Biology Reference
In-Depth Information
around the same time, the filamentous intercentriolar linker that has held the two
parental centrioles in close proximity throughout interphase disassembles in a
process known as centrosome disjunction. This leaves the two pairs of duplicated
centrioles as distinct and independent structures that can now be moved to opposite
poles of the cell through the action of microtubule-based motor proteins, such as
Eg5. Again, this process is phosphorylation-dependent, with the kinases, Nek2 and
SIK2, directly phosphorylating centriolar linker proteins, and with these two
kinases themselves the downstream targets of phosphoregulation involving Plk1
and Mst2, in the case of Nek2, and PKA, in the case of SIK2 (Ahmed et al.
2010
;
Mardin et al.
2011
; Mardin et al.
2010
; O'Regan et al.
2007
).
To date, protein degradation has not been strongly implicated in regulating the
onset of either centrosome maturation or disjunction. The remodeling of micro-
tubule organization that occurs upon mitotic onset may be due in part to dis-
placement of the ninein-like protein, Nlp, which anchors c-tubulin ring complexes
to the centrosome in interphase, but not mitosis (Casenghi et al.
2003
). Dis-
placement of Nlp occurs in response to Plk1, and possibly Nek2, phosphorylation
(Casenghi et al.
2003
; Rapley et al.
2005
); however, Nlp is also targeted for
degradation by the APC/C in a manner that may require phosphorylation by Cdk1
(Wang and Zhan
2007
; Zhao et al.
2010
). That said, it seems unlikely that the rapid
change in centrosome size associated with maturation is in any way dependent on
Nlp degradation. The centriole linker proteins, C-Nap1 and rootletin, are also
displaced from the centrosome following phosphorylation, but in this case there is
no evidence that these proteins are degraded (Bahe et al.
2005
; Mayor et al.
2002
).
Indeed, as mitosis is a relatively short event and cells need to reestablish the
interphase centrosome architecture from the beginning of G1, then it makes sense
for the cell to retain what are often very large proteins. C-Nap1, for example,
immediately loads back onto centrosomes at the end of mitosis presumably as a
result of its dephosphorylation (Mayor et al.
2002
).
In contrast, many of the regulators that trigger these two events are degraded at
some point after mitotic entry and this may also be very important to allow rapid
reassembly of the centrosome structure in G1. Nek2, Plk1, and Aurora A are all
targeted by the APC/C for proteasomal-mediated degradation. Interestingly, Nek2
is degraded earlier than these other kinases in a manner that is independent of the
spindle assembly checkpoint (Hayes et al.
2006
). This requires Cdc20, although in
the case of Nek2 degradation the role of Cdc20 is to promote its ubiquitylation
rather than its recruitment to the APC/C (Kimata et al.
2008
). Plk1 and Aurora A
are degraded much later in mitosis presumably reflecting their requirement for
additional mitotic processes, such as spindle organization, chromosome segrega-
tion, and cytokinesis. Their degradation is mediated by the APC/C in partnership
with its other co-activator, Cdh1 (Floyd et al.
2008
). The importance of Plk1 and
Aurora A degradation for completion of cytokinesis and cell division is well
established and almost certainly explains why interfering with APC/C
Cdh1
function
late in mitosis leads to multinucleated cells and centrosome amplification (Kim
et al.
2011
; Wang and Kung
2011
).
