GSK-3β targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3β inactivation correlates with Cdc25A overproduction in human cancers

The Cdc25A phosphatase positively regulates cell-cycle transitions, is degraded by the proteosome throughout interphase and in response to stress, and is overproduced in human cancers. The kinases targeting Cdc25A for proteolysis during early cell-cycle phases have not been identified, and mechanistic insight into the cause of Cdc25A overproduction in human cancers is lacking. Here, we demonstrate that glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylates Cdc25A to promote its proteolysis in early cell-cycle phases. Phosphorylation by GSK-3 beta requires priming of Cdc25A, and this can be catalyzed by polo-like kinase 3 (PIk-3). Importantly, a strong correlation between Cdc25A overproduction and GSK-3 beta inactivation was observed in human tumor tissues, indicating that GSK-3 beta inactivation may account for Cdc25A overproduction in a subset of human tumors.