Many fingers on the mitotic trigger: post-translational regulation of the Cdc25C phosphatase.
The mitotic inducer Cdc25 phosphatase controls the activation of Cdc2/cyclin B protein kinase and entry into mitosis in eukaryotic cells. Cdc25C is highly regulated by multiple post-translational modifications within its N-terminal regulatory domain and site-specific protein interactions. Phosphorylation of one inhibitory site targeted by multiple kinases determines the timing of Cdc25C activation and arrests cells in G2 in response to checkpoint, stress, developmental and extracellular signals. In mitosis, phosphorylation of several Ser/Thr residues and Pin1-catalysed peptidyl-proline isomerisation produces activation. Phosphorylation of one activating site is antagonistic to the proximal inhibitory site and maintains Cdc25C activity during mitosis. Phosphorylation and interacting proteins also modulate the nuclear import and export signals on Cdc25C, inducing dramatic changes in its localisation within the cell. Thus, the regulation of Cdc25C activity and localization integrates multiple signals that govern the decision to enter mitosis.
Hutchins
James R A
JR
Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee Scotland, UK. james.hutchins@cancer.org.uk
Clarke
Paul R
PR
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D019926:Cyclin B; D003593:Cytoplasm / Q000378:metabolism; D016195:G2 Phase / Q000502:physiology; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D021382:Protein Sorting Signals / Q000502:physiology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014981:Xenopus / Q000235:genetics / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D019926:Cyclin B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D021382:Protein Sorting Signals; D016203:CDC2 Protein Kinase; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase