title: CDK Substrate Phosphorylation and Ordering the Cell Cycle.
abstract: S phase and mitotic onset are brought about by the action of multiple different cyclin-CDK complexes. However, it has been suggested that changes in the total level of CDK kinase activity, rather than substrate specificity, drive the temporal ordering of S phase and mitosis. Here, we present a phosphoproteomics-based systems analysis of CDK substrates in fission yeast and demonstrate that the phosphorylation of different CDK substrates can be temporally ordered during the cell cycle by a single cyclin-CDK. This is achieved by rising CDK activity and the differential sensitivity of substrates to CDK activity over a wide dynamic range. This is combined with rapid phosphorylation turnover to generate clearly resolved substrate-specific activity thresholds, which in turn ensures the appropriate ordering of downstream cell-cycle events. Comparative analysis with wild-type cells expressing multiple cyclin-CDK complexes reveals how cyclin-substrate specificity works alongside activity thresholds to fine-tune the patterns of substrate phosphorylation.
authors.affiliation: Cell Cycle Laboratory, The Francis Crick Institute, London NW1 1AT, UK. Electronic address: matthew.swaffer@crick.ac.uk.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Swaffer
authors.affiliation: Cell Cycle Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Protein Analysis and Proteomics Platform, The Francis Crick Institute, London NW1 1AT, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Jones
authors.affiliation: Protein Analysis and Proteomics Platform, The Francis Crick Institute, London NW1 1AT, UK.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Flynn
authors.affiliation: Protein Analysis and Proteomics Platform, The Francis Crick Institute, London NW1 1AT, UK.
authors.forename: Ambrosius P
authors.initials: AP
authors.lastname: Snijders
authors.affiliation: Cell Cycle Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Laboratory of Yeast Genetics and Cell Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Nurse
mesh_terms: D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D008938:Mitosis; D010766:Phosphorylation; D012568:Schizosaccharomyces / Q000166:cytology* / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*
chemical_list: D016213:Cyclins; D029702:Schizosaccharomyces pombe Proteins; D018844:Cyclin-Dependent Kinases
keywords: CDK; S phase; cell cycle; cyclin-dependent kinase; kinase; mitosis; phosphoproteomics; phosphorylation