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Related Experiment Videos

Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways.

Nobumoto Watanabe1, Harumi Arai, Jun-Ichi Iwasaki

  • 1Antibiotics Laboratory, Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. nwatanab@riken.jp

Proceedings of the National Academy of Sciences of the United States of America
|August 9, 2005
PubMed
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Somatic Wee1A degradation is crucial for M phase onset. CDK phosphorylation of Wee1A serine 123 promotes its binding to beta-TrCP, facilitating degradation and mitotic progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Somatic Wee1A, an inhibitory kinase for cyclin-dependent kinase (CDK), is degraded via the proteasome at M phase onset.
  • This degradation is mediated by the E3 ubiquitin ligase SCF(beta-TrCP), which recognizes substrates through phosphodegron motifs.
  • Wee1A lacks the canonical phosphodegron, but phosphorylation of S53 and S123 by Plk1 and CDK, respectively, is required for beta-TrCP binding.

Purpose of the Study:

  • To elucidate the role of serine 123 (S123) phosphorylation in Wee1A binding to beta-TrCP.
  • To investigate the mechanisms by which S123 phosphorylation facilitates Wee1A degradation.
  • To determine the importance of Wee1A phosphorylation-dependent degradation for mitosis.

Main Methods:

  • Investigated the interaction between phosphorylated Wee1A (pS123) and beta-TrCP.

Related Experiment Videos

  • Utilized protein kinase assays to identify kinases phosphorylating Wee1A.
  • Employed a specific inhibitor of CK2 to assess the role of Wee1A degradation in mitosis.

    • Main Results:

    • CDK phosphorylation of Wee1A at S123 promotes beta-TrCP binding through three mechanisms.
    • pS123 directly interacts with beta-TrCP and primes phosphorylation by Plk1 (at S53) and CK2 (at S121), creating two phosphodegrons.
    • CK2 phosphorylation of S121 is dependent on prior S123 phosphorylation, generating a second beta-TrCP binding site.

    Conclusions:

    • Phosphorylation of Wee1A at S123 by CDK is a key event regulating its degradation.
    • This phosphorylation event creates multiple binding sites for SCF(beta-TrCP), ensuring efficient Wee1A downregulation.
    • Phosphorylation-dependent degradation of Wee1A is essential for the timely initiation of mitosis.