Kinase Subfamily CDK20

Kinase Classification: Group CMGC: Family CDK: Subfamily CDK20

CDK20 (CCRK)

CDK20 is a cyclin-associated kinase that likely activates CDK2 or other CDKs, and RCK family kinases, 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.

Domain Structure

Most CDK20 have a kinase domain flanked by short non-domain regions. The activation loop conserves a T/S that is the major phosphorylation site of CDK kinases (T160 in CDK2) but has not been seen to be phosphorylated.

Evolutionary Range

A single CDK20 gene is found in all animals, including CDK20/CCRK in mammals, dyf-18 in C.elegans and CG6800 in Drosophila. Scattered homologs exist in several protists, including chytrid fungi and some basidiomycetes, 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).

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 [7]. Separately human CDK20 was shown to phosphorylate the MOK kinase ICK (CILK1 in human cells [8], correlating with the Chlamydomonas finding that LF2 was epistatic to LF4 in a flagellar regrowth phenotype. C. elegans CDK20, dyf-18 was shown to be a transcriptional target of the RFX (daf-19) cilium master transcription factor [9]. dyf-18 and the dyf-5/M04C9.5, a MAK, are both implicated in control of cilium length and branching in nematode neurons, are supporessors of the kif17 kinesin, and are localized at the distal end of sensory cilia [10, 11]

Another report shows human CDK20 to be stabilized by binding to the Bromi (TBC1D32) 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 [12]. 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. Bromi and another interacting protein, FAM149B1, are both conserved across animals and found in chytrids, oomycetes, and scattered other basal organisms, in a pattern similar to that of CDK20, suggesting that their interaction, or association with cilia, is ancient.

Disease Association

Human CDK20 has been implicated in several forms of cancer by its overexpression and RNAi phenotypes [2, 13, 14]. A cardiac-selective splice isoform has been implicated in heart failure and to promote growth and survival [15]. 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 (Feng, PMID=21747169).

Gerard 12:06, 21 July 2011 (PDT) Gerard 15:01, 15 December 2022 (PDT)

References

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3. Wohlbold L, Larochelle S, Liao JC, Livshits G, Singer J, Shokat KM, and Fisher RP. The cyclin-dependent kinase (CDK) family member PNQALRE/CCRK supports cell proliferation but has no intrinsic CDK-activating kinase (CAK) activity. Cell Cycle. 2006 Mar;5(5):546-54. DOI:10.4161/cc.5.5.2541 |
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7. 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 |
8. 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 |
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10. Yi P, Xie C, and Ou G. The kinases male germ cell-associated kinase and cell cycle-related kinase regulate kinesin-2 motility in Caenorhabditis elegans neuronal cilia. Traffic. 2018 Jul;19(7):522-535. DOI:10.1111/tra.12572 |
11. Maurya AK, Rogers T, and Sengupta P. A CCRK and a MAK Kinase Modulate Cilia Branching and Length via Regulation of Axonemal Microtubule Dynamics in Caenorhabditis elegans. Curr Biol. 2019 Apr 22;29(8):1286-1300.e4. DOI:10.1016/j.cub.2019.02.062 |
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13. Wu GQ, Xie D, Yang GF, Liao YJ, Mai SJ, Deng HX, Sze J, Guan XY, Zeng YX, Lin MC, and Kung HF. Cell cycle-related kinase supports ovarian carcinoma cell proliferation via regulation of cyclin D1 and is a predictor of outcome in patients with ovarian carcinoma. Int J Cancer. 2009 Dec 1;125(11):2631-42. DOI:10.1002/ijc.24630 |
14. Ng SS, Cheung YT, An XM, Chen YC, Li M, Li GH, Cheung W, Sze J, Lai L, Peng Y, Xia HH, Wong BC, Leung SY, Xie D, He ML, Kung HF, and Lin MC. Cell cycle-related kinase: a novel candidate oncogene in human glioblastoma. J Natl Cancer Inst. 2007 Jun 20;99(12):936-48. DOI:10.1093/jnci/djm011 |
16. Tam LW, Wilson NF, and Lefebvre PA. A CDK-related kinase regulates the length and assembly of flagella in Chlamydomonas. J Cell Biol. 2007 Mar 12;176(6):819-29. DOI:10.1083/jcb.200610022 |