A processive phosphorylation circuit with multiple kinase inputs and mutually diversional routes controls G1/S...

Area of Science:

• Cellular signaling
• Molecular biology
• Biochemistry

Background:

• Multisite phosphorylation networks of cyclin-dependent kinase (CDK) targets reveal complex signaling pathways.
• Disordered proteins encode signal processing routes.
• The CDK inhibitor Sic1 serves as a model target with specific phosphorylation motifs.

Purpose of the Study:

• To uncover a signal processing mechanism involving multi-step competition between phosphorylation routes within the S-CDK-Sic1 complex.
• To understand how intracomplex phosphorylation controls Sic1 degradation.
• To investigate the integration of G1- and S-CDK activities and MAPK signaling.

Main Methods:

• Analysis of multisite phosphorylation networks.
• Investigating the S-CDK-Sic1 inhibitory complex.
• Studying competing phosphorylation routes and their effect on Sic1 degradation.
• Examining the integration of MAPK signaling.

Main Results:

• A signal processing mechanism involving multi-step competition between phosphorylation routes was uncovered.
• Intracomplex phosphorylation directly controls Sic1 degradation.
• Sequential integration of G1- and S-CDK activities is achieved while maintaining S-CDK inhibition.
• Competing phosphorylation routes prevent premature Sic1 degradation.
• MAPK integration tunes the competition of alternative phosphorylation paths.

Conclusions:

• Mutually diversional phosphorylation circuits represent a general mechanism for processing multiple kinase signals.
• These circuits coordinate cellular decisions in eukaryotes.
• The S-CDK-Sic1 complex demonstrates a novel way to integrate cell cycle kinase activities.