The Clp1/Cdc14 phosphatase contributes to the robustness of cytokinesis by association with anillin-related Mid1

Clifford, Dawn M.; Wolfe, Benjamin; Roberts-Galbraith, Rachel H.; McDonald, W. Hayes; Yates, John R.; Gould, Kathleen L.

doi:10.1083/jcb.200709060

Cited by 94 publications

(125 citation statements)

References 45 publications

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“…Our work confirms and extends previous work (17) showing that Clp1 dampens Cdk1 activity by dephosphorylating and inactivating Cdc25. Clp1 facilitates proper contractile ring dynamics and timely cytokinesis by antagonizing Cdk1 phosphorylations that negatively regulate the septation initiation network (SIN) and antagonize contractile ring formation (26,(32)(33)(34)(35). Our data show that abrogation of Clp1-Cdc25 feedback reduces the abruptness of cytokinesis.…”

Section: Discussionmentioning

confidence: 60%

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Lu¹,

Domingo-Sananes

Huzarska³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cyclin-dependent kinase 1 (Cdk1) kinase dephosphorylation and activation by Cdc25 phosphatase are essential for mitotic entry. Activated Cdk1 phosphorylates Cdc25 and other substrates, further activating Cdc25 to form a positive feedback loop that drives the abrupt G2/mitosis switch. Conversely, mitotic exit requires Cdk1 inactivation and reversal of Cdk1 substrate phosphorylation. This dephosphorylation is mediated, in part, by Clp1/Cdc14, a Cdk1-antagonizing phosphatase, which reverses Cdk1 phosphorylation of itself, Cdc25, and other Cdk1 substrates. Thus, Cdc25 phosphoregulation is essential for proper G2-M transition, and its contributions to cell cycle control have been modeled based on studies using Xenopus and human cell extracts. Because cell extract systems only approximate in vivo conditions where proteins interact within dynamic cellular environments, here, we use Schizosaccharomyces pombe to characterize, both experimentally and mathematically, the in vivo contributions of Cdk1-mediated phosphorylation of Cdc25 to the mitotic transition. Through comprehensive mapping of Cdk1 phosphosites on Cdc25 and characterization of phosphomutants, we show that Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation, the precision of mitotic entry, and unvarying cell length but not Cdc25 localization or abundance. We propose a mathematical model that explains Cdc25 regulation by Cdk1 through a distributive and disordered phosphorylation mechanism that ultrasensitively activates Cdc25. We also show that Clp1/Cdc14 dephosphorylation of Cdk1 sites on Cdc25 controls the proper timing of cell division, a mechanism that is likely due to the double negative feedback loop between Clp1/Cdc14 and Cdc25 that controls the abruptness of the mitotic exit switch. mitotic bistability | multisite phosphorylation

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Section: Discussionmentioning

confidence: 60%

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Lu¹,

Domingo-Sananes

Huzarska³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Schizosaccharomyces pombe Cdc14/Flp1 primarily participates in the regulation of the phosphatase Cdc25 and cytokinesis (19). Vertebrate CDC14s have been linked to diverse functions ranging from centrosome maturation and separation, DNA damage checkpoint control, DNA repair, and cytokinesis control (20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion

Chen

Uddin

Voit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cell adhesion and migration are highly dynamic biological processes that play important roles in organ development and cancer metastasis. Their tight regulation by small GTPases and protein phosphorylation make interrogation of these key processes of great importance. We now show that the conserved dualspecificity phosphatase human cell-division cycle 14A (hCDC14A) associates with the actin cytoskeleton of human cells. To understand hCDC14A function at this location, we manipulated native loci to ablate hCDC14A phosphatase activity (hCDC14A PD ) in untransformed hTERT-RPE1 and colorectal cancer (HCT116) cell lines and expressed the phosphatase in HeLa FRT T-Rex cells. Ectopic expression of hCDC14A induced stress fiber formation, whereas stress fibers were diminished in hCDC14A PD cells. hCDC14A PD cells displayed faster cell migration and less adhesion than wild-type controls. hCDC14A colocalized with the hCDC14A substrate kidneyand brain-expressed protein (KIBRA) at the cell leading edge and overexpression of KIBRA was able to reverse the phenotypes of hCDC14A PD cells. Finally, we show that ablation of hCDC14A activity increased the aggressive nature of cells in an in vitro tumor formation assay. Consistently, hCDC14A is down-regulated in many tumor tissues and reduced hCDC14A expression is correlated with poorer survival of patients with cancer, to suggest that hCDC14A may directly contribute to the metastatic potential of tumors. Thus, we have uncovered an unanticipated role for hCDC14A in cell migration and adhesion that is clearly distinct from the mitotic and cytokinesis functions of Cdc14/Flp1 in budding and fission yeast.CDC14 | cell migration | cell adhesion | phosphatase

