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

被引:169
作者
Watanabe, N
Arai, H
Iwasaki, J
Shiina, M
Ogata, K
Hunter, T
Osada, H
机构
[1] RIKEN, Antibiot Lab, Discovery Res Inst, Wako, Saitama 3510198, Japan
[2] Saitama Univ, Grad Sch Sci & Engn, Dept Mol Biol, Sakura, Saitama 3388570, Japan
[3] Toyo Univ, Fac Engn, Dept Appl Chem, Kawagoe, Saitama 3508585, Japan
[4] Yokohama City Univ, Sch Med, Dept Biochem, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan
[5] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA
关键词
polo-like kinase 1; ubiquitin; cell cycle; CK2; beta-TrCP;
D O I
10.1073/pnas.0500410102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
At the onset of M phase, the activity of somatic Wee1 (Wee1 A), the inhibitory kinase for cyclin-dependent kinase (CDK), is down-regulated primarily through proteasome-dependent degradation after ubiquitination by the E3 ubiquitin ligase SCPbeta-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.
引用
收藏
页码:11663 / 11668
页数:6
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