ArticleProceedings of the National Academy of Sciences of the United States of America2005
Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers.
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121 citing papers in PubMed, 227 citations in OpenAlex.
- Bora, CEP192 and Cenexin regulate distinct Plk1-dependent cell and centrosome cycle transitions.Nature communications · 2026Article
- WEE1 kinase in cancer: Molecular mechanisms and inhibitor insights.EXCLI journal · 2026Review
- Article
- The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation.Cell reports · 2025Article
- The cAMP-PKA signaling initiates mitosis by phosphorylating Bora.Nature communications · 2025Article
- βTrCP facilitates MRN complex localization on chromatin to enhance DNA repair.Communications biology · 2025Article
- Preparation for mitosis requires gradual CDK1 activation.iScience · 2025Article
- Clinical relevance of PLK1 in epithelial ovarian cancer.Frontiers in pharmacology · 2025Review
- N-Glycoside of Indolo[2,3-Pharmaceuticals (Basel, Switzerland) · 2024Article
- The Potential for Targeting GCancers · 2024Review
- mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction.Cell reports · 2024Article
- Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis.Cell reports · 2024Article
- Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia.Genome biology · 2024Article
- A new wave of innovations within the DNA damage response.Signal transduction and targeted therapy · 2023Review
- The CUL4B-based E3 ubiquitin ligase regulates mitosis and brain development by recruiting phospho-specific DCAFs.The EMBO journal · 2023Article
- Review
- A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1.Oncogene · 2022Article
- Present and Future Perspective on PLK1 Inhibition in Cancer Treatment.Frontiers in oncology · 2022Review
- PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice.EMBO reports · 2021Article
- IL-37-induced activation of glycogen synthase kinase 3β promotes IL-1R8/Sigirr phosphorylation, internalization, and degradation in lung epithelial cells.Journal of cellular physiology · 2021Article
61 more citing papers are in PubMed but not listed here.
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7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
At the onset of M phase, the activity of somatic Wee1 (Wee1A), the inhibitory kinase for cyclin-dependent kinase (CDK), is down-regulated primarily through proteasome-dependent degradation after ubiquitination by the E3 ubiquitin ligase SCF(beta-TrCP). The F-box protein beta-TrCP (beta-transducin repeat-containing protein), the substrate recognition component of the ubiquitin ligase, binds to its substrates through a conserved binding motif (phosphodegron) containing two phosphoserines, DpSGXXpS. Although Wee1A lacks this motif, phosphorylation of serines 53 and 123 (S53 and S123) of Wee1A by polo-like kinase 1 (Plk1) and CDK, respectively, are required for binding to beta-TrCP. The sequence surrounding phosphorylated S53 (DpSAFQE) is similar to the conserved beta-TrCP-binding motif; however, the role of S123 phosphorylation (EEGFGSSpSPVK) in beta-TrCP binding was not elucidated. In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2), to create two phosphodegrons on Wee1A. In the case of Plk1, S123 phosphorylation created a polo box domain-binding motif (SpSP) on Wee1A to accelerate phosphorylation of S53 by Plk1. CK2 could phosphorylate S121, but only if S123 was phosphorylated first, thereby generating the second beta-TrCP-binding site (EEGFGpS121). Using a specific inhibitor of CK2, we showed that the phosphorylation-dependent degradation of Wee1A is important for the proper onset of mitosis.
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