Kinase Subfamily CDK14

Kinase Classification: Group CMGC: Family CDK: Subfamily CDK11

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

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