NIPA Defines an SCF-Type Mammalian E3 Ligase that Regulates Mitotic Entry

• Published in: Cell 2005-07, Vol.122 (1), p.45-57
• Main Authors: Bassermann, Florian, von Klitzing, Christine, Münch, Silvia, Bai, Ren-Yuan, Kawaguchi, Hiroyuki, Morris, Stephan W., Peschel, Christian, Duyster, Justus
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Cell Cycle - physiology; Cell Cycle Proteins; Cell Line; Cercopithecus aethiops; COS Cells; Cyclin B - physiology; Cyclin B1; Gene Silencing; HeLa Cells; Humans; Mice; Mitosis - physiology; Molecular Sequence Data; NIH 3T3 Cells; Nuclear Proteins - biosynthesis; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Phosphorylation; RNA, Small Interfering - metabolism; SKP Cullin F-Box Protein Ligases - biosynthesis; SKP Cullin F-Box Protein Ligases - classification; SKP Cullin F-Box Protein Ligases - metabolism; SKP Cullin F-Box Protein Ligases - physiology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2005.04.034

The regulated oscillation of protein expression is an essential mechanism of cell cycle control. The SCF class of E3 ubiquitin ligases is involved in this process by targeting cell cycle regulatory proteins for degradation by the proteasome, with the F-box subunit of the SCF specifically recruiting a given substrate to the SCF core. Here we identify NIPA (nuclear interaction partner of ALK) as a human F-box-containing protein that defines an SCF-type E3 ligase (SCF NIPA) controlling mitotic entry. Assembly of this SCF complex is regulated by cell-cycle-dependent phosphorylation of NIPA, which restricts substrate ubiquitination activity to interphase. We show nuclear cyclin B1 to be a substrate of SCF NIPA. Inactivation of NIPA by RNAi results in nuclear accumulation of cyclin B1 in interphase, activation of cyclin B1-Cdk1 kinase activity, and premature mitotic entry. Thus, SCF NIPA-based ubiquitination may regulate S-phase completion and mitotic entry in the mammalian cell cycle.