Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1
Department of Biochemistry and Molecular Pharmacology
Biochemistry | Cell Biology | Molecular Biology
Eukaryotic cell division is often regulated by extracellular signals. In budding yeast, signaling from mating pheromones arrests the cell cycle in G1 phase. This arrest requires the protein Far1, which is thought to antagonize the G1/S transition by acting as a Cdk inhibitor (CKI), although the mechanisms remain unresolved. Recent studies found that G1/S cyclins (Cln1 and Cln2) recognize Cdk substrates via specific docking motifs, which promote substrate phosphorylation in vivo. Here, we show that these docking interactions are inhibited by pheromone signaling and that this inhibition requires Far1. Moreover, Far1 mutants that cannot inhibit docking are defective at cell-cycle arrest. Consistent with this arrest function, Far1 outcompetes substrates for association with G1/S cyclins in vivo, and it is present in large excess over G1/S cyclins during the precommitment period where pheromone can impose G1 arrest. Finally, a comparison of substrates that do and do not require docking suggests that Far1 acts as a multimode inhibitor that antagonizes both kinase activity and substrate recognition by Cln1/2-Cdk complexes. Our findings uncover a novel mechanism of Cdk regulation by external signals and shed new light on Far1 function to provide a revised view of cell-cycle arrest in this model system.
CDK Inhibitor, Kinase-substrate docking
DOI of Published Version
Pope PA, Bhaduri S, Pryciak PM. Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1. Curr Biol. 2014 Jun 16;24(12):1390-6. doi: 10.1016/j.cub.2014.05.002.
Current biology : CB
Pope PA, Bhaduri S, Pryciak PM. (2014). Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1. Morningside Graduate School of Biomedical Sciences Student Publications. https://doi.org/10.1016/j.cub.2014.05.002.. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1863