Regulation of Mih1/Cdc25 by protein phosphatase 2A and casein kinase 1

Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2008; 180(5):931-45. DOI: 10.1083/jcb.200711014
Source: PubMed


The Cdc25 phosphatase promotes entry into mitosis by removing cyclin-dependent kinase 1 (Cdk1) inhibitory phosphorylation. Previous work suggested that Cdc25 is activated by Cdk1 in a positive feedback loop promoting entry into mitosis; however, it has remained unclear how the feedback loop is initiated. To learn more about the mechanisms that regulate entry into mitosis, we have characterized the function and regulation of Mih1, the budding yeast homologue of Cdc25. We found that Mih1 is hyperphosphorylated early in the cell cycle and is dephosphorylated as cells enter mitosis. Casein kinase 1 is responsible for most of the hyperphosphorylation of Mih1, whereas protein phosphatase 2A associated with Cdc55 dephosphorylates Mih1. Cdk1 appears to directly phosphorylate Mih1 and is required for initiation of Mih1 dephosphorylation as cells enter mitosis. Collectively, these observations suggest that Mih1 regulation is achieved by a balance of opposing kinase and phosphatase activities. Because casein kinase 1 is associated with sites of polar growth, it may regulate Mih1 as part of a signaling mechanism that links successful completion of growth-related events to cell cycle progression.

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    • "The premature mitotic entry in pta2Δ cells (Figure 5C, D) resembles the reported phenotypes of both the catalytic and regulatory B-type subunits of PP2A phosphatase [61], [62], consistent with synthetic lethality that we observe in pta2Δwee1-50 cells (Figure S5) and with a reported function of PP2A in the regulation of phosphorylation state and activity of Cdc25 that has been described in S. cerevisiae and X. laevis [63], [64]. "
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    • "This could be an explanation for the observed differences in the cell cycle regulation of different organism. Indeed, recent results in plants show that the regulatory network interactions greatly differ from the yeast or metazoan systems [62] and even in the yeast there are some opposing ideas about the importance of some of the interactions [63], [64]. Such uncertainty in the presence or absence of some regulations might cause a problem in understanding cell cycle regulation. "
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    • "In contrast , we know very little about how the Cdc25 homolog Mih1p is regulated. Mih1p abundance does not vary through the cell cycle, but Mih1p phosphorylation undergoes dramatic changes, with hyperphosphorylation predominating in interphase and dephosphorylation accompanying mitosis (Pal et al. 2008). Mih1p appears to be mostly cytoplasmic (although not detectably excluded from the nucleus) for almost the entire cell cycle, except for a brief interval during mitotic exit when it becomes heavily concentrated in the nucleus (Keaton et al. 2008). "
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