A processive phosphorylation circuit with multiple kinase inputs and mutually diversional routes controls G1/S decision
Open Access
- 15 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-14
- https://doi.org/10.1038/s41467-020-15685-z
Abstract
Studies on multisite phosphorylation networks of cyclin-dependent kinase (CDK) targets have opened a new level of signaling complexity by revealing signal processing routes encoded into disordered proteins. A model target, the CDK inhibitor Sic1, contains linear phosphorylation motifs, docking sites, and phosphodegrons to empower an N-to-C terminally directed phosphorylation process. Here, we uncover a signal processing mechanism involving multi-step competition between mutually diversional phosphorylation routes within the S-CDK-Sic1 inhibitory complex. Intracomplex phosphorylation plays a direct role in controlling Sic1 degradation, and provides a mechanism to sequentially integrate both the G1- and S-CDK activities while keeping S-CDK inhibited towards other targets. The competing phosphorylation routes prevent premature Sic1 degradation and demonstrate how integration of MAPK from the pheromone pathway allows one to tune the competition of alternative phosphorylation paths. The mutually diversional phosphorylation circuits may be a general way for processing multiple kinase signals to coordinate cellular decisions in eukaryotes.Keywords
This publication has 74 references indexed in Scilit:
- Mechanism of Cell Cycle Entry Mediated by the Intrinsically Disordered Protein p27Kip1ACS Chemical Biology, 2012
- Cascades of multisite phosphorylation control Sic1 destruction at the onset of S phaseNature, 2011
- Distinct Interactions Select and Maintain a Specific Cell FateMolecular Cell, 2011
- Dynamics of Cdk1 Substrate Specificity during the Cell CycleMolecular Cell, 2011
- Positive feedback of G1 cyclins ensures coherent cell cycle entryNature, 2008
- Role of Intrinsic Flexibility in Signal Transduction Mediated by the Cell Cycle Regulator, p27Kip1Journal of Molecular Biology, 2008
- A Mechanism for Cell-Cycle Regulation of MAP Kinase Signaling in a Yeast Differentiation PathwayCell, 2007
- p27 Phosphorylation by Src Regulates Inhibition of Cyclin E-Cdk2Cell, 2007
- A versatile toolbox for PCR‐based tagging of yeast genes: new fluorescent proteins, more markers and promoter substitution cassettesYeast, 2004
- Functional profiling of the Saccharomyces cerevisiae genomeNature, 2002