The SCF–FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication

  title={The SCF–FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication},
  author={Anja Puklowski and Yahya Homsi and Debora Keller and Martin May and Sangeeta Chauhan and Uta Kossatz and Viktor Gr{\"u}nwald and Stefan Kubicka and Andreas Pich and Michael P. Manns and Ingrid Hoffmann and Pierre G{\"o}nczy and Nisar Peter Malek},
  journal={Nature Cell Biology},
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. ) 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 , ) as a critical… 

The ubiquitin ligase FBXW7 targets the centriolar assembly protein HsSAS-6 for degradation and thereby regulates centriole duplication

It is shown that the E3 ubiquitin ligase F-box and WD repeat domain–containing 7 (FBXW7), a subunit of the SCF ubiquit in ligase, down-regulates spindle assembly 6 homolog (HsSAS-6), a key protein required for procentriole cartwheel assembly, and thereby regulates centriole duplication.

The SKP1-Cullin-F-box E3 ligase βTrCP and CDK2 cooperate to control STIL abundance and centriole number

Proteomics approaches are combined with the use of MLN4924, a generic inhibitor of SCF E3 ubiquitin ligases, to monitor changes in the cellular abundance of centriole duplication factors, and a connection between this new pathway and CDK2 is uncovered, indicating that CDK 2 and SCF-βTrCP cooperate via STIL to control centrioles biogenesis.

The C. elegans F-box proteins LIN-23 and SEL-10 antagonize centrosome duplication by regulating ZYG-1 levels

In C. elegans, similar to Drosophila and humans, it is found that the Slimb/&bgr;TrCP homolog LIN-23 regulates ZYG-1 levels, and it is shown that a second F-box protein, SEL-10, also contributes to ZYg-1 regulation, which suggests these proteins function cooperatively.

SCFFbxw5 targets MCAK in G2/M to facilitate ciliogenesis in the following cell cycle

A novel regulatory event of ciliogenesis that occurs already within the G2/M phase of the preceding cell cycle is identified, including MCAK.

Cell cycle: Keeping centrosome numbers in check

  • R. David
  • Biology
    Nature Reviews Molecular Cell Biology
  • 2011
The findings identify an intricate regulatory mechanism ensuring that centrosome duplication occurs only once per cell cycle: FBXW5, as part of an SCF E3 ligase, targets SAS6 to prevent centrosomes duplication during S phase but is itself inhibited by the APC/C during G1 and by PLK4 during the G1–S transition.

SCFFbxw5 targets kinesin‐13 proteins to facilitate ciliogenesis

A novel regulatory event of ciliogenesis that begins already within the G2 phase of the preceding cell cycle is proposed, which can be rescued by concomitant knockdown of MCAK, K if2a or Kif2b.

Novel E3 ligase component FBXL7 ubiquitinates and degrades Aurora A, causing mitotic arrest

It is shown that a previously undescribed E3 ligase component belonging to the SCF (Skp-Cullin1-F-box protein) E3ligase family, SCFFBXL7, impairs cell proliferation by mediating Aurora A polyubiquitination and degradation.

Polo-like kinase 4 maintains centriolar satellite integrity by phosphorylation of centrosomal protein 131 (CEP131)

It is observed that although PLK4-mediated phosphorylation of Ser-78 is dispensable for CEP131 localization, ciliogenesis, and centriole duplication, it is essential for maintaining the integrity of centriolar satellites.

The UBR box E3 ligases Poe and Hyd are required for efficient Pericentrin degradation

This study suggests that Poe and Hyd directly bind the N-terminus of PLP and target it for degradation, ensuring proper centriole/basal body assembly and male fertility.



Components of an SCF ubiquitin ligase localize to the centrosome and regulate the centrosome duplication cycle.

It is shown that in mammalian cells the Skp1 protein and the cullin Cul1 are localized to interphase and mitotic centrosomes and to the cytoplasm and nucleus, and candidate centrosomal F-box proteins are identified.

SCFCyclin F controls centrosome homeostasis and mitotic fidelity via CP110 degradation

It is proposed that SCFCyclin F-mediated degradation of CP110 is required for the fidelity of mitosis and genome integrity.

Cullin 1 functions as a centrosomal suppressor of centriole multiplication by regulating polo-like kinase 4 protein levels.

The results suggest that CUL1 may function as a tumor suppressor by regulating PLK4 protein levels and thereby restraining excessive daughter centriole formation at maternal centrioles.

Regulation of E2F through ubiquitin-proteasome-dependent degradation: stabilization by the pRB tumor suppressor protein.

Evidence is provided that E2FI protein levels are regulated by the ubiquitin-proteasome-dependent degradation pathway and an overlapping region of E2F1 that facilitates complex formation with retinoblastoma tumor suppressor protein, pRB is identified.

The role of the destruction box and its neighbouring lysine residues in cyclin B for anaphase ubiquitin‐dependent proteolysis in fission yeast: defining the D‐box receptor

The K0‐N70 construct was neither polyubiquitinated nor degraded in vitro, but it blocked the growth of strains of yeast in which anaphase‐promoting complex/cyclosome function was compromised by mutation, and specifically inhibited proteolysis of APC/C substrates in vivo.

WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase.

FBW5-DDB1-CUL4-ROC1 is an E3 ubiquitin ligase regulating TSC2 protein stability and TSC complex turnover, indicating that protein turnover also plays a critical role in TSC regulation.

Systematic analysis and nomenclature of mammalian F-box proteins.

The current expectation is that all cullin-containing ligases will share the modular nature of the original SCF family of ligases, which form a superfamily of modular E3s that use cullin proteins as a scaffold.

SAS-6 defines a protein family required for centrosome duplication in C. elegans and in human cells

HsSAS-6 is also required for centrosome duplication, indicating that the function of SAS-6-related proteins has been widely conserved during evolution.

The Polo kinase Plk4 functions in centriole duplication

It is identified that Plk4 is required — in cooperation with Cdk2, CP110 and Hs-SAS6 — for the precise reproduction of centrosomes during the cell cycle and this findings provide an attractive explanation for the crucial function of PlK4 in cell proliferation.