WEE

WEE kinases impose the G2/M checkpoint by phosphorylating cyclin-dependent kinases on residues of the ATP-binding cleft. WEE1 phosphorylates CDK1 at Tyr15, and also modifies CDK2, whereas MYT1 (PKMYT1) is membrane-associated and phosphorylates both Thr14 and Tyr15; WEE2 is an oocyte-specific paralog. This inhibitory phosphorylation is reversed by the CDC25 phosphatases, allowing mitotic entry once DNA is intact and replication complete. WEE1 is activated downstream of DNA damage signaling and is overexpressed in many cancers, so the inhibitor adavosertib is used to force p53-deficient tumors into premature mitosis together with chemotherapy or radiation. WEE2 mutations cause oocyte maturation arrest and female infertility.