Negative feedback regulation of calcineurin-dependent Prz1 transcription factor by the CaMKK-CaMK1 axis in fission yeast.
Bottom Line: 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+).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.
Affiliation: 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.Show MeSH
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Mentions: Under normal growing conditions, calcineurin (Ppb1), Cmk1 and probably Ckk2 are inactive (Figure 9), and under these circumstances, Prz1 remains in the cytoplasm, phosphorylated by Cmk1 and most probably by additional kinases, since the deletion of cmk1 does not provoke the immediate translocation of Prz1 to the nucleus. In response to an increase in Ca2+, the Ppb1, Cmk1 and Ckk2 proteins are activated. In this scenario, active Ppb1 activates Prz1 by dephosphorylation and consequently Prz1 translocation to the nucleus to activate its target genes, one of which is cmk1. An increase in Ca2+ also activates Cmk1. Activation of Cmk1 kinase occurs in two steps, first by binding Ca2+/CaM and second through phosphorylation by Ckk2 (Figure 9). Active Cmk1 has two important functions during the Ca2+ response that maintain cell homeostasis: inhibition of cell cycle progression by phosphorylation of the Cdc25 protein (Figure 9) and inhibition of Prz1-dependent transcription, which can be toxic to the cell, through phosphorylation of Prz1 and subsequent exit from the nucleus (Figure 9). Thus, while both activation and inactivation of Prz1 is regulated by Ca2+, the kinetics is different. The activation by Ppb1 is faster than the following inactivation by Cmk1.
Affiliation: 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.