Biology Reference
In-Depth Information
(Rotin and Kumar
2009
) and other classes of RING ligases such as the Forkhead
and RING domain (FHA-RING) proteins are also involved in cell cycle control
(Brooks and Heimsath
2008
).
8.6 HECT-Type Ligases and the Centrosome
There is little data suggesting that HECT-type ligases regulate centrosome biol-
ogy. However, E6-AP, the quintessential HECT E3 ligase, is recruited to aggre-
somes upon proteasome inhibition (Mishra et al.
2009
), although no association of
E6-AP with the centrosome has been reported under normal conditions. In con-
trast, the HECT-type ligase Smurf2 has been reported to localize to centrosomes
(Osmundson et al.
2008
). However, several spindle checkpoint proteins localize to
centrosomes at the same time, and Smurf2 depletion inhibits the spindle assembly
checkpoint, suggesting that the centrosomal localization may not be directly rel-
evant to centrosome biology per se. Accordingly, it is not yet clear whether there is
any
centrosomal
significance
for
the
presence
of
HECT-type
ligases
at
centrosomes.
8.7 APC/C and the Centrosome
Soon after its discovery in 1995, subunits of the APC/C were reported to localize
to mitotic centrosomes in human cells (Kurasawa and Todokoro
1999
; Tugendr-
eich et al.
1995
), and mutations in makos, which encodes the fruit fly Cdc27, an
APC/C subunit, enhance centrosomal defects seen in polo mutants (Deak et al.
2003
). In human cells Cdc14a, the phosphatase that regulates Cdh1, localizes
predominantly to centrosomes (Bembenek and Yu
2001
), and Cdc20 was shown to
dynamically associate with mitotic centrosomes in a microtubule-independent
manner (Kallio et al.
2002
). Moreover, the Cdc20 binding protein Speriolin is
required for centrosomal localization of Cdc20 during spermatogenesis (Goto and
Eddy
2004
), and the ability of the Cdc20 inhibitor RASSF1A to block Cdc20
activity requires its localization to centrosomes (Song et al.
2005
), implicating
centrosomes in the control of the APC/C.
Accordingly, it is perhaps not surprising that the first protein shown to be
degraded specifically at centrosomes is the APC/C substrate cyclin B. The initial
indication that cyclin B degradation was subject to spatial as well as temporal
control came from cell fusion studies showing that spindles in fused cells exit
mitosis independently despite being in a common cytoplasm, demonstrating local
control over cyclin B degradation (Rieder et al.
1997
). In support of this con-
clusion, cyclin B degradation was shown to be required for mitotic exit in syncytial
fruit fly embryos (Su et al.
1998
), despite previous observations that cyclin B is not
completely degraded in early embryos (Edgar et al.
1994
). Cyclin B degradation
