Cyclin-dependent kinase

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CDK2 (cyan) complex with cyclin A2 (green), ATP analog roscovitine and monothioglycerol (PDB code 3ddq)

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1 Function
2 Relevance
3 Disease
4 Structural highlights
5 3D structures of cyclin-dependent kinase

Function

Cyclin-dependent kinase (CDK) or Cell division protein kinase are serine/threonine protein kinases which are important to the regulation of the cell cycle. CDKs are small proteins which contain just a kinase domain. In order to function, CDK binds the regulatory protein cyclin. CDKs phosphorylate their substrates at a consensus tetrapeptide. The CDK classes differ by the binding cyclin and their function in human.^[1]

CDK1 binds cyclin and forms a complex which phosphorylates a variety of substrates which are involved in cell cycle progression^[2]

•CDK2 is involved in the control of the cell cycle. It interacts with the regulatory protein cyclin A2. Phosphorylation at Thr14 or Tyr15 inactivates it; phosphorylation at Thr160 (T160P) – activates it^[3]. See also Intrinsically Disordered Protein.
•CDK3 binds cyclin C and functions during the G1 phase^[4].
•For details on CDK4 see Cyclin Dependent Kinase-4 and Palbociclib.

CDK5 binds p53 and functions during transcription^[5].

•CDK6 binds cyclin D and functions during the G1 phase^[6]. See also Palbociclib and Abemaciclib.

CDK7 may serve as a direct link between transcription regulation and the cell cycle^[7].

•CDK8 binds cyclin C and functions during transcription^[8].
•CDK9 regulates gene transcription elongation by phosphorylating the C-terminal domain of RNA polymerase II^[9].
•CDK11 plays a role in regulating cell cycle, RNA transcription and processing, neuronal function and apoptosis^[10].
•CDK12 phosphorylates the C-terminal domain of the large subunit of RNA polymerase II. Acts as a regulator of transcription elongation^[11].
•CDK13 is required for RNA splicing^[12].
•CDK16 plays a role in vesicle-mediated transport processes and exocytosis^[13].

Relevance

CDK is a potential target for anti-cancer therapy. Overexprssion of CDK2 is indicator of oral cancer^[14]. CDK2 may be a suitable drug target for melanoma^[15]. Inhibition of CDK5 alleviates the cardiac phenotypes of Timothy Syndrome^[16]. Up-regulated CDK6 activity is associated with several types of cancers and thus its inhibitors can serve as cancer drug targets^[17]. Overexprssion of CDK7 is associated with unfavorable prognosis of oral squamous cells carcinoma^[18]. CDK16 negatively modulates p53 signaling pathway to promote radio resistance and hence represents a therapeutic target for lung cancer radiotherapy^[19].

Disease

CDK12 mutations have been found in several malignancies including ovarian carcinoma^[20].

Structural highlights

The kinase is located in a . near the binding site is required for kinase activity.^[21]

