Mechanism of Cell Cycle Entry Mediated by the Intrinsically Disordered Protein p27Kip1

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• 作者：Li Ou ; M. Brett Waddell ; Richard W. Kriwacki
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：April 20, 2012
• 年：2012
• 卷：7
• 期：4
• 页码：678-682
• 全文大小：258K
• 年卷期：v.7,no.4(April 20, 2012)
• ISSN：1554-8937

文摘

p27^Kip1 (p27), a prototypical intrinsically disordered protein (IDP), regulates eukaryotic cell division through interactions with cyclin-dependent kinase (Cdk)/cyclin complexes. The activity, stability, and subcellular localization of p27 are regulated by phosphorylation. We illustrate how p27 integrates regulatory signals from several non-receptor tyrosine kinases (NRTKs) to activate Cdk4 and initiate cell cycle entry. Unmodified p27 potently inhibits Cdk/cyclin complexes, including Cdk4/cyclin D (IC₅₀, 1 nM). Some NRTKs (e.g., Abl) phosphorylate p27 on Tyr 88, which facilitates a second modification on Tyr 74 by another NRTK (e.g., Src). Importantly, this second modification causes partial reactivation of Cdk4 within ternary complexes containing doubly Tyr phosphorylated p27. Partial activation of Cdk4 initiates entry into the cell division cycle. Therefore, p27鈥檚 disordered features enable NRTKs to sequentially promote a phosphorylation cascade that controls cell fate. Beyond cell cycle control, these results illustrate general concepts regarding why IDPs are well-suited for roles in signaling and regulation in biological systems.