780393679533.
6. ^ a b c d e Łukasik P, Załuski M, Gutowska I (March 2021). "Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review". International Journal of Molecular Sciences. 22 (6): 2935. doi:10.3390/ijms22062935. PMC 7998717. PMID 33805800.
7. ^ Knockaert M, Meijer L (September 2002). "Identifying in vivo targets of cyclin-dependent kinase inhibitors by affinity chromatography". Biochemical Pharmacology. Cell Signaling, Transcription and Translation as Therapeutic Targets. 64 (5–6): 819–825. doi:10.1016/S0006-2952(02)01144-9. PMID 12213575.
8. ^ a b c d Malumbres M (June 30, 2014). "Cyclin-dependent kinases". Genome Biology. 15 (6) 122. doi:10.1186/gb4184. PMC 4097832. PMID 25180339.
9. ^ a b Li Y, Zhang J, Gao W, Zhang L, Pan Y, Zhang S, Wang Y (April 2015). "Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2". International Journal of Molecular Sciences. 16 (5): 9314–9340. doi:10.3390/ijms16059314. PMC 4463590. PMID 25918937.
10. ^ Merrick KA, Larochelle S, Zhang C, Allen JJ, Shokat KM, Fisher RP (December 2008). "Distinct activation pathways confer cyclin-binding specificity on Cdk1 and Cdk2 in human cells". Molecular Cell. 32 (5): 662–672. doi:10.1016/j.molcel.2008.10.022. PMC 2643088. PMID 19061641.
11. ^ a b Massacci G, Perfetto L, Sacco F (November 2023). "The Cyclin-dependent kinase 1: more than a cell cycle regulator". British Journal of Cancer. 129 (11): 1707–1716. doi:10.1038/s41416-023-02468-8. PMC 10667339. PMID 37898722.
12. ^ Zabihi M, Lotfi R, Yousefi AM, Bashash D (April 2023). "Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities". Journal of Cancer Research and Clinical Oncology. 149 (4): 1585–1606. doi:10.1007/s00432-022-04135-6. PMC 11796601. PMID 35781526. S2CID 250244736.
13. ^ Liu CY, Zhao WL, Wang JX, Zhao XF (July 22, 2015). "Cyclin-dependent kinase regulatory subunit 1 promotes cell proliferation by insulin regulation". Cell Cycle. 14 (19): 3045–3057. doi:10.1080/15384101.2015.1053664. PMC 4825559. PMID 26199131.
14. ^ Jones T, Ramos da Silva S, Bedolla R, Ye F, Zhou F, Gao SJ (March 1, 2014). "Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition". Cell Cycle. 13 (5): 845–858. doi:10.4161/cc.27758. PMC 3979920. PMID 24419204.
15. ^ Li W, Allen ME, Rui Y, Ku L, Liu G, Bankston AN, et al. (November 2016). "p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses". The Journal of Neuroscience. 36 (44): 11283–11294. doi:10.1523/JNEUROSCI.1155-16.2016. PMC 5148244. PMID 27807169.
16. ^ Bao L, Lan XM, Zhang GQ, Bao X, Li B, Ma DN, et al. (January 2023). "Cdk5 activation promotes Cos-7 cells transition towards neuronal-like cells". Translational Neuroscience. 14 (1) 20220318. doi:10.1515/tnsci-2022-0318. PMC 10612488. PMID 37901140.
17. ^ Gonzalez L, Nebreda AR (November 2020). "RINGO/Speedy proteins, a family of non-canonical activators of CDK1 and CDK2". Seminars in Cell & Developmental Biology. 1. Cyclins edited by Josep Clotet. 107: 21–27. doi:10.1016/j.semcdb.2020.03.010. hdl:2445/157997. PMID 32317145. S2CID 216073305.
18. ^ a b Ghafouri-Fard S, Khoshbakht T, Hussen BM, Dong P, Gassler N, Taheri M, et al. (October 2022). "A review on the role of cyclin dependent kinases in cancers". Cancer Cell International. 22 (1) 325. doi:10.1186/s12935-022-02747-z. PMC 9583502. PMID 36266723.
19. ^ Singh R, Bhardwaj VK, Sharma J, Das P, Purohit R (October 2022). "Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration" (PDF). Journal of Biomolecular Structure & Dynamics. 40 (17): 7693–7701. doi:10.1080/07391102.2021.1900918. PMID 33749525. S2CID 232309609.
20. ^ Xiao Y, Dong J (August 2023). "Coming of Age: Targeting Cyclin K in Cancers". Cells. 12 (16): 2044. doi:10.3390/cells12162044. PMC 10453554. PMID 37626854.
21. ^ a b c Mughal MJ, Bhadresha K, Kwok HF (January 2023). "CDK inhibitors from past to present: A new wave of cancer therapy". Seminars in Cancer Biology. 88: 106–122. doi:10.1016/j.semcancer.2022.12.006. PMID 36565895.
22. ^ Łukasik P, Baranowska-Bosiacka I, Kulczycka K, Gutowska I (March 2021). "Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action". International Journal of Molecular Sciences. 22 (6): 2806. doi:10.3390/ijms22062806. PMC 8001317. PMID 33802080.
23. ^ Sánchez-Martínez C, Lallena MJ, Sanfeliciano SG, de Dios A (October 2019). "Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019)". Bioorganic & Medicinal Chemistry Letters. 29 (20) 126637. doi:10.1016/j.bmcl.2019.126637. PMID 31477350. S2CID 201805102.
24. ^ Solaki M, Ewald JC (August 17, 2018). "Fueling the Cycle: CDKs in Carbon and Energy Metabolism". Frontiers in Cell and Developmental Biology. 6 93. doi:10.3389/fcell.2018.00093. PMC 6107797. PMID 30175098.

