Alternative titles; symbols
HGNC Approved Gene Symbol: WEE1
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:9,573,670-9,589,985 (from NCBI)
Igarashi et al. (1991) cloned the human homolog of wee1, a cell cycle regulatory gene, by transcomplementation of a Schizosaccharomyces pombe wee1 mutant. The human WEE1 gene is expressed as a 3-kb mRNA that encodes a predicted 432-amino acid protein. Human WEE1 has 29% amino acid identity to S. pombe wee1 protein in the central serine/threonine kinase domain.
Using Northern blot analysis, Nakanishi et al. (2000) detected high expression of a 3.8-kb WEE1 transcript in testis, with much lower expression in brain, pancreas, uterus, and lung.
Igarashi et al. (1991) demonstrated that the kinase domain of human WEE1 was sufficient to complement the fission yeast wee1 mutation. Overexpression of human WEE1 in S. pombe generated very elongated cells because of inhibition of the G2-M transition.
Parker and Piwnica-Worms (1992) demonstrated that the human WEE1 kinase phosphorylated the p34(CDC2) (CDK1; 116940)-cyclin B (CCNB1; 123836) complex on tyr15 and inactivated the p34(CDC2)-cyclin B kinase. This inhibition was reversed by the CDC25C protein (157680), which catalyzed the dephosphorylation of p34(CDC2).
McGowan and Russell (1993) demonstrated that WEE1 blocks cell division when overexpressed in HeLa cells. They independently demonstrated that purified human WEE1 phosphorylates p34(CDC2) exclusively on tyr15 in vitro; no thr14 phosphorylation was detected.
The wee1 tyrosine kinase and cdc25 tyrosine phosphatase of fission yeast play antagonistic roles in the induction of mitosis through cdc2 regulation. Heald et al. (1993) showed that the human wee1-like tyrosine kinase is a nuclear protein that ensures the completion of DNA replication before mitosis in cells expressing otherwise catastrophic levels of CDC2 activators. The human WEE1 tyrosine kinase appears to coordinate the transition between DNA replication and mitosis by protecting the nucleus from cytoplasmically activated CDC2 kinase.
Nakanishi et al. (2000) found that WEE1 phosphorylated CDK1 associated with cyclin B1 and, to a lesser extent, CDK2 (116953) associated with cyclin A1 (CCNA1; 604036) or cyclin E1 (CCNE1; 123837).
Matsuo et al. (2003) studied the regenerating liver of mice and demonstrated that the circadian clock controls expression of cell cycle-related genes that in turn modulate the expression of active cyclin B1-Cdc2 kinase, a key regulator of mitosis. Among these genes, Matsuo et al. (2003) found that expression of Wee1 was directly regulated by the molecular components of the circadian clockwork. In contrast, the circadian clockwork oscillated independently of the cell cycle in single cells. Matsuo et al. (2003) concluded that the intracellular circadian clockwork can control the cell division cycle directly and unidirectionally in proliferating cells.
WEE1 must be downregulated at the onset of mitosis to ensure rapid activation of CDC2. Watanabe et al. (2004) showed that phosphorylation of WEE1 by CDC2 on ser123 and by PLK1 (602098) on ser53 creates phosphodegrons (signals for degradation) for the beta-TRCP (see BTRC; 603482)-containing SCF E3 ubiquitin ligase complex, thereby inducing proteasome-dependent WEE1 degradation. Watanabe et al. (2004) also found evidence for a feedback loop between CDC2 and WEE1 that depends on ubiquitination and protein degradation.
Watanabe et al. (2005) found that phosphorylation of ser123 of WEE1 by CDC2 accelerated phosphorylation of ser53 by PLK1. Phosphorylation of ser123 also allowed phosphorylation of ser121 by CK2 (see CSNK2A1; 115440), thereby creating a second beta-TRCP-binding site.
By fluorescence in situ hybridization, Taviaux and Demaille (1993) demonstrated that the WEE1 gene is located on 11p15.3-p15.1.
Heald, R., McLoughlin, M., McKeon, F. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated cdc2 kinase. Cell 74: 463-474, 1993. [PubMed: 8348613] [Full Text: https://doi.org/10.1016/0092-8674(93)80048-j]
Igarashi, M., Nagata, A., Jinno, S., Suto, K., Okayama, H. Wee1(+)-like gene in human cells. Nature 353: 80-83, 1991. [PubMed: 1840647] [Full Text: https://doi.org/10.1038/353080a0]
Matsuo, T., Yamaguchi, S., Mitsui, S., Emi, A., Shimoda, F., Okamura, H. Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255-259, 2003. [PubMed: 12934012] [Full Text: https://doi.org/10.1126/science.1086271]
McGowan, C. H., Russell, P. Human Wee1 kinase inhibits cell division by phosphorylating p34cdc2 exclusively on Tyr15. EMBO J. 12: 75-85, 1993. [PubMed: 8428596] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb05633.x]
Nakanishi, M., Ando, H., Watanabe, N., Kitamura, K., Ito, K., Okayama, H., Miyamoto, T., Agui, T., Sasaki, M. Identification and characterization of human Wee1B, a new member of the Wee1 family of Cdk-inhibitory kinases. Genes Cells 5: 839-847, 2000. [PubMed: 11029659] [Full Text: https://doi.org/10.1046/j.1365-2443.2000.00367.x]
Parker, L. L., Piwnica-Worms, H. Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science 257: 1955-1957, 1992. [PubMed: 1384126] [Full Text: https://doi.org/10.1126/science.1384126]
Taviaux, S. A., Demaille, J. G. Localization of human cell cycle regulatory genes CDC25C to 5q31 and WEE1 to 11p15.3-11p.15.1 by fluorescence in situ hybridization. Genomics 15: 194-196, 1993. [PubMed: 8432534] [Full Text: https://doi.org/10.1006/geno.1993.1032]
Watanabe, N., Arai, H., Iwasaki, J., Shiina, M., Ogata, K., Hunter, T., Osada, H. Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways. Proc. Nat. Acad. Sci. 102: 11663-11668, 2005. [PubMed: 16085715] [Full Text: https://doi.org/10.1073/pnas.0500410102]
Watanabe, N., Arai, H., Nishihara, Y., Taniguchi, M., Watanabe, N., Hunter, T., Osada, H. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCF(beta-TrCP). Proc. Nat. Acad. Sci. 101: 4419-4424, 2004. [PubMed: 15070733] [Full Text: https://doi.org/10.1073/pnas.0307700101]