Dephosphorylation of cyclin-dependent kinases by type 2C protein phosphatases.
Activating phosphorylation of cyclin-dependent protein kinases (CDKs) is necessary for their kinase activity and cell cycle progression. This phosphorylation is carried out by the Cdk-activating kinase (CAK); in contrast, little is known about the corresponding protein phosphatase. We show that type 2C protein phosphatases (PP2Cs) are responsible for this dephosphorylation of Cdc28p, the major budding yeast CDK. Two yeast PP2Cs, Ptc2p and Ptc3p, display Cdc28p phosphatase activity in vitro and in vivo, and account for approximately 90% of Cdc28p phosphatase activity in yeast extracts. Overexpression of PTC2 or PTC3 results in synthetic lethality in strains temperature-sensitive for yeast CAK1, and disruptions of PTC2 and PTC3 suppress the growth defect of a cak1 mutant. Furthermore, PP2C-like enzymes are the predominant phosphatases toward human Cdk2 in HeLa cell extracts, indicating that the substrate specificity of PP2Cs toward CDKs is evolutionarily conserved.
Cheng
A
A
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8024, USA.
Ross
K E
KE
Kaldis
P
P
Solomon
M J
MJ
D017489:CDC28 Protein Kinase, S cerevisiae / Q000378:metabolism; D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013045:Species Specificity; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D005656:Fungal Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D010769:Phosphothreonine; D017346:Protein Serine-Threonine Kinases; D017489:CDC28 Protein Kinase, S cerevisiae; D018844:Cyclin-Dependent Kinases; C087358:PTC1 protein, S cerevisiae; C000607464:PTC3 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D000095043:Cyclin-Dependent Kinase-Activating Kinase