Biology Reference
In-Depth Information
by targeting Mps1 for proteasome-dependent degradation. Mps1 is a multifunc-
tional protein kinase (Fisk
2011
) that localizes to centrosomes (Kasbek et al.
2010
;
Fisk et al.
2003
; Fisk and Winey
2001
; Liu et al.
2003
; Tyler et al.
2009
) and
participates in several aspects of centrosome duplication [reviewed in (Pike and
Fisk
2011
)] including procentriole assembly (Yang et al.
2010
; Kasbek et al.
2010
)
and centriole maturation (Yang et al.
2010
). These centrosomal activities of Mps1
are controlled by an Mps1 degradation signal (MDS) that promotes the protea-
some-dependent degradation of Mps1 at centrosomes and whose function is sup-
pressed by Cdk2 phosphorylation (Kasbek et al.
2007
). While Cdk2 has been
shown to antagonize the APC/C-dependent degradation of Cdc6 to limit DNA
replication (Mailand and Diffley
2005
), the MDS has no known APC/C or SCF
targeting motifs (Kasbek et al.
2007
). However, while Mps1 may be dispensable
for centriole assembly (Pike and Fisk
2011
), preventing its degradation at cen-
trosomes causes centriole overproduction (Kanai et al.
2007
; Kasbek
2009
), and
Mps1 thus fits the expectation of an OAZ substrate. Indeed, OAZ binds to Mps1
via the MDS, and targets Mps1 for proteasome-mediated degradation at centro-
somes (Kasbek et al.
2010
). Increasing OAZ activity promotes degradation of the
centrosomal pool of Mps1 and causes a delay in centriole assembly, while
decreasing OAZ activity increases the level of the centrosomal Mps1 pool and
causes Mps1-dependent centrosome reduplication (Kasbek et al.
2010
). This
degradation appears to occur specifically at centrosomes, because Cdk2 has little
affect on the whole cell levels of Mps1, and because the centrosomal levels of a
version of Mps1 tethered to centrosomes via the PACT domain show proteasome-
and Cdk2-dependence that reflect that of the endogenous protein (Kasbek et al.
2007
). Interestingly, cytoplasmic Mps1 levels are controlled by a D-box in its
N-terminus that can bind to both Cdc20 and Cdh1 and promote its APC/C-
dependent degradation (Cui et al.
2010
). This suggests that APC/C could cooperate
with OAZ to control centrosome duplication by limiting the amount of cytoplas-
mic Mps1 available for delivery to centrosomes. However, as discussed above the
APC/C is present at centrosomes, suggesting the possibility that multiple inputs
might control the degradation of Mps1 at centrosomes.
8.11 Non-Proteasomal Degradation Pathways
at the Centrosome
In addition to the proteasome-dependent degradation pathways discussed above,
there are many additional proteolytic activities that have been localized to centro-
somes and/or shown to regulate centrosome biology. One striking example is the
protease separase, initially described for its role in destroying the cohesin ring at
anaphase onset [reviewed in (Nasmyth
2005
)]. In addition to its role in regulating
sister chromatid cohesion, separase has been shown localize to centrosomes and
regulate centriole disengagement both in vitro and in vivo (Tsou and Stearns
2006
).
It was further shown that centriole disengagement requires the catalytic activity of
