The SCF/Slimb Ubiquitin Ligase Limits Centrosome Amplification through Degradation of SAK/PLK4

• Published in: Current biology 2009-01, Vol.19 (1), p.43-49
• Main Authors: Cunha-Ferreira, Inês, Rodrigues-Martins, Ana, Bento, Inês, Riparbelli, Maria, Zhang, Wei, Laue, Ernest, Callaini, Giuliano, Glover, David M., Bettencourt-Dias, Mónica
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Calcium-Binding Proteins - metabolism; Cell Cycle Proteins - metabolism; CELLBIO; Centrioles - physiology; Centrosome - metabolism; DNA Primers - genetics; Drosophila - metabolism; Drosophila - physiology; Drosophila Proteins - metabolism; Flow Cytometry; Immunoprecipitation; Mass Spectrometry; Microscopy, Electron, Transmission; Mutagenesis, Site-Directed; Nuclear Proteins - metabolism; Protein-Serine-Threonine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Staphylococcal Protein A - metabolism; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2008.11.037

Centrioles are essential for the formation of microtubule-derived structures, including cilia and centrosomes. Abnormalities in centrosome number and structure occur in many cancers and are associated with genomic instability [1]. In most dividing animal cells, centriole formation is coordinated with DNA replication and is highly regulated such that only one daughter centriole forms close to each mother centriole [1, 2]. Centriole formation is triggered and dependent on a conserved kinase, SAK/PLK4 [3–8]. Downregulation and overexpression of SAK/PLK4 is associated with cancer in humans, mice, and flies [9–11]. Here we show that centrosome amplification is normally inhibited by degradation of SAK/PK4 degradation, mediated by the SCF/Slimb ubiquitin ligase. This complex physically interacts with SAK/PLK4, and in its absence, SAK/PLK4 accumulates, leading to the striking formation of multiple daughter centrioles surrounding each mother. This interaction is mediated via a conserved Slimb binding motif in SAK/PLK4, mutations of which leads to centrosome amplification. This regulation is likely to be conserved, because knockout of the ortholog of Slimb, β-Trcp1 in mice, also leads to centrosome amplification [12]. Because the SCF/β-Trcp complex plays an important role in cell-cycle progression, our results lead to new understanding of the control of centrosome number and how it may go awry in human disease.