View source for Kinase Subfamily CDK14

__NOTOC__
[[kinase classification|Kinase Classification]]: [[Kinase_Group_CMGC|Group CMGC]]: [[Kinase_Family_CDK|Family CDK]]: [[Kinase_Subfamily_CDK14|Subfamily CDK14]]

====CDK14 (PFTAIRE)====

====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 [[Kinase_Subfamily_CDK16|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 <cite>Stanyon</cite>, while CDK14 also interacts with Cyclin Y <cite>Jiang</cite>. Eip63E knockdown causes a cell cycle phenotype of lowered mitotic index <cite>Bettencourt-Dias</cite>. Human CDK14 also interacts with Cyclin D3 and p21 (Cip1) and is implicated in G1 cell cycle progression <cite>Shu</cite>.

====Other Functions====
Drosophila Eip63E and mammalian CDK14 have both been shown to interact with 14-3-3 proteins <cite>Gao, Stanyon</cite> 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 <cite>Davidson</cite>.

Human CDK14 phosphorylates Caldesmon, an actin filament-stabilizing protein, and may promote cell migration in hepatocellular carcinoma (HCC) <cite>Leung</cite>, where CDK14 expression confers poor prognosis <cite>Pang</cite>. CDK14 knockdown in HCC cells decreases motility and induces increased Beta-Actin and transgelin2 (TAGLN2) phosphorylation <cite>Leung2</cite>. 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 <cite>Barrios-Rodiles</cite> 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 <cite>Tang</cite>, 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 <cite>Stowers</cite>, similar to Cyclin Y <cite>Liu</cite>. 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 <cite>Jiang</cite>, while 14-3-3 binding (above) may anchor in the cytoplasm. Two putative nuclear localization sequences were found in human CDK14 <cite>Gao</cite>.

====References====
<biblio>
#Barrios-Rodiles pmid=15761153
#Bettencourt-Dias pmid=15616552
#Davidson pmid=20059949
#Gao pmid=16775625
#Jiang pmid=19524571
#Leung pmid=21184254
#Leung2 pmid=21577206
#Liu pmid=20100936
#Pang pmid=17559150
#Shu pmid=17517622
#Stanyon pmid=15575970
#Stowers pmid=10772789
#Tang pmid=16461467
</biblio>