Kinase Subfamily CDK14

Kinase Classification: Group CMGC: Family CDK: Subfamily CDK14

Evolution

Unique to all animals. Single-copy in invertebrates including worm (ZC123.1), and fly (Eip63E), but is expanded to two members in vertebrates (CDK14-15, aka PFTAIRE1-2 or PFTK1-2). Within the CDK subfamilies, CDK14 (PFTAIRE) and CDK16 (PCTAIRE) are the most similar to each other.

Domain Structure

All members have a central kinase domain, flanked by ~100-200 AA on the N-terminus and ~50 AA on the C-terminal side, with no other known domains. All conserve the PFTAIRE motif in the cyclin-binding region.

Cyclin and Cell Cycle Association

Drosophila Eip63E associates with Cyclin C and Cyclin Y [1], while CDK14 also interacts with Cyclin Y [2]. Eip63E knockdown causes a cell cycle phenotype of lowered mitotic index [3]. Human CDK14 also interacts with Cyclin D3 and p21 (Cip1) and is implicated in G1 cell cycle progression [4].

Other Functions

Drosophila Eip63E and mammalian CDK14 have both been shown to interact with 14-3-3 proteins [1, 5] and a binding site has been mapped in CDK14, though it is not conserved.

CDK14-Cyclin Y in both Drosophila and human bind to and phosphorylate the transmembrane Wnt co-receptor LRP6 (Low-density lipoprotein receptor related protein 6; named Arrow in Drosophila). The increased expression/activity of Cyclin Y at G2/M is paralleled by an increase in Wnt signaling at this stage [6].

Human CDK14 phosphorylates Caldesmon, an actin filament-stabilizing protein, and may promote cell migration in hepatocellular carcinoma (HCC) [7], where CDK14 expression confers poor prognosis [8]. CDK14 knockdown in HCC cells decreases motility and induces increased Beta-Actin and transgelin2 (TAGLN2) phosphorylation [9]. The authors propose a model where CDK14 phosphorylates and inactivates TAGLN2, blocking its inhibition of actin fibre formation.

Human CDK14 also interacts with components of the TGFb signaling pathway [10] and with the secretion-associated septin SEPT8.

Human CDK14 was one of four four negative regulators of insulin-responsive glucose transport found in an kinase RNAi screen [11], along with CDK16, IKKa and NIK.

Vertebrate CDK15 and worm ZC123.1 have not been characterized, apart from a single high-throughput interaction reported between CDK15 and CDK2.

Regulation

All CDK14 have a tyrosine in the ATP binding loop, in a conserved GeGsYA motif. This tyrosine is seen to be phosphorylated in both human and mouse CDK14 and CDK15 (http://www.phosphosite.org). This position is equivalent to the Wee1-phosphorylated inhibitory site in CDK1. No phosphorylation has been seen in the activation loop.

Developmental Roles

CDK14 appears to have an unusual focus in late development: Drosophila Eip63E is induced by the moulting hormone ecdysone and is required for metamorphosis, though it is also required in embyronic and larval stages [12], similar to Cyclin Y [13]. It also binds a predicted juvenile hormone-interacing protein, CG8997.

Subcellular location

Human CDK14 is seen in the nucleus and cytoplasm (http://proteinatlas.org). Cyclin Y is membrane associated by myristylation, and may recruit CDK14 to the plasma membrane [2], while 14-3-3 binding (above) may anchor in the cytoplasm. Two putative nuclear localization sequences were found in human CDK14 [5].

References

1. Stanyon CA, Liu G, Mangiola BA, Patel N, Giot L, Kuang B, Zhang H, Zhong J, and Finley RL Jr. A Drosophila protein-interaction map centered on cell-cycle regulators. Genome Biol. 2004;5(12):R96. DOI:10.1186/gb-2004-5-12-r96 |
2. Jiang M, Gao Y, Yang T, Zhu X, and Chen J. Cyclin Y, a novel membrane-associated cyclin, interacts with PFTK1. FEBS Lett. 2009 Jul 7;583(13):2171-8. DOI:10.1016/j.febslet.2009.06.010 |
3. Bettencourt-Dias M, Giet R, Sinka R, Mazumdar A, Lock WG, Balloux F, Zafiropoulos PJ, Yamaguchi S, Winter S, Carthew RW, Cooper M, Jones D, Frenz L, and Glover DM. Genome-wide survey of protein kinases required for cell cycle progression. Nature. 2004 Dec 23;432(7020):980-7. DOI:10.1038/nature03160 |
4. Shu F, Lv S, Qin Y, Ma X, Wang X, Peng X, Luo Y, Xu BE, Sun X, and Wu J. Functional characterization of human PFTK1 as a cyclin-dependent kinase. Proc Natl Acad Sci U S A. 2007 May 29;104(22):9248-53. DOI:10.1073/pnas.0703327104 |
5. Gao Y, Jiang M, Yang T, Ni J, and Chen J. A Cdc2-related protein kinase hPFTAIRE1 from human brain interacting with 14-3-3 proteins. Cell Res. 2006 Jun;16(6):539-47. DOI:10.1038/sj.cr.7310071 |
6. Davidson G, Shen J, Huang YL, Su Y, Karaulanov E, Bartscherer K, Hassler C, Stannek P, Boutros M, and Niehrs C. Cell cycle control of wnt receptor activation. Dev Cell. 2009 Dec;17(6):788-99. DOI:10.1016/j.devcel.2009.11.006 |
7. Leung WK, Ching AK, and Wong N. Phosphorylation of Caldesmon by PFTAIRE1 kinase promotes actin binding and formation of stress fibers. Mol Cell Biochem. 2011 Apr;350(1-2):201-6. DOI:10.1007/s11010-010-0699-8 |
8. Pang EY, Bai AH, To KF, Sy SM, Wong NL, Lai PB, Squire JA, and Wong N. Identification of PFTAIRE protein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells. Hepatology. 2007 Aug;46(2):436-45. DOI:10.1002/hep.21691 |
9. Leung WK, Ching AK, Chan AW, Poon TC, Mian H, Wong AS, To KF, and Wong N. A novel interplay between oncogenic PFTK1 protein kinase and tumor suppressor TAGLN2 in the control of liver cancer cell motility. Oncogene. 2011 Nov 3;30(44):4464-75. DOI:10.1038/onc.2011.161 |
10. Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, and Wrana JL. High-throughput mapping of a dynamic signaling network in mammalian cells. Science. 2005 Mar 11;307(5715):1621-5. DOI:10.1126/science.1105776 |
11. Tang X, Guilherme A, Chakladar A, Powelka AM, Konda S, Virbasius JV, Nicoloro SM, Straubhaar J, and Czech MP. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2087-92. DOI:10.1073/pnas.0507660103 |
12. Stowers RS, Garza D, Rascle A, and Hogness DS. The L63 gene is necessary for the ecdysone-induced 63E late puff and encodes CDK proteins required for Drosophila development. Dev Biol. 2000 May 1;221(1):23-40. DOI:10.1006/dbio.2000.9685 |
13. Liu D and Finley RL Jr. Cyclin Y is a novel conserved cyclin essential for development in Drosophila. Genetics. 2010 Apr;184(4):1025-35. DOI:10.1534/genetics.110.114017 |