Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction.

Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA.
The Cdc25A protein phosphatase drives cell-cycle transitions by activating cyclin-dependent protein kinases. Failure to regulate Cdc25A leads to deregulated cell-cycle progression, bypass of cell-cycle checkpoints and genome instability. Ubiquitin-mediated proteolysis has an important role in balancing Cdc25A levels. Cdc25A contains a DS(82)G motif whose phosphorylation is targeted by beta-TrCP E3 ligase during interphase. Targeting beta-TrCP to Cdc25A requires phosphorylation of serines 79 (S79) and 82 (S82). Here, we report that casein kinase 1 alpha (CK1alpha) phosphorylates Cdc25A on both S79 and S82 in a hierarchical manner requiring prior phosphorylation of S76 by Chk1 or GSK-3beta. This facilitates beta-TrCP binding and ubiquitin-mediated proteolysis of Cdc25A throughout interphase and after exposure to genotoxic stress. The priming of Cdc25A by at least three kinases (Chk1, GSK-3beta, CK1alpha), some of which also require priming, ensures diverse extra- and intracellular signals interface with Cdc25A to precisely control cell division.
Mesh Terms:
Casein Kinase Ialpha, DNA Damage, HeLa Cells, Humans, Luciferases, Firefly, Phosphorylation, Ubiquitin, beta-Transducin Repeat-Containing Proteins, cdc25 Phosphatases
Oncogene Jun. 10, 2010; 29(23);3324-34 [PUBMED:20348946]
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