External links

[edit]

• Cyclin-Dependent+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

v t e Intracellular signaling peptides and proteins
MAP	see MAP kinase pathway
Calcium	Intracellular calcium-sensing proteins Calcineurin Ca2+/calmodulin-dependent protein kinase
G protein	Heterotrimeric cAMP: Heterotrimeric G protein Gs/Gi Adenylate cyclase cAMP 3',5'-cyclic-AMP phosphodiesterase Protein kinase A cGMP: Transducin Gustducin Guanylate cyclase cGMP 3',5'-cyclic-GMP phosphodiesterase Protein kinase G G alpha subunit Gα GNAO1 GNAI1 GNAI2 GNAI3 GNAT1 GNAT2 GNAT3 GNAZ GNAS GNAL GNAQ GNA11 GNA12 GNA13 GNA14 GNA15/GNA16 G beta-gamma complex Gβ GNB1 GNB2 GNB3 GNB4 GNB5 Gγ GNGT1 GNGT2 GNG2 GNG3 GNG4 GNG5 GNG7 GNG8 GNG10 GNG11 GNG12 GNG13 BSCL2 G protein-coupled receptor kinase AMP-activated protein kinase Monomeric ARFs Rabs Ras HRAS KRAS NRAS Rhos Arfs Ran Rhebs Raps RGKs
Cyclin	Cyclin-dependent kinase inhibitor protein Cyclin-dependent kinase Cyclin
Lipid	Phosphoinositide phospholipase C Phospholipase C
Other protein kinase	Serine/threonine: Casein kinase 1 2 eIF-2 kinase EIF2AK3 Glycogen synthase kinase GSK1 GSK2 GSK-3 GSK3A GSK3B IκB kinase CHUK IKK2 IKBKG Interleukin-1 receptor associated kinase IRAK1 IRAK2 IRAK3 IRAK4 Lim kinase LIMK1 LIMK2 p21-activated kinases PAK1 PAK2 PAK3 PAK4 Rho-associated protein kinase ROCK1 ROCK2 Ribosomal s6 kinase RPS6KA1 Tyrosine: ZAP70 Focal adhesion protein-tyrosine kinase PTK2 PTK2B BTK Serine/threonine/tyrosine Dual-specificity kinase DYRK1A DYRK1B DYRK2 DYRK3 DYRK4 Arginine Arginine kinase McsB
Other protein phosphatase	Serine/threonine: Protein phosphatase 2 Tyrosine: protein tyrosine phosphatase: Receptor-like protein tyrosine phosphatase Sh2 domain-containing protein tyrosine phosphatase both: Dual-specificity phosphatase
Apoptosis	see apoptosis signaling pathway
GTP-binding protein regulators	see GTP-binding protein regulators
Other	Activating transcription factor 6 Signal transducing adaptor protein I-kappa B protein Mucin-4 Olfactory marker protein Phosphatidylethanolamine binding protein EDARADD PRKCSH
see also deficiencies of intracellular signaling peptides and proteins

