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1.
PLoS Biol ; 19(1): e3001029, 2021 01.
Article in English | MEDLINE | ID: mdl-33395410

ABSTRACT

Endosomal trafficking of receptors and associated proteins plays a critical role in signal processing. Until recently, it was thought that trafficking was shut down during cell division. Thus, remarkably, the regulation of trafficking during division remains poorly characterized. Here we delineate the role of mitotic kinases in receptor trafficking during asymmetric division. Targeted perturbations reveal that Cyclin-dependent Kinase 1 (CDK1) and Aurora Kinase promote storage of Fibroblast Growth Factor Receptors (FGFRs) by suppressing endosomal degradation and recycling pathways. As cells progress through metaphase, loss of CDK1 activity permits differential degradation and targeted recycling of stored receptors, leading to asymmetric induction. Mitotic receptor storage, as delineated in this study, may facilitate rapid reestablishment of signaling competence in nascent daughter cells. However, mutations that limit or enhance the release of stored signaling components could alter daughter cell fate or behavior thereby promoting oncogenesis.


Subject(s)
Aurora Kinases/physiology , CDC2 Protein Kinase/physiology , Mitosis/physiology , Receptors, Fibroblast Growth Factor/metabolism , Animals , Animals, Genetically Modified , Aurora Kinases/genetics , CDC2 Protein Kinase/genetics , Cell Cycle Proteins/metabolism , Ciona intestinalis/embryology , Ciona intestinalis/genetics , Embryo, Nonmammalian , Mitosis/genetics , Protein Transport/genetics , Receptors, Fibroblast Growth Factor/genetics , Receptors, Growth Factor/genetics , Receptors, Growth Factor/metabolism , Signal Transduction/genetics , Tissue Distribution/genetics
2.
Cell Microbiol ; 18(8): 1106-1120, 2016 08.
Article in English | MEDLINE | ID: mdl-26833682

ABSTRACT

Aurora kinases are eukaryotic serine/threonine protein kinases that regulate key events associated with chromatin condensation, centrosome and spindle function and cytokinesis. Elucidating the roles of Aurora kinases in apicomplexan parasites is crucial to understand the cell cycle control during Plasmodium schizogony or Toxoplasma endodyogeny. Here, we report on the localization of two previously uncharacterized Toxoplasma Aurora-related kinases (Ark2 and Ark3) in tachyzoites and of the uncharacterized Ark3 orthologue in Plasmodium falciparum erythrocytic stages. In Toxoplasma gondii, we show that TgArk2 and TgArk3 concentrate at specific sub-cellular structures linked to parasite division: the mitotic spindle and intranuclear mitotic structures (TgArk2), and the outer core of the centrosome and the budding daughter cells cytoskeleton (TgArk3). By tagging the endogenous PfArk3 gene with the green fluorescent protein in live parasites, we show that PfArk3 protein expression peaks late in schizogony and localizes at the periphery of budding schizonts. Disruption of the TgArk2 gene reveals no essential function for tachyzoite propagation in vitro, which is surprising giving that the P. falciparum and P. berghei orthologues are essential for erythrocyte schizogony. In contrast, knock-down of TgArk3 protein results in pronounced defects in parasite division and a major growth deficiency. TgArk3-depleted parasites display several defects, such as reduced parasite growth rate, delayed egress and parasite duplication, defect in rosette formation, reduced parasite size and invasion efficiency and lack of virulence in mice. Our study provides new insights into cell cycle control in Toxoplasma and malaria parasites and highlights Aurora kinase 3 as potential drug target.


Subject(s)
Aurora Kinases/physiology , Protozoan Proteins/physiology , Toxoplasma/enzymology , Toxoplasmosis/parasitology , Animals , Female , Host-Parasite Interactions , Mice , Protein Transport , Toxoplasma/physiology , Toxoplasma/ultrastructure , Virulence
3.
J Cell Biol ; 208(6): 713-27, 2015 Mar 16.
Article in English | MEDLINE | ID: mdl-25778919

ABSTRACT

The segregation of centromeres and telomeres at mitosis is coordinated at multiple levels to prevent the formation of aneuploid cells, a phenotype frequently observed in cancer. Mitotic instability arises from chromosome segregation defects, giving rise to chromatin bridges at anaphase. Most of these defects are corrected before anaphase onset by a mechanism involving Aurora B kinase, a key regulator of mitosis in a wide range of organisms. Here, we describe a new role for Aurora B in telomere dispersion and disjunction during fission yeast mitosis. Telomere dispersion initiates in metaphase, whereas disjunction takes place in anaphase. Dispersion is promoted by the dissociation of Swi6/HP1 and cohesin Rad21 from telomeres, whereas disjunction occurs at anaphase after the phosphorylation of condensin subunit Cnd2. Strikingly, we demonstrate that deletion of Ccq1, a telomeric shelterin component, rescued cell death after Aurora inhibition by promoting the loading of condensin on chromosome arms. Our findings reveal an essential role for telomeres in chromosome arm segregation.


