Biology Reference
In-Depth Information
While the Z-L
3
VS study did not identify specific proteases, caspase-2 (Narine
et al.
2010
), tripeptidyl-peptidase II [TPP II; (Stavropoulou et al.
2005
)], and
membrane type-1 matrix metalloproteinase [MT1-MMP; (Golubkov et al.
2005a
)]
have been reported at centrosomes. While no substrates were identified for cas-
pase-2 or TPP II, TPP II is overexpressed in Burkitt's Lymphoma where it pro-
motes centrosome amplification and mitotic infidelity (Stavropoulou et al.
2005
).
However, a relevant centrosomal substrate has been identified for MT1-MMP.
Although best known for its pericellular activities, MT1-MMP was shown to traffic
to the centrosome subsequent to its endocytosis (Golubkov et al.
2005a
), where it
directly cleaves centrosomal pericentrin (Golubkov et al.
2005b
), leading to
mitotic spindle abnormalities and aneuploidy (Golubkov et al.
2005a
; Golubkov
et al.
2005b
). Overexpression of MT1-MMP leads to the accumulation of peri-
centrin cleavage fragments, multipolar spindles, and aneuploidy, and pericentrin
cleavage fragments are observed in tumor biopsies (Golubkov et al.
2005b
).
MMPs have long been known to play a role in tumorigenesis through their
cleavage of extracellular matrix proteins, which has clear implications for tumor
metastasis. However, the ability of MT1-MMP to cleave pericentrin at centro-
somes suggests that MMPs may additionally play a role in the establishment of
aneuploidy, and it will be interesting to determine to what extent the centrosomal
effects of MT1-MMP contribute to its ability to promote cellular transformation
and tumorigenesis (Soulie et al.
2005
).
8.12 Other Relevant Degradation Events
Recent studies suggest that proteasome activity may have a very broad role in
centriole assembly and function. Protein phosphatase 2A (PP2A) was recently
shown to control centrosome duplication in flies (Kotadia et al.
2008
) and worms
(Kitagawa et al.
2011
; Schlaitz et al.
2007
; Song et al.
2011
), and in worms it does
so at least in part through the proteasome-dependent control of the levels of Sas-5
(Song et al.
2011
), although degradation of Sas-5 per se was not demonstrated.
Interestingly, it now appears that the STIL protein is the human Sas-5 ortholog,
based on its similarity to D. melanogaster Ana2 (Stevens et al.
2010
). STIL/hSas5
was recently shown to regulate the function of CHFR (Castiel et al.
2011
), a
RING-type E3 ligase [reviewed in (Brooks and Heimsath
2008
)] responsible for
the regulation of the antephase checkpoint, a newly emerging checkpoint that
prevents entry into mitosis in the absence of sufficient cellular energy and/or
arrests mitosis in response to mitotic stress [reviewed in (Chin and Yeong
2010
)].
CHFR was found to be upregulated in STIL depleted cells, leading to inhibition of
proliferation and multiple centrosome defects, likely through the degradation of
the CHFR substrate Plk1 (Castiel et al.
2011
). While CHFR has not been reported
to localize to centrosomes, the regulation of CHFR by STIL/hSas5 implicates
centrosomes in the control of CHFR and the antephase checkpoint. It further
suggests that centriole assembly factors may both be controlled by and control