v t e Cell cycle proteins
Cyclin	A (A1, A2) B (B1, B2, B3) D (D1, D2, D3) E (E1, E2)
CDK	1 2 3 4 5 6 7 8 9 10 11A 11B 12 13 14 CDK-activating kinase
CDK inhibitor	INK4a/ARF (p14arf/p16, p15, p18, p19) cip/kip (p21, p27, p57)
P53 p63 p73 family	p53 p63 p73
Other	Cdc2 Cdc25 Cdc42 Cellular apoptosis susceptibility protein E2F Maturation promoting factor Wee Cullin (CUL7)
Phases andcheckpoints	Interphase G1 phase S phase G2 phase M phase Mitosis (Preprophase Prophase Prometaphase Metaphase Anaphase Telophase) Cytokinesis Cell cycle checkpoints Restriction point Spindle checkpoint Postreplication checkpoint Other cellular phases Apoptosis G0 phase Meiosis

v t e Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)
Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20) Non-specific serine/threonine protein kinases (EC 2.7.11.1) LATS1 LATS2 MAST1 MAST2 STK38 STK38L CIT ROCK1 SGK SGK2 SGK3 Protein kinase B AKT1 AKT2 AKT3 Ataxia telangiectasia mutated mTOR EIF-2 kinases PKR HRI EIF2AK3 EIF2AK4 Wee1 WEE1 Pyruvate dehydrogenase kinase (EC 2.7.11.2) PDK1 PDK2 PDK3 PDK4 Dephospho-(reductase kinase) kinase (EC 2.7.11.3) AMP-activated protein kinase α PRKAA1 PRKAA2 β PRKAB1 PRKAB2 γ PRKAG1 PRKAG2 PRKAG3 3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring) kinase (EC 2.7.11.4) BCKDK BCKDHA BCKDHB (isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5) IDH2 IDH3A IDH3B IDH3G (tyrosine 3-monooxygenase) kinase (EC 2.7.11.6) STK4 Myosin-heavy-chain kinase (EC 2.7.11.7) Aurora kinase Aurora A kinase Aurora B kinase Aurora C kinase Fas-activated serine/threonine kinase (EC 2.7.11.8) FASTK STK10 Goodpasture-antigen-binding protein kinase (EC 2.7.11.9) - IκB kinase (EC 2.7.11.10) CHUK IKK2 TBK1 IKBKE IKBKG IKBKAP cAMP-dependent protein kinase (EC 2.7.11.11) Protein kinase A PRKACG PRKACB PRKACA PRKY cGMP-dependent protein kinase (EC 2.7.11.12) Protein kinase G PRKG1 Protein kinase C (EC 2.7.11.13) Protein kinase C Protein kinase Cζ PKC alpha PRKCB1 PRKCD PRKCE PRKCH PRKCG PRKCI PRKCQ Protein kinase N1 PKN2 PKN3 Rhodopsin kinase (EC 2.7.11.14) Rhodopsin kinase Beta adrenergic receptor