title: Negative feedback regulation of calcineurin-dependent Prz1 transcription factor by the CaMKK-CaMK1 axis in fission yeast.
abstract: Calcium signals trigger the translocation of the Prz1 transcription factor from the cytoplasm to the nucleus. The process is regulated by the calcium-activated phosphatase calcineurin, which activates Prz1 thereby maintaining active transcription during calcium signalling. When calcium signalling ceases, Prz1 is inactivated by phosphorylation and exported to the cytoplasm. In budding yeast and mammalian cells, different kinases have been reported to counter calcineurin activity and regulate nuclear export. Here, we show that the Ca(2+)/calmodulin-dependent kinase Cmk1 is first phosphorylated and activated by the newly identified kinase CaMKK2 homologue, Ckk2, in response to Ca(2+). Then, active Cmk1 binds, phosphorylates and inactivates Prz1 transcription activity whilst at the same time cmk1 expression is enhanced by Prz1 in response to Ca(2+). Furthermore, Cdc25 phosphatase is also phosphorylated by Cmk1, inducing cell cycle arrest in response to an increase in Ca(2+). Moreover, cmk1 deletion shows a high tolerance to chronic exposure to Ca(2+), due to the lack of cell cycle inhibition and elevated Prz1 activity. This work reveals that Cmk1 kinase activated by the newly identified Ckk2 counteracts calcineurin function by negatively regulating Prz1 activity which in turn is involved in activating cmk1 gene transcription. These results are the first insights into Cmk1 and Ckk2 function in Schizosaccharomyces pombe.
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona 08036, Catalunya, Spain.
authors: Eugenia
authors: E
authors: Cisneros-Barroso
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona 08036, Catalunya, Spain.
authors: Tula
authors: T
authors: Yance-Chávez
authors: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae, Higashi-Osaka 577-8502, Japan.
authors: Ayako
authors: A
authors: Kito
authors: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae, Higashi-Osaka 577-8502, Japan.
authors: Reiko
authors: R
authors: Sugiura
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona 08036, Catalunya, Spain.
authors: Alba
authors: A
authors: Gómez-Hierro
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona 08036, Catalunya, Spain.
authors: David
authors: D
authors: Giménez-Zaragoza
authors: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona 08036, Catalunya, Spain aliguerosa@ub.edu.
authors: Rosa
authors: R
authors: Aligue
mesh_terms: D002118:Calcium; D020013:Calcium Signaling; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000737:chemistry / Q000378:metabolism*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D025461:Feedback, Physiological; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D009997:Osmotic Pressure; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D012568:Schizosaccharomyces / Q000201:enzymology / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593219:Prz1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; D014157:Transcription Factors; C000593217:CKK2 protein, S pombe; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C000593218:Cmk1 protein, S pombe; C570820:Cdc25 protein, S pombe; D010749:Phosphoprotein Phosphatases; D002118:Calcium