3D structures of cyclin-dependent kinase

Cyclin-dependent kinase 3D structures

References

↑ Larsen NA, Turner JM, Stevens J, Rosser SJ, Basran A, Lerner RA, Bruce NC, Wilson IA. Crystal structure of a bacterial cocaine esterase. Nat Struct Biol. 2002 Jan;9(1):17-21. PMID:11742345 doi:10.1038/nsb742
↑ Liu P, Kao TP, Huang H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene. 2008 Aug 7;27(34):4733-44. doi: 10.1038/onc.2008.104. Epub 2008 Apr 14. PMID:18408765 doi:http://dx.doi.org/10.1038/onc.2008.104
↑ Gu Y, Rosenblatt J, Morgan DO. Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. EMBO J. 1992 Nov;11(11):3995-4005. PMID:1396589
↑ Yan GX, Zhang J, Shodhan A, Tian M, Miao W. Cdk3, a conjugation-specific cyclin-dependent kinase, is essential for the initiation of meiosis in Tetrahymena thermophila. Cell Cycle. 2016 Sep 16;15(18):2506-14. doi: 10.1080/15384101.2016.1207838. Epub , 2016 Jul 15. PMID:27420775 doi:http://dx.doi.org/10.1080/15384101.2016.1207838
↑ Sahlgren CM, Mikhailov A, Vaittinen S, Pallari HM, Kalimo H, Pant HC, Eriksson JE. Cdk5 regulates the organization of Nestin and its association with p35. Mol Cell Biol. 2003 Jul;23(14):5090-106. doi: 10.1128/mcb.23.14.5090-5106.2003. PMID:12832492 doi:http://dx.doi.org/10.1128/mcb.23.14.5090-5106.2003
↑ Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077-86. PMID:8114739
↑ Ko LJ, Shieh SY, Chen X, Jayaraman L, Tamai K, Taya Y, Prives C, Pan ZQ. p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner. Mol Cell Biol. 1997 Dec;17(12):7220-9. PMID:9372954
↑ Donner AJ, Ebmeier CC, Taatjes DJ, Espinosa JM. CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat Struct Mol Biol. 2010 Feb;17(2):194-201. doi: 10.1038/nsmb.1752. Epub 2010, Jan 24. PMID:20098423 doi:http://dx.doi.org/10.1038/nsmb.1752
↑ Narita T, Ishida T, Ito A, Masaki A, Kinoshita S, Suzuki S, Takino H, Yoshida T, Ri M, Kusumoto S, Komatsu H, Imada K, Tanaka Y, Takaori-Kondo A, Inagaki H, Scholz A, Lienau P, Kuroda T, Ueda R, Iida S. Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma. Blood. 2017 Aug 31;130(9):1114-1124. PMID:28646117 doi:10.1182/blood-2016-09-741983
↑ Trembley JH, Loyer P, Hu D, Li T, Grenet J, Lahti JM, Kidd VJ. Cyclin dependent kinase 11 in RNA transcription and splicing. Prog Nucleic Acid Res Mol Biol. 2004;77:263-88. PMID:15196895 doi:10.1016/S0079-6603(04)77007-5
↑ Dubbury SJ, Boutz PL, Sharp PA. CDK12 regulates DNA repair genes by suppressing intronic polyadenylation. Nature. 2018 Dec;564(7734):141-145. doi: 10.1038/s41586-018-0758-y. Epub 2018 Nov, 28. PMID:30487607 doi:http://dx.doi.org/10.1038/s41586-018-0758-y
↑ Greenleaf AL. Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium. Transcription. 2019 Apr;10(2):91-110. doi: 10.1080/21541264.2018.1535211. Epub, 2018 Oct 22. PMID:30319007 doi:http://dx.doi.org/10.1080/21541264.2018.1535211
↑ Dixon-Clarke SE, Shehata SN, Krojer T, Sharpe TD, von Delft F, Sakamoto K, Bullock AN. Structure and inhibitor specificity of the PCTAIRE-family kinase CDK16. Biochem J. 2017 Feb 20;474(5):699-713. doi: 10.1042/BCJ20160941. PMID:28057719 doi:http://dx.doi.org/10.1042/BCJ20160941
↑ Mihara M, Shintani S, Nakahara Y, Kiyota A, Ueyama Y, Matsumura T, Wong DT. Overexpression of CDK2 is a prognostic indicator of oral cancer progression. Jpn J Cancer Res. 2001 Mar;92(3):352-60. doi: 10.1111/j.1349-7006.2001.tb01102.x. PMID:11267947 doi:http://dx.doi.org/10.1111/j.1349-7006.2001.tb01102.x
↑ Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK, Golub TR, Fisher DE. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell. 2004 Dec;6(6):565-76. doi: 10.1016/j.ccr.2004.10.014. PMID:15607961 doi:http://dx.doi.org/10.1016/j.ccr.2004.10.014
↑ Song L, Park SE, Isseroff Y, Morikawa K, Yazawa M. Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome. Stem Cell Reports. 2017 Jul 11;9(1):50-57. doi: 10.1016/j.stemcr.2017.05.028., Epub 2017 Jun 22. PMID:28648896 doi:http://dx.doi.org/10.1016/j.stemcr.2017.05.028
↑ Tadesse S, Yu M, Kumarasiri M, Le BT, Wang S. Targeting CDK6 in cancer: State of the art and new insights. Cell Cycle. 2015;14(20):3220-30. doi: 10.1080/15384101.2015.1084445. PMID:26315616 doi:http://dx.doi.org/10.1080/15384101.2015.1084445
↑ Jiang L, Huang R, Wu Y, Diao P, Zhang W, Li J, Li Z, Wang Y, Cheng J, Yang J. Overexpression of CDK7 is associated with unfavourable prognosis in oral squamous cell carcinoma. Pathology. 2019 Jan;51(1):74-80. doi: 10.1016/j.pathol.2018.10.004. Epub 2018 Nov, 22. PMID:30473182 doi:http://dx.doi.org/10.1016/j.pathol.2018.10.004
↑ Torras J, Aleman C. Determination of new Cu+, Cu2+, and Zn2+ Lennard-Jones ion parameters in acetonitrile. J Phys Chem B. 2013 Sep 12;117(36):10513-22. doi: 10.1021/jp402545g. Epub 2013, Aug 28. PMID:23944296 doi:http://dx.doi.org/10.1021/jp402545g
↑ Paculova H, Kohoutek J. The emerging roles of CDK12 in tumorigenesis. Cell Div. 2017 Oct 27;12:7. doi: 10.1186/s13008-017-0033-x. eCollection 2017. PMID:29090014 doi:http://dx.doi.org/10.1186/s13008-017-0033-x
↑ Bettayeb K, Oumata N, Echalier A, Ferandin Y, Endicott JA, Galons H, Meijer L. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene. 2008 Oct 2;27(44):5797-807. Epub 2008 Jun 23. PMID:18574471 doi:10.1038/onc.2008.191