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“…We found, unexpectedly, that Clp1 accumulation at the CR was defective in all tested CPC mutations. Clp1 contributes to CR stability and the fidelity of cytokinesis (Trautmann and McCollum, 2005;Chen et al, 2008;Clifford et al, 2008). Yet, because Clp1 is nonessential in S. pombe, its loss at the CR perturbs, but does not normally prevent, cytokinesis.…”

Section: Discussionmentioning

confidence: 99%

“…The CPC Genetically Interacts with the S. pombe Cytokinetic Apparatus Clp1 accumulation at the CR is required for the fidelity of cytokinesis (Trautmann and McCollum, 2005;Chen et al, 2008;Clifford et al, 2008). Furthermore, temperature-sensitive alleles of CR components exhibit a strong genetic interaction with mid1⌬ , which encodes a Mid1 mutant that lacks the region necessary to recruit Clp1 to the CR .…”

Section: Molecular Biology Of the Cell 3652mentioning

confidence: 99%

“…These observations are in striking contrast to what was seen in wild-type clp1-GFP sid4-RFP cells, in which Clp1-GFP localized strongly to the CR initially in metaphase ( Figure 6E, left column, t ϭ 0) and continued on the CR through anaphase ( Figure 6E, left column, t ϭ 2-10). Accordingly, disruption of CPC function severely affected Clp1 accumulation at the CR.The CPC Genetically Interacts with the S. pombe Cytokinetic Apparatus Clp1 accumulation at the CR is required for the fidelity of cytokinesis (Trautmann and McCollum, 2005;Chen et al, 2008;Clifford et al, 2008). Furthermore, temperature-sensitive alleles of CR components exhibit a strong genetic interaction with mid1⌬ , which encodes a Mid1 mutant that lacks the region necessary to recruit Clp1 to the CR .…”

mentioning

confidence: 99%

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A Link between Aurora Kinase and Clp1/Cdc14 Regulation Uncovered by the Identification of a Fission Yeast Borealin-Like Protein

Bohnert

Chen

Clifford

et al. 2009

MBoC

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The chromosomal passenger complex (CPC) regulates various events in cell division. This complex is composed of a catalytic subunit, Aurora B kinase, and three nonenzymatic subunits, INCENP, Survivin, and Borealin. Together, these four subunits interdependently regulate CPC function, and they are highly conserved among eukaryotes. However, a Borealin homologue has never been characterized in the fission yeast, Schizosaccharomyces pombe. Here, we isolate a previously uncharacterized S. pombe protein through association with the Cdc14 phosphatase homologue, Clp1/Flp1, and identify it as a Borealin-like member of the CPC. Nbl1 (novel Borealin-like 1) physically associates with known CPC components, affects the kinase activity and stability of the S. pombe Aurora B homologue, Ark1, colocalizes with known CPC subunits during mitosis, and shows sequence similarity to human Borealin. Further analysis of the Clp1-Nbl1 interaction indicates that Clp1 requires CPC activity for proper accumulation at the contractile ring (CR). Consistent with this, we describe negative genetic interactions between mutant alleles of CPC and CR components. Thus, this study characterizes a fission yeast Borealin homologue and reveals a previously unrecognized connection between the CPC and the process of cytokinesis in S. pombe. INTRODUCTIONTo ensure successful cell division, sister chromatids must segregate to opposite poles of dividing cells in mitosis and be partitioned into two new daughter cells during cytokinesis (Pines and Rieder, 2001). Highly intricate mechanisms control these processes, with various macromolecular complexes coordinating their activities such that the integrity of cell division is maintained. The chromosomal passenger complex (CPC), which is composed of a catalytic subunit, Aurora B kinase, and three nonenzymatic subunits, INCENP, Survivin, and Borealin, functions as one of these critical regulatory complexes. As its name implies, this complex travels on chromosomes to various sites during cell division such that it can execute specific tasks at distinct locations and times (Earnshaw and Bernat, 1991). These functions include, but are not limited to, chromosome condensation, stabilization of the mitotic spindle, correction of improper kinetochore-microtubule attachments, and regulation of cytokinesis (for reviews, see Vagnarelli and Earnshaw, 2004;Vader et al., 2006;Ruchaud et al., 2007).The four CPC subunits are highly interdependent for proper localization, activity, and stability (Ruchaud et al., 2007). Consistent with such interdependency, these subunits are widely conserved among eukaryotes (Ruchaud et al., 2007). However, it has proven difficult to identify Borealin homologues in yeasts. Though some have speculated that yeast Borealin homologues might not exist because of fusion of the Borealin and Survivin subunits into a single yeast Survivin homologue (Vader et al., 2006), recent evidence suggests that there are in fact yeast Borealin homologues (Nakajima et al., 2009). Nonetheless, a Borealin homologue in th...

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The Clp1/Cdc14 phosphatase contributes to the robustness of cytokinesis by association with anillin-related Mid1

Cited by 94 publications

References 45 publications

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion

A Link between Aurora Kinase and Clp1/Cdc14 Regulation Uncovered by the Identification of a Fission Yeast Borealin-Like Protein

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