title: The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication.
abstract: Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 (ref. 3) as its targeting subunit. Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles. We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 is a cell-cycle-regulated protein with expression levels peaking at the G1/S transition. We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. In summary, we show that a cell-cycle-regulated SCF complex is regulated by the kinase PLK4, and that this in turn restricts centrosome re-duplication through degradation of the centriolar protein HsSAS-6.
authors: Institute for Molecular Biology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.
authors: Anja
authors: A
authors: Puklowski
authors: Yahya
authors: Y
authors: Homsi
authors: Debora
authors: D
authors: Keller
authors: Martin
authors: M
authors: May
authors: Sangeeta
authors: S
authors: Chauhan
authors: Uta
authors: U
authors: Kossatz
authors: Viktor
authors: V
authors: Grünwald
authors: Stefan
authors: S
authors: Kubicka
authors: Andreas
authors: A
authors: Pich
authors: Michael P
authors: MP
authors: Manns
authors: Ingrid
authors: I
authors: Hoffmann
authors: Pierre
authors: P
authors: Gönczy
authors: Nisar P
authors: NP
authors: Malek
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D002502:Centrioles / Q000502:physiology; D018385:Centrosome / Q000502:physiology*; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000502:physiology*; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C528759:FBXW5 protein, human; D034741:RNA, Small Interfering; C497202:SASS6 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases