Wee1family

Wee1 family refers to a group of conserved protein kinases that regulate cell cycle progression by restraining entry into mitosis. The canonical vertebrate members are WEE1 and MYT1, while in other organisms related kinases such as SWE1 in budding yeast and Mik1 in fission yeast are considered part of the same family. These kinases share a characteristic catalytic domain and regulatory regions that support their role in maintaining the G2/M checkpoint.

The primary function of Wee1 family kinases is to phosphorylate cyclin-dependent kinases (CDKs) on specific tyrosine residues, notably Tyr15 on CDK1 (and sometimes Tyr15 on CDK2). This phosphorylation inhibits CDK activity and prevents premature activation of the Cdk1/cyclin B complex, thereby delaying mitotic entry. In response to DNA damage or replication stress, checkpoint signaling pathways upregulate Wee1 activity or stability, while opposing phosphatases such as Cdc25 remove inhibitory phosphates to resume cell cycle progression. The net result is a controlled delay that allows DNA repair before mitosis.

Structurally, Wee1 family kinases possess a protein kinase catalytic domain with regulatory extensions that influence localization and substrate interaction. Evolutionarily, they are found across and beyond opisthokonts, with gene duplications giving rise to distinct paralogs in vertebrates (for example, WEE1 and MYT1) and single Wee1-family members in many other eukaryotes.

In clinical research, Wee1 inhibitors (for example, adavosertib) are being investigated as cancer therapeutics. By abrogating the G2/M checkpoint, these inhibitors can enhance the efficacy of DNA-damaging agents in tumor cells, particularly those with defective p53 signaling, while raising considerations about toxicity and resistance.