kinase (EC 2.7.11.15) Beta adrenergic receptor kinase Beta adrenergic receptor kinase-2 G-protein coupled receptor kinases (EC 2.7.11.16) GRK4 GRK5 GRK6 Ca2+/calmodulin-dependent (EC 2.7.11.17) BRSK2 CAMK1 CAMK1A CAMK1B CAMK1D CAMK1G CAMK2 CAMK2A CAMK2B CAMK2D CAMK2G CAMK4 MLCK CASK CHEK1 CHEK2 DAPK1 DAPK2 DAPK3 STK11 MAPKAPK2 MAPKAPK3 MAPKAPK5 MARK1 MARK2 MARK3 MARK4 MELK MKNK1 MKNK2 NUAK1 NUAK2 OBSCN PASK PHKG1 PHKG2 PIM1 PIM2 PKD1 PRKD2 PRKD3 PSKH1 SNF1LK2 KIAA0999 STK40 SNF1LK SNRK SPEG TSSK2 Kalirin TRIB1 TRIB2 TRIB3 TRIO Titin DCLK1 Myosin light-chain kinase (EC 2.7.11.18) MYLK MYLK2 MYLK3 MYLK4 Phosphorylase kinase (EC 2.7.11.19) PHKA1 PHKA2 PHKB PHKG1 PHKG2 Elongation factor 2 kinase (EC 2.7.11.20) EEF2K STK19 Polo kinase (EC 2.7.11.21) PLK1 PLK2 PLK3 PLK4
Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30) Polo kinase (EC 2.7.11.21) PLK1 PLK2 PLK3 PLK4 Cyclin-dependent kinase (EC 2.7.11.22) CDK1 CDK2 CDKL2 CDK3 CDK4 CDK5 CDKL5 CDK6 CDK7 CDK8 CDK9 CDK10 CDK12 CDC2L5 PCTK1 PCTK2 PCTK3 PFTK1 CDC2L1 (RNA-polymerase)-subunit kinase (EC 2.7.11.23) RPS6KA5 RPS6KA4 P70S6 kinase P70-S6 Kinase 1 RPS6KB2 RPS6KA2 RPS6KA3 RPS6KA1 RPS6KC1 Mitogen-activated protein kinase (EC 2.7.11.24) Extracellular signal-regulated MAPK1 MAPK3 MAPK4 MAPK6 MAPK7 MAPK12 MAPK15 C-Jun N-terminal MAPK8 MAPK9 MAPK10 P38 mitogen-activated protein MAPK11 MAPK13 MAPK14 MAP3K (EC 2.7.11.25) MAP kinase kinase kinases MAP3K1 MAP3K2 MAP3K3 MAP3K4 MAP3K5 MAP3K6 MAP3K7 MAP3K8 RAFs ARAF BRAF KSR1 KSR2 MLKs MAP3K12 MAP3K13 MAP3K9 MAP3K10 MAP3K11 MAP3K7 ZAK CDC7 MAP3K14 Tau-protein kinase (EC 2.7.11.26) TPK1 TTK GSK-3 (acetyl-CoA carboxylase) kinase (EC 2.7.11.27) - Tropomyosin kinase (EC 2.7.11.28) - Low-density-lipoprotein receptor kinase (EC 2.7.11.29) - Receptor protein serine/threonine kinase (EC 2.7.11.30) Bone morphogenetic protein receptors BMPR1 BMPR1A BMPR1B BMPR2 ACVR1 ACVR1B ACVR1C ACVR2A ACVR2B ACVRL1 Anti-Müllerian hormone receptor
Dual-specificity kinases (EC 2.7.12) MAP2K MAP2K1 MAP2K2 MAP2K3 MAP2K4 MAP2K5 MAP2K6 MAP2K7

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Portal:

• Biology