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Cyclin A and Cks1 promote kinase consensus switching to non-proline-directed CDK1 phosphorylation

Lookup NU author(s): Svitlana Korolchuk, Professor Jane Endicott

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Abstract

© 2023 The Author(s)Ordered protein phosphorylation by CDKs is a key mechanism for regulating the cell cycle. How temporal order is enforced in mammalian cells remains unclear. Using a fixed cell kinase assay and phosphoproteomics, we show how CDK1 activity and non-catalytic CDK1 subunits contribute to the choice of substrate and site of phosphorylation. Increases in CDK1 activity alter substrate choice, with intermediate- and low-sensitivity CDK1 substrates enriched in DNA replication and mitotic functions, respectively. This activity dependence is shared between Cyclin A- and Cyclin B-CDK1. Cks1 has a proteome-wide role as an enhancer of multisite CDK1 phosphorylation. Contrary to the model of CDK1 as an exclusively proline-directed kinase, we show that Cyclin A and Cks1 enhance non-proline-directed phosphorylation, preferably on sites with a +3 lysine residue. Indeed, 70% of cell-cycle-regulated phosphorylations, where the kinase carrying out this modification has not been identified, are non-proline-directed CDK1 sites.

Publication metadata

Author(s): al-Rawi A, Kaye E, Korolchuk S, Endicott JA, Ly T

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2023

Volume: 42

Issue: 3

Print publication date: 28/03/2023

Online publication date: 24/02/2023

Acceptance date: 02/02/2023

Date deposited: 09/03/2023

ISSN (electronic): 2211-1247

Publisher: Cell Press

URL: https://doi.org/10.1016/j.celrep.2023.112139

DOI: 10.1016/j.celrep.2023.112139

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