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1.
Sci Rep ; 12(1): 19501, 2022 11 14.
Article in English | MEDLINE | ID: mdl-36376357

ABSTRACT

The fission yeast mitogen-activated kinase (MAPK) Sty1 is essential for cell survival in response to different environmental insults. In unstimulated cells, Sty1 forms an inactive ternary cytoplasmatic complex with the MAPKK Wis1 and the MAPKAP kinase Srk1. Wis1 phosphorylates and activates Sty1, inducing the nuclear translocation of the complex. Once in the nucleus, Sty1 phosphorylates and activates Srk1, which in turns inhibits Cdc25 and cell cycle progression, before being degraded in a proteasome-dependent manner. In parallel, active nuclear Sty1 activates the transcription factor Atf1, which results in the expression of stress response genes including pyp2 (a MAPK phosphatase) and srk1. Despite its essentiality in response to stress, persistent activation of the MAPK pathway can be deleterious and induces cell death. Thus, timely pathway inactivation is essential to ensure an appropriate response and cell viability. Here, uncover a role for the MAPKAP kinase Srk1 as an essential component of a negative feedback loop regulating the Sty1 pathway through phosphorylation and inhibition of the Wis1 MAPKK. This feedback regulation by a downstream kinase in the pathway highlights an additional mechanism for fine-tuning of MAPK signaling. Thus, our results indicate that Srk1 not only facilitates the adaptation to stress conditions by preventing cell cycle progression, but also plays an instrumental role regulating the upstream kinases in the stress MAPK pathway.


Subject(s)
Schizosaccharomyces pombe Proteins , Schizosaccharomyces , Feedback , Gene Expression Regulation, Fungal , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , Mitogens/metabolism , Phosphorylation , Schizosaccharomyces/genetics , Schizosaccharomyces pombe Proteins/metabolism
2.
PLoS One ; 10(11): e0143037, 2015.
Article in English | MEDLINE | ID: mdl-26575035

ABSTRACT

BACKGROUND: Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is required for diverse cellular functions. Mammalian CaMKK activates CaMKs and also the evolutionarily-conserved AMP-activated protein kinase (AMPK). The fission yeast Schizosaccharomyces pombe CaMKK, Ssp1, is required for tolerance to limited glucose through the AMPK, Ssp2, and for the integration of cell growth and division through the SAD kinase Cdr2. RESULTS: Here we report that Ssp1 controls the G2/M transition by regulating the activity of the CaMK Srk1. We show that inhibition of Cdc25 by Srk1 is regulated by Ssp1; and also that restoring growth polarity and actin localization of ssp1-deleted cells by removing the actin-monomer-binding protein, twinfilin, is sufficient to suppress the ssp1 phenotype. CONCLUSIONS: These findings demonstrate that entry into mitosis is mediated by a network of proteins, including the Ssp1 and Srk1 kinases. Ssp1 connects the network of components that ensures proper polarity and cell size with the network of proteins that regulates Cdk1-cyclin B activity, in which Srk1 plays an inhibitory role.


Subject(s)
Actins/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , HSP70 Heat-Shock Proteins/physiology , Mitogen-Activated Protein Kinases/metabolism , Schizosaccharomyces pombe Proteins/metabolism , Schizosaccharomyces pombe Proteins/physiology , Schizosaccharomyces/enzymology , Cell Cycle Proteins/metabolism , Microbial Viability , Mitosis , Nuclear Proteins/metabolism , Phosphoprotein Phosphatases/metabolism , Phosphorylation , Protein-Tyrosine Kinases/metabolism , Schizosaccharomyces/cytology , Schizosaccharomyces/growth & development
3.
Biochim Biophys Acta ; 1783(9): 1595-604, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18474252

ABSTRACT

The nucleosome assembly protein Nap1 has been implicated in various cellular functions such as histone shuttling into the nucleus, nucleosome assembly, chromatin remodelling, transcriptional control and cell-cycle regulation in Saccharomyces cerevisiae. In Schizosaccharomyces pombe nap1 null mutant cells are viable but they showed a delay in the onset of mitosis which is rescued by the absence of the replication Cds1 checkpoint kinase. In contrast, the absence of the DNA-damage Chk1 checkpoint kinase is unable to rescue the delay. Moreover, the double nap1 cds1 mutant cells lose viability and cells show positive H2AX phosphorylation, suggesting that the viability of nap1-deleted cells is due to the Cds1 kinase. We also show that overexpression of Nap1 protein blocks the cell cycle in G1 phase.


Subject(s)
Cell Cycle Proteins/metabolism , Molecular Chaperones/metabolism , Nuclear Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Schizosaccharomyces pombe Proteins/metabolism , Schizosaccharomyces/genetics , Amino Acid Sequence , Cell Cycle Proteins/genetics , Cell Proliferation , Cell Survival , Checkpoint Kinase 2 , Chromatin/metabolism , Cytoskeleton/metabolism , DNA Replication , G1 Phase , Gene Deletion , Genomic Instability , Mitosis , Molecular Chaperones/genetics , Molecular Sequence Data , Nuclear Proteins/genetics , Protein Serine-Threonine Kinases/genetics , Schizosaccharomyces/cytology , Schizosaccharomyces/metabolism , Schizosaccharomyces pombe Proteins/genetics , Sequence Homology, Amino Acid
4.
Mol Biol Cell ; 19(4): 1670-9, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18272791

ABSTRACT

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. The Schizosaccharomyces pombe SAPK Sty1/Spc1 orchestrates general changes in gene expression in response to diverse forms of cytotoxic stress. Here we show that Sty1/Spc1 is bound to its target, the Srk1 kinase, when the signaling pathway is inactive. In response to stress, Sty1/Spc1 phosphorylates Srk1 at threonine 463 of the regulatory domain, inducing both activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25, and dissociation of Srk1 from the SAPK, which leads to Srk1 degradation by the proteasome.


Subject(s)
Mitogen-Activated Protein Kinases/metabolism , Schizosaccharomyces pombe Proteins/metabolism , Schizosaccharomyces/metabolism , Active Transport, Cell Nucleus , Amino Acid Substitution , Cell Cycle/physiology , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Enzyme Activation , Enzyme Stability , Fungal Proteins/antagonists & inhibitors , Fungal Proteins/genetics , Fungal Proteins/metabolism , Gene Expression Regulation, Fungal , MAP Kinase Signaling System , Mitogen-Activated Protein Kinases/chemistry , Mitogen-Activated Protein Kinases/genetics , Models, Biological , Mutagenesis, Site-Directed , Phosphorylation , Proteasome Endopeptidase Complex/metabolism , Protein Structure, Tertiary , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Schizosaccharomyces/cytology , Schizosaccharomyces/genetics , Schizosaccharomyces pombe Proteins/chemistry , Schizosaccharomyces pombe Proteins/genetics , Signal Transduction , Threonine/chemistry , ras-GRF1/antagonists & inhibitors , ras-GRF1/genetics , ras-GRF1/metabolism
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