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SCF β -TrCP
SCF Fbxw5
APC/C Cdh1
SCF Cyclin F
G1/S
G2
G1
Plk4 SAS-6
SAS-4/CPAP CP110
Plk4
SAS-6
SAS-4/CPAP
CP110
Excess centriole
numbers
Excess centriole
length
Fig. 9.2 Control of centriole biogenesis and elongation by ubiquitin ligases. Procentriole
formation is dependent upon both Plk4 and SAS-6. Excess amounts of either protein leads to the
formation of multiple procentrioles in a rosette arrangement around a single centriole. Their
abundance is therefore strictly controlled to ensure only one procentriole forms per existing
centriole. SCF b-TrCP targets Plk4 for destruction while SCF Fbxw5 , which is itself regulated by
Plk4, targets SAS-6 for destruction. Procentriole elongation occurs as the cell progresses through
S and G2 phases, and is regulated by the positive and negative regulators, SAS-4/CPAP and
CP110, respectively. Excess SAS-4/CPAP leads to excessively long centrioles, while, conversely,
loss of CP110 causes the same phenotype. However, the abundance of both proteins is strictly
regulated, by the APC/C Cdh1
for SAS-4/CPAP, and SCF Cyclin F
for CP110
Plk4 activity is regulated in large part then at the expression level and spe-
cifically by degradation, which is catalyzed by the SCF ubiquitin ligase, in con-
junction with the b-TrCP (also called Slimb in Drosophila) F-box protein. b-TrCP
was in fact demonstrated to have an important role in regulating centrosome
duplication in Drosophila and mice well before the identification of Plk4 (Wojcik
et al. 2000 ; Guardavaccaro et al. 2003 ), and has also been shown to localize to
centrioles. It is now clear that b-TrCP interacts with Plk4 via a conserved b-TrCP
binding motif on Plk4 and that mutation of this site, or depletion of b-TrCP, leads
to Plk4 stabilization and centriole overduplication (Cunha-Ferreira et al. 2009 ;
Rogers et al. 2009 ). As indicated above, the SCF recognizes its substrates fol-
lowing their post-translational modification, usually phosphorylation. In this case,
Plk4 regulates its own degradation through autophosphorylation at a number of
sites within a multiphosphodegron, within which lies the b-TrCP-binding site
(Cunha-Ferreira et al. 2009 ; Rogers et al. 2009 ; Guderian et al. 2010 ; Holland et al.
2010 ). Plk4 stability is therefore under direct control of its own activity providing
an important negative feedback mechanism that presumably helps to limit cen-
triole duplication to once per cell cycle.
Interestingly, Plk4 activity does not peak at the time of centriole biogenesis in
S-phase; instead, it remains at a relatively low level throughout interphase due to
the stimulation of its own degradation. In contrast, Plk4 is stabilized in mitosis
allowing its activity to rise at this point in the cell cycle. This stabilization can be
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