Interaction between ROCK II and Nucleophosmin/B23 in the Regulation of Centrosome Duplication

Department of Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267-0521, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 01/2007; 26(23):9016-34. DOI: 10.1128/MCB.01383-06
Source: PubMed


Nucleophosmin (NPM)/B23 has been implicated in the regulation of centrosome duplication. NPM/B23 localizes between two centrioles
in the unduplicated centrosome. Upon phosphorylation on Thr199 by cyclin-dependent kinase 2 (CDK2)/cyclin E, the majority of centrosomal NPM/B23 dissociates from centrosomes, but some
NPM/B23 phosphorylated on Thr199 remains at centrosomes. It has been shown that Thr199 phosphorylation of NPM/B23 is critical for the physical separation of the paired centrioles, an initial event of the centrosome
duplication process. Here, we identified ROCK II kinase, an effector of Rho small GTPase, as a protein that localizes to centrosomes
and physically interacts with NPM/B23. Expression of the constitutively active form of ROCK II promotes centrosome duplication,
while down-regulation of ROCK II expression results in the suppression of centrosome duplication, especially delaying the
initiation of centrosome duplication during the cell cycle. Moreover, ROCK II regulates centrosome duplication in its kinase
and centrosome localization activity-dependent manner. We further found that ROCK II kinase activity is significantly enhanced
by binding to NPM/B23 and that NPM/B23 acquires a higher binding affinity to ROCK II upon phosphorylation on Thr199. Moreover, physical interaction between ROCK II and NPM/B23 in vivo occurs in association with CDK2/cyclin E activation and
the emergence of Thr199-phosphorylated NPM/B23. All these findings point to ROCK II as the effector of the CDK2/cyclin E-NPM/B23 pathway in the regulation
of centrosome duplication.

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Available from: Kozo Kaibuchi, Jul 02, 2014
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    • "Loss of RASSF1A or RAB6C [47],[48] or over-activation of Ras and Rho small GTPases [8],[49] induces centrosome amplification, multipolar spindles and aneuploidy. While mechanisms by which RAB6C prevents centrosome amplification are undefined, several of the other GTPases have been shown to act through pathways involving phosphorylated NPM-T199 [8],[50], similar to RABL6A. For instance, Ras promotes Cdk2 and Cdk4-mediated phosphorylation of NPM-T199 [8] whereas Rho A binds and partially activates the Rho associated kinase, ROