Phosphatase Subfamily CDC14
Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily CDC14
CDC14 is a cell cycle phosphatase that dephosphorylates cyclin dependent kinases (CDKs).
Evolution
CDC14 is found in most eukaryotes with the exception of higher plants. Vertebrates have two members, CDC14A and CDC14B. Many primates have an additional CDC14C [1], though its functional relevance in human is not clear, as it may be a pseudogene.
Domain Architecture
CDC14 has twin DSP phosphatase domains, separated by an alpha helix. The N-terminal domain is a pseudophosphatase. CDC14 also has a conserved nuclear export sequence (NES) at the C terminus.
C. elegans cdc-14 has multiple isoforms and the longest one has a THAP domain at C-terminal. The THAP domain is a DNA-binding domain similar to P element transposase. However, the domain combination is dubious. ESTs suggest that the the THAP domain may belong to another gene.
Yeast CDC14 has a C-terminal sequence (517-551), which acts as a nuclear localization signal (NLS) in vivo and binds to Kap121p (also known as Pse1p), a nuclear import carrier (karyopherin/importin), in a Gsp1p-GTP-dependent manner in vitro [2]. In human, Kap121 (Pse1) ortholog can be found (IPO5), but human CDC14A and CDC14B have NLSs at N-terminal instead of C-terminal and it is unclear whether IPO5 binds to this region [3].
Function
Yeast cdc14 is required for mitotic exit, though this is not seen in most other species [4, 5]. In vertebrates, there are conflicting reports on the functions of the Cdc14 isoforms, but there is evidence for involvement in regulating mitotic entry, centrosome duplication, DNA repair, and cytokinesis [4, 5].
Human CDC14A and CDC14B show functional redundancy in double-strand breaks repair [6], and their unique functions are not well understood.
Yeast CDC14
Cdc14 associated with Iqg1, dependent on several CHD-flanking Cdk sites, and efficiently dephosphorylated these sites in vitro. Iqg1, an IQGAP family member, is an essential protein in Saccharomyces cerevisiae required for assembly and contraction of the actomyosin ring. It has a calponin homology domain (CHD) that mediates the localization of F-actin to the ring which only occurs after anaphase [7].
References
- Rosso L, Marques AC, Weier M, Lambert N, Lambot MA, Vanderhaeghen P, and Kaessmann H. Birth and rapid subcellular adaptation of a hominoid-specific CDC14 protein. PLoS Biol. 2008 Jun 10;6(6):e140. DOI:10.1371/journal.pbio.0060140 |
- Kobayashi J, Hirano H, and Matsuura Y. Crystal structure of the karyopherin Kap121p bound to the extreme C-terminus of the protein phosphatase Cdc14p. Biochem Biophys Res Commun. 2015 Jul 31;463(3):309-14. DOI:10.1016/j.bbrc.2015.05.060 |
- Gray CH, Good VM, Tonks NK, and Barford D. The structure of the cell cycle protein Cdc14 reveals a proline-directed protein phosphatase. EMBO J. 2003 Jul 15;22(14):3524-35. DOI:10.1093/emboj/cdg348 |
- Mocciaro A and Schiebel E. Cdc14: a highly conserved family of phosphatases with non-conserved functions?. J Cell Sci. 2010 Sep 1;123(Pt 17):2867-76. DOI:10.1242/jcs.074815 |
- Bremmer SC, Hall H, Martinez JS, Eissler CL, Hinrichsen TH, Rossie S, Parker LL, Hall MC, and Charbonneau H. Cdc14 phosphatases preferentially dephosphorylate a subset of cyclin-dependent kinase (Cdk) sites containing phosphoserine. J Biol Chem. 2012 Jan 13;287(3):1662-9. DOI:10.1074/jbc.M111.281105 |
- Lin H, Ha K, Lu G, Fang X, Cheng R, Zuo Q, and Zhang P. Cdc14A and Cdc14B Redundantly Regulate DNA Double-Strand Break Repair. Mol Cell Biol. 2015 Nov;35(21):3657-68. DOI:10.1128/MCB.00233-15 |
- Miller DP, Hall H, Chaparian R, Mara M, Mueller A, Hall MC, and Shannon KB. Dephosphorylation of Iqg1 by Cdc14 regulates cytokinesis in budding yeast. Mol Biol Cell. 2015 Aug 15;26(16):2913-26. DOI:10.1091/mbc.E14-12-1637 |
