Practice question

G2/M commitment governed by antagonism between inhibitory Wee1/Myt1 kinases and activating Cdc25 phosphatases acting on CDK1-Cyclin B. Wee1 encodes nuclear tyrosine kinase belonging to WEE family capable of phosphorylating both threonine and tyrosine. Active during S and G2 phases, Wee1 phosphorylates CDK1 at conserved glycine rich loop residues Thr14 and Tyr15 positioned near ATP binding cleft. These phosphates sterically hinder ATP orientation and substrate catalysis maintaining low activity even though cyclin B accumulates to high levels, effectively preventing premature mitotic entry while replication completes. Inhibition reinforced by Myt1 membrane associated kinase adding Thr14 modification. At mitotic threshold, rising Plk1 and CDK1 phosphorylate Wee1 creating phosphodegron recognized by SCF-betaTrCP ligase for ubiquitination and degradation plus nuclear export, while concurrently activating Cdc25C. Cdc25 removes Thr14/Tyr15 phosphates reversing inhibition. DNA damage checkpoint activates Chk1 which phosphorylates Cdc25 isoforms causing 14-3-3 sequestration and stabilizes Wee1 to enforce G2 arrest. Pharmacological Wee1 inhibitors like adavosertib force premature mitosis in cancer cells with accumulated damage causing mitotic catastrophe. 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.