The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

Abstract

The Cdc14 phosphatase is a key regulator of mitosis in the budding yeast Saccharomyces cerevisiae. Cdc14 was initially described as playing an essential role in the control of cell cycle progression by promoting mitotic exit on the basis of its capacity to counteract the activity of the cyclin-dependent kinase Cdc28/Cdk1. A compiling body of evidence, however, has later demonstrated that this phosphatase plays other multiple roles in the regulation of mitosis at different cell cycle stages. Here, we summarize our current knowledge about the pivotal role of Cdc14 in cell cycle control, with a special focus in the most recently uncovered functions of the phosphatase.

Keywords: Cdc14; autophagy; cytokinesis; genome stability; mitotic exit; nucleolus; phosphatase.

Figure 1

Cdc14 phosphatase is sequestered into the nucleolus through binding to Net1/Cfi1 [6]. While inactive in this cellular compartment, Cdc14 cannot initiate DNA and spindle pole body (SPB) reduplication cycles [27,28,43,44], and the phosphorylated state of the RNA polymerases that preserve the transcriptional activity of sub-telomeric and ribosomal DNA (rDNA) regions can be maintained [34]. At the metaphase-to-anaphase transition, FEAR together with Plk and Cdk downregulate PP2A-Cdc55 (inhibitory red line) and trigger Net1/Cfi1 phosphorylation to promote the first releasing wave of Cdc14 into the nucleus (green arrow) [45,46]. Once at this location, Cdc14 activity (black line) progressively downregulates cyclin-dependent kinase (Cdk) phosphorylation, thereby promoting rDNA and telomere condensation through RNA polymerase I and II inhibition to facilitate the segregation of these chromosomal regions [33,34,47,48] and also priming the activation of the mitotic exit network (MEN) pathway [49,50]. Nucleolar hyper-condensation blocks efficient Cdc14 release (inhibitory blue line) [32]. Cdc14 further participates in the DNA damage response by anchoring DNA lesions to the SPBs, in this way facilitating their repair [51]. In anaphase, Cdc55 phosphorylation by Cdk1-Clb2 stimulates full Net1/Cfi1 and Cdc14 disassociation and, subsequently, completes Cdc14 activation (inhibitory red line) [52]. The final release of Cdc14 to the cytoplasm globally reverses Cdk activity in coordination with PPA2-Cdc55 and PPA2-Rts1 phosphatases, supporting exit from mitosis [53]. Excitingly, Cdc14 also works as a central hub that coordinates mitotic progression with signaling pathways such as high-osmolarity glycerol (HOG) or target of rapamycin complex 1 (TORC1) [54,55,56]. Notably, however, Cdc14 functions are not restricted to cell cycle regulation, as the phosphatase can also induce autophagy under starvation stress [42].