Kinase Subfamily CDK20

Kinase Classification: Group CMGC: Family CDK

CDK20 (CCRK)

CDK20 is a cyclin-associated kinase that likely activates CDK2 or other CDKs, and has an emerging role in cilium biology and possibly hedgehog signaling. Also known as CCRK (Cell Cycle Regulated Kinase), CDK20 is most similar to CDK7 in sequence. Like CDK7, it has been reported to be a CDK-activating kinase (CAK) [1, 2], though this is disputed [3], and it is also reported to interact with cyclin H [4]. Its cyclin-binding motif (PNQALRE) is relatively well conserved, though distinct from that of CDK7 (NRTLARE), the better-known partner of cyclin H.

Evolutionary Range

A single CDK20 gene is found in all animals. Scattered homologs exist in several protists, including a chytrid fungus, Phytophthora, and the alga Chlamydomonas, but not higher plants. This pattern is similar to that of many other cilium-related genes, and correlates to the loss of all cilia in Dictyostelium, higher plants and non-chytrid fungi [5, 6] (nematodes have lost motile cilia, but have a divergent CDK20 homolog).

Disease Association

Human CDK20 has been implicated in several forms of cancer by its overexpression and RNAi phenotypes [2, 7, 8]. A cardiac-selective splice isoform has been implicated in heart failure and to promote growth and survival [9]. These experiments also show a consistent phenotype implicating CDK20 in the G1-to-S phase transition in cell cycle of the cancer cells examined. In hepatocellular carcinoma, CDK20 expression correlates with tumor progression, expression is induced by androgen receptor, and participates in Wnt pathway signaling to drive proliferation [10]

CDK20 function and cilia

Multiple lines of evidence also point to a role for CDK20 in flagellum biosynthesis: Mutants in Chlamydomonas CDK20 (called LF2 - long flagella 2) disrupt flagellum length control and assembly. LF2 interacts genetically with LF4, which encodes a MOK subfamily kinase [11, 12, 12, 13, 14, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26], correlating with the Chlamydomonas finding that LF2 was epistatic to LF4 in a flagellar regrowth phenotype. C. elegans CCRK was shown to be a transcriptional target of the RFX (daf-19) cilium master transcription factor [27].

Another report shows human CDK20 to be stabilized by binding to the Bromi protein. Bromi is poorly understood, but seems to link the axoneme of the flagellum to the plasma membrane. Bromi effects the localization of Gli2 in the flagellum and so influences hedgehog signaling [28]. Curiously, antibody staining by the protein atlas (http://proteinatlas.org) shows Bromi specifically in the mitochondrion, while CDK20 is found in the nucleus and the mitochondrion.

Gerard 12:06, 21 July 2011 (PDT)

References

2. An X, Ng SS, Xie D, Zeng YX, Sze J, Wang J, Chen YC, Chow BK, Lu G, Poon WS, Kung HF, Wong BC, and Lin MC. Functional characterisation of cell cycle-related kinase (CCRK) in colorectal cancer carcinogenesis. Eur J Cancer. 2010 Jun;46(9):1752-61. DOI:10.1016/j.ejca.2010.04.007 |
6. Avidor-Reiss T, Maer AM, Koundakjian E, Polyanovsky A, Keil T, Subramaniam S, and Zuker CS. Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis. Cell. 2004 May 14;117(4):527-39. DOI:10.1016/s0092-8674(04)00412-x |
10. Feng H, Cheng AS, Tsang DP, Li MS, Go MY, Cheung YS, Zhao GJ, Ng SS, Lin MC, Yu J, Lai PB, To KF, and Sung JJ. Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis. J Clin Invest. 2011 Aug;121(8):3159-75. DOI:10.1172/JCI45967 |
11. Asleson CM and Lefebvre PA. Genetic analysis of flagellar length control in Chlamydomonas reinhardtii: a new long-flagella locus and extragenic suppressor mutations. Genetics. 1998 Feb;148(2):693-702. DOI:10.1093/genetics/148.2.693 |
26. Fu Z, Larson KA, Chitta RK, Parker SA, Turk BE, Lawrence MW, Kaldis P, Galaktionov K, Cohn SM, Shabanowitz J, Hunt DF, and Sturgill TW. Identification of yin-yang regulators and a phosphorylation consensus for male germ cell-associated kinase (MAK)-related kinase. Mol Cell Biol. 2006 Nov;26(22):8639-54. DOI:10.1128/MCB.00816-06 |
28. Ko HW, Norman RX, Tran J, Fuller KP, Fukuda M, and Eggenschwiler JT. Broad-minded links cell cycle-related kinase to cilia assembly and hedgehog signal transduction. Dev Cell. 2010 Feb 16;18(2):237-47. DOI:10.1016/j.devcel.2009.12.014 |

Leftout

1. Feng pmid=21747169
2. Fu pmid=16954377
3. Ko pmid=20159594
4. Li pmid=15137946
5. Liu pmid=14597612
6. Ng pmid=17565152
7. Phirke pmid=21740898
8. Qui pmid=18508765
9. Tam pmid=17353359
10. Wohlbold pmid=16552187
11. Wu pmid=19672860