Which enzyme removes inhibitory phosphate from CDK1 to activate mitosis?
Release from Wee1-mediated inhibition is pivotal for mitotic entry, executed by Cdc25 family of dual specificity phosphatases capable of hydrolyzing phospho-threonine, phospho-serine and phospho-tyrosine. Three isoforms A, B, C exist in mammals, each with N-terminal regulatory domain containing 14-3-3 binding sites, nuclear export signals, Polo box binding motifs, and C-terminal catalytic domain bearing HCX5R active site with catalytic cysteine. During unperturbed cycle Cdc25B initiates activation at centrosomes early G2, followed by Cdc25C amplifying response. Polo-like kinase 1 phosphorylates Cdc25C at Ser214 enhancing activity, while CDK1 itself phosphorylates N-terminus creating positive feedback leading to abrupt switch. Checkpoint kinases Chk1 and Chk2 phosphorylate Ser216 promoting 14-3-3 sigma binding and cytoplasmic retention to maintain inhibitory phosphorylations on CDK1-Cyclin B. Active Cdc25 dephosphorylates CDK1 Tyr15 and Thr14 within activation segment exposing ATP-binding residues for catalysis increasing MPF activity more than hundredfold within minutes. In fission yeast cdc25 mutants delay mitosis increasing cell length, overexpression shortens size confirming role as dose-dependent mitotic inducer opposing Wee1 length regulatory pathway. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.
Ref: Nilsson & Hoffmann, Cdc25 Phosphatases Activate CDK1 for Mitosis, Cell Cycle 2000; Alberts et al., Chapter 17, Cdc25 Function.