Human Cdc14A regulates Wee1 stability by counteracting CDK-mediated phosphorylation.
The activity of Cdk1-cyclin B1 mitotic complexes is regulated by the balance between the counteracting activities of Wee1/Myt1 kinases and Cdc25 phosphatases. These kinases and phosphatases must be strictly regulated to ensure proper mitotic timing. One masterpiece of this regulatory network is Cdk1, which promotes Cdc25 activity and suppresses inhibitory Wee1/Myt1 kinases through direct phosphorylation. The Cdk1-dependent phosphorylation of Wee1 primes phosphorylation by additional kinases such as Plk1, triggering Wee1 degradation at the onset of mitosis. Here we report that Cdc14A plays an important role in the regulation of Wee1 stability. Depletion of Cdc14A results in a significant reduction in Wee1 protein levels. Cdc14A binds to Wee1 at its amino-terminal domain and reverses CDK-mediated Wee1 phosphorylation. In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues. Thus the lack of phosphorylation of these two residues prevents the interaction with Plk1 and the consequent efficient Wee1 degradation at the onset of mitosis. These data support the hypothesis that Cdc14A counteracts Cdk1-cyclin B1 activity through Wee1 dephosphorylation.
Instituto de Biología Molecular y Celular del Cáncer and Departamento de Microbiología y Genética, Universidad de Salamanca/Consejo Superior de Investigaciones Científicas, 37007 Salamanca, Spain.
Sara
S
Ovejero
Patricia
P
Ayala
Avelino
A
Bueno
María P
MP
Sacristán
D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055550:Protein Stability; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D009687:Nuclear Proteins; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D020687:cdc25 Phosphatases; D000097869:Polo-Like Kinase 1; C499349:WEE1 protein, human; C120902:CDC14A protein, human