Kinase Subfamily CDK20

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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 (Feng, PMID=21747169).

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 [10]. Separately human CDK20 was shown to phosphorylate the MOK kinase ICK in human cells [11], 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 [12].

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 [13]. 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

  1. Liu Y, Wu C, and Galaktionov K. p42, a novel cyclin-dependent kinase-activating kinase in mammalian cells. J Biol Chem. 2004 Feb 6;279(6):4507-14. DOI:10.1074/jbc.M309995200 | PubMed ID:14597612 | HubMed [Liu]
  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 | PubMed ID:20466538 | HubMed [An]
  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 | PubMed ID:16552187 | HubMed [Wohlbold]
  4. Qiu H, Dai H, Jain K, Shah R, Hong C, Pain J, Tian B, Vatner DE, Vatner SF, and Depre C. Characterization of a novel cardiac isoform of the cell cycle-related kinase that is regulated during heart failure. J Biol Chem. 2008 Aug 8;283(32):22157-65. DOI:10.1074/jbc.M710459200 | PubMed ID:18508765 | HubMed [Qui]
  5. Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, and Dutcher SK. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell. 2004 May 14;117(4):541-52. PubMed ID:15137946 | HubMed [Li]
  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. PubMed ID:15137945 | HubMed [Avidor]
  7. 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 | PubMed ID:19672860 | HubMed [Wu]
  8. 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 | PubMed ID:17565152 | HubMed [Ng]
  9. 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. PubMed ID:9504917 | HubMed [Asleson]
  10. 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 | PubMed ID:16954377 | HubMed [Fu]
  11. Phirke P, Efimenko E, Mohan S, Burghoorn J, Crona F, Bakhoum MW, Trieb M, Schuske K, Jorgensen EM, Piasecki BP, Leroux MR, and Swoboda P. Transcriptional profiling of C. elegans DAF-19 uncovers a ciliary base-associated protein and a CDK/CCRK/LF2p-related kinase required for intraflagellar transport. Dev Biol. 2011 Sep 1;357(1):235-47. DOI:10.1016/j.ydbio.2011.06.028 | PubMed ID:21740898 | HubMed [Phirke]
  12. 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 | PubMed ID:20159594 | HubMed [Ko]
  13. 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 | PubMed ID:17353359 | HubMed [Tam]
All Medline abstracts: PubMed | HubMed