A Family of Putative Tumor Suppressors Is Structurally and Functionally Conserved in Humans and Yeast

Abstract

In Saccharomyces cerevisiae the CDC14 gene is essential for cell cycle progression. Strains carrying the cdc14-1 ts allele enter the cell cycle and arrest at restrictive temperatures. We have identified two human cDNAs encoding proteins which share sequence identity to the yeast CDC14p. The cell cycle arrest in cdc14-1 ts can be specifically complemented by the human cDNAs suggesting that they are functionally equivalent to the yeast CDC14 gene. Another clone identified in the search for human CDC14-like proteins corresponded to the putative tumor suppressor gene PTEN/MMAC1 (phosphatase and tensin homologue deleted on chromosome 10 or mutated in multiple advanced cancers 1). Analysis of the PTEN/MMAC1 showed that it did not complement the cdc14-1 ts allele and that it is more closely related to the yeast open reading frame YNL128W. Human CDC14p and PTEN/MMAC1 were expressed as recombinant proteins, and both were shown to have kinetic properties characteristic of dual specific phosphatases. The human CDC14p was localized in the nucleus while PTEN/MMAC1 has been reported to be localized in the cytoplasm. Our results suggest that CDC14 and YNL128W/PTEN/MMAC1 represent two related, but distinct, families of human and yeast phosphatases.

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

“…Perhaps Cdc14 can counteract CDK1 activity in mitosis, thereby regulating mitotic exit and cytokinesis. On the basis of the functional conservation between yeast and human Cdc14 [19,20] it seems obvious to assume that fly Cdc14 plays a key role in mitosis and cytokinesis, but as already mentioned there is currently no scientific evidence available that strongly supports this assumption. Hopefully future research will unveil whether and how the fly Cdc14 phosphatase is regulating exit of mitosis.…”

“…Is this also the case in mammalian cells? Considering that human Cdc14 can compensate for the loss of Cdc14 in budding and fission yeast [19,20], the initial answer is a clear yes. However, as is the case for most cellular processes in mammals, the picture is more complicated.…”

“…Intriguingly, the core signalling module of the MEN/SIN is composed of highly conserved members of the Ste20-like kinase family [12][13][14], the MOB co-activator protein family [15], the LATS/NDR kinase family [16,17], and the Cdc14 protein phosphatase family [18]. The MEN/SIN pathway is very highly conserved from yeast to humans, since human Cdc14 can even compensate for the loss of Cdc14 in budding and fission yeast [19,20].…”

A role for the Cdc14-family phosphatase Flp1p at the end of the cell cycle in controlling the rapid degradation of the mitotic inducer Cdc25p in fission yeast

“…elegans and Homo sapiens on the basis of sequence similarity to the budding yeast Saccharomyces cerevisiae protein (Li et al, 1997;Cueille et al, 2001;Trautmann et al, 2001;Gruneberg et al, 2002). (All) Cdc14 proteins characterised to date are dual-specificity protein phosphatases that share a core of approximately 300 amino acids towards the amino terminus that includes a strictly conserved protein-phosphatase domain motif (Gray et al, 2003).…”

Human Cdc14A Reverses CDK1 Phosphorylation of Cdc25A on Serines 115 and 320

“…[9][10][11] In human cells, two Cdc14 isoforms -Cdc14A and Cdc14B-have been identified. 12 The function of these phosphatases remains poorly understood, although it is known that Cdc14A plays an important role in the centrosome cycle and mitotic regulation. 13,14 An important goal to elucidate the functions of human Cdc14 phosphatases is the identification of their substrates.…”