NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry.
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.
Bassermann
Florian
F
Department of Internal Medicine III, Technical University of Munich, 81675 Munich, Germany.
von Klitzing
Christine
C
Münch
Silvia
S
Bai
Ren-Yuan
RY
Kawaguchi
Hiroyuki
H
Morris
Stephan W
SW
Peschel
Christian
C
Duyster
Justus
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002522:Chlorocebus aethiops; D019926:Cyclin B / Q000502:physiology; D056744:Cyclin B1; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis / Q000145:classification / Q000378:metabolism* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C477288:ZC3HC1 protein, human; D044843:SKP Cullin F-Box Protein Ligases