Biology Reference
In-Depth Information
Fig. 10.1 The Rho-ROCK II and CDK2/cyclin E-NPM pathways link the RTK activation and
initiation of centrosome duplication. The RTKs activated by the binding of growth factors
activates Rho-GEFs, which in turn promotes exchange of Rho-GDP to Rho-GTP. Rho-GTP is
then recruited to centrosomes, and binds to ROCK II at centrosomes. In late G1 phase, CDK2-
cyclin E is activated, and phosphorylates NPM/B23 likely at centrosomes. NPM/B23 acquires a
high binding affinity to ROCK II upon phosphorylation by CDK2-cyclin E, and binds to and
superactivates ROCK II. The super activated ROCK II then triggers initiation of centrosome
duplication. At the same time, CDK2-cyclin E targets proteins, including pRB which inhibits E2F
transcriptional factor through direct binding. Upon phosphorylation by CDK2-cyclin E, pRB
dissociates from E2F, resulting in activation of E2F and consequentially initiation of DNA
replication
with ROCK II (Nakagawa et al.
1996
). ROCK I also localize to centrosomes, and is
implicated in proper positioning of centrosomes (Chevrier et al.
2002
). ROCK I is
dispensable for initiation of centrosome duplication as long as ROCK II is present.
However, in the absence of ROCK II, ROCK I comes into replace the ROCK II
function to promote centrosome duplication, but not as efficiently as ROCK II,
resulting in the delay in the initiation of centrosome duplication. The reason behind
the inefficient triggering of centrosome duplication by ROCK I is that unlike ROCK
II, ROCK I cannot be super activated by nucleophosmin binding (discussed in details
below) (Ma et al.
2006
).
