Biology Reference
In-Depth Information
ROCK II is present at centrosomes throughout the cell cycle, and activated Rho
(Rho-GTP) proteins are found at centrosomes much more than the inactive Rho
(Rho-GDP) proteins (Kanai et al.
2010
). Thus, Rho is likely recruited to centro-
somes as Rho-GTP (after activation by Rho-GEFs), and binds to ROCK II at
centrosomes. There are three major Rho isoforms, RhoA, B and C, and they share
85 % sequence identity (Etienne-Manneville and Hall
2002
), yet each isoform is
known to function in the specific cellular events (Wheeler and Ridley
2004
).
Although all isoforms are capable of binding and activating ROCK II in vitro,
RhoA and RhoC, but not RhoB, are involved in the regulation of centrosome
duplication. For instance, ectopic expression of constitutively active forms of
RhoA (RhoA-V14) as well as RhoC (RhoC-V14) leads to promotion of centro-
some duplication, while expression of RhoB-V14 has no effect on centrosome
duplication (Kanai et al.
2010
). The inability of RhoB to function in the regulation
of centrosome duplication appears to be in part by its inability to localize to
centrosomes. Although the primary target of RhoA and RhoC appears to be
ROCK II for the regulation of centrosome duplication, both RhoA and RhoC are
required for centrosome duplication. For instance, depletion of either RhoA or
RhoC alone results in inhibition of centrosome duplication. Since expression of
excess RhoA in the RhoC-depleted cells as well as expression of excess RhoC in
the RhoA-depleted cells allow centrosome duplication, it is likely that RhoA and
RhoC comprise the total amount of Rho proteins necessary for activating ROCK II
(especially those present at centrosome) to promote centrosome duplication (Ka-
nai et al.
2010
). However, it remains as a possibility that RhoA and RhoC may also
activate
distinct
targets
in
addition
to
ROCK
II
for
promoting
centrosome
duplication.
Because activated RTKs signals to a number of pathways, the pathways other
than the Rho-ROCK II pathway may also be involved in the promotion of cen-
trosome duplication. For instance, activation of many RTKs leads to upregulation
of STAT (signal transducer and activator) transcriptional factors. The activity of
STAT3 has been shown to be essential for centrosome duplication by inducing the
expression of some key centrosomal proteins such as PCM-1 and c-tubulin (Metge
et al.
2004
). STAT3 induces expression of those proteins not by direct upregula-
tion of the transcription of the respective genes, but does so indirectly likely by
upregulating other transcriptional factor(s). STAT5, another member of the STAT
family, has also been shown to promote centrosome duplication via inducing
expression of Aurora-A (also known as STK15 and BTAK) (Hung et al.
2008
),
which is a positive regulator of centrosome duplication (Zhou et al.
1998
). This
study shows that the ligand-activated EGF receptor is translocated into the
nucleus, and recruited to the AT-rich sequence sites of the Aurora-A promoter
through interacting with STAT5.
In sum, RTKs activated by growth factor binding transmit the signal to cen-
trosomes to duplicate through activation of the Rho-ROCK II pathway and tran-
scriptional induction of the key centrosomal proteins and positive regulatory
protein(s) essential for centrosome duplication. It should be noted here that other
downstream pathways of RTKs may also function to link the RTK activation and
