GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta 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-3beta (GSK-3beta) phosphorylates Cdc25A to promote its proteolysis in early cell-cycle phases. Phosphorylation by GSK-3beta requires priming of Cdc25A, and this can be catalyzed by polo-like kinase 3 (Plk-3). Importantly, a strong correlation between Cdc25A overproduction and GSK-3beta inactivation was observed in human tumor tissues, indicating that GSK-3beta inactivation may account for Cdc25A overproduction in a subset of human tumors.
Kang
Tiebang
T
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
Wei
Yongkun
Y
Honaker
Yuchi
Y
Yamaguchi
Hiroshi
H
Appella
Ettore
E
Hung
Mien-Chie
MC
Piwnica-Worms
Helen
H
D000818:Animals; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004789:Enzyme Activation / Q000528:radiation effects; D004795:Enzyme Stability / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding / Q000528:radiation effects; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000528:radiation effects; D011839:Radiation, Ionizing; D025801:Ubiquitin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism*
D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D010769:Phosphothreonine; D010768:Phosphoserine; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000071877:Checkpoint Kinase 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D020687:cdc25 Phosphatases