Subject(s)
Aurora Kinases/physiology , Chromosomes, Fungal/physiology , Schizosaccharomyces pombe Proteins/physiology , Schizosaccharomyces/enzymology , Telomere/metabolism , Adenosine Triphosphatases/metabolism , Cell Cycle Proteins/metabolism , Chromatin/metabolism , Chromosomal Proteins, Non-Histone/metabolism , DNA-Binding Proteins/metabolism , Mitosis , Multiprotein Complexes/metabolism , Nondisjunction, Genetic , Nuclear Proteins/metabolism , Phosphoproteins/metabolism , Phosphorylation , Protein Processing, Post-Translational , Schizosaccharomyces/cytology , Schizosaccharomyces/genetics , Schizosaccharomyces pombe Proteins/metabolism , Shelterin Complex , Spindle Apparatus/metabolism , Telomere-Binding Proteins/metabolism
4.
Nat Commun ; 5: 5312, 2014 Nov 12.
Article in English | MEDLINE | ID: mdl-25387524

ABSTRACT

In yeast, the initiation of telomere replication at the late S phase involves in combined actions of kinases on Cdc13, the telomere binding protein. Cdc13 recruits telomerase to telomeres through its interaction with Est1, a component of telomerase. However, how cells terminate the function of telomerase at G2/M is still elusive. Here we show that the protein phosphatase 2A (PP2A) subunit Pph22 and the yeast Aurora kinase homologue Ipl1 coordinately inhibit telomerase at G2/M by dephosphorylating and phosphorylating the telomerase recruitment domain of Cdc13, respectively. While Pph22 removes Tel1/Mec1-mediated Cdc13 phosphorylation to reduce Cdc13-Est1 interaction, Ipl1-dependent Cdc13 phosphorylation elicits dissociation of Est1-TLC1, the template RNA component of telomerase. Failure of these regulations prevents telomerase from departing telomeres, causing perturbed telomere lengthening and prolonged M phase. Together our results demonstrate that differential and additive actions of PP2A and Aurora on Cdc13 limit telomerase action by removing active telomerase from telomeres at G2/M phase.


Subject(s)
Aurora Kinases/physiology , Cell Division/physiology , G2 Phase/physiology , Protein Phosphatase 2/physiology , Saccharomyces cerevisiae Proteins/physiology , Telomerase/physiology , Telomere-Binding Proteins/physiology , Telomere/physiology , Aurora Kinases/metabolism , Protein Phosphatase 2/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Telomerase/metabolism , Telomere/metabolism , Telomere-Binding Proteins/metabolism
5.
Nucleic Acids Res ; 42(20): 12469-82, 2014 Nov 10.
Article in English | MEDLINE | ID: mdl-25300489

ABSTRACT

The structural organization of chromosomes is essential for their correct function and dynamics during the cell cycle. The assembly of DNA into chromatin provides the substrate for topoisomerases and condensins, which introduce the different levels of superhelical torsion required for DNA metabolism. In particular, Top2 and condensin are directly involved in both the resolution of precatenanes that form during replication and the formation of the intramolecular loop that detects tension at the centromeric chromatin during chromosome biorientation. Here we show that histone depletion activates the spindle assembly checkpoint (SAC) and impairs sister chromatid decatenation, leading to chromosome mis-segregation and lethality in the absence of the SAC. We demonstrate that histone depletion impairs chromosome biorientation and activates the Aurora-dependent pathway, which detects tension problems at the kinetochore. Interestingly, SAC activation is suppressed by the absence of Top2 and Smc2, an essential component of condensin. Indeed, smc2-8 suppresses catenanes accumulation, mitotic arrest and growth defects induced by histone depletion at semi-permissive temperature. Remarkably, SAC activation by histone depletion is associated with condensin-mediated alterations of the centromeric chromatin. Therefore, our results reveal the importance of a precise interplay between histone supply and condensin/Top2 for pericentric chromatin structure, precatenanes resolution and centromere biorientation.


Subject(s)
Adenosine Triphosphatases/physiology , Chromatin/chemistry , Chromosomes, Fungal/chemistry , DNA-Binding Proteins/physiology , Histones/physiology , M Phase Cell Cycle Checkpoints , Multiprotein Complexes/physiology , Aurora Kinases/physiology , Centromere/physiology , Chromosome Segregation , DNA Topoisomerases, Type II/physiology , Metaphase , Nucleosomes/physiology , S Phase Cell Cycle Checkpoints , Saccharomyces cerevisiae Proteins/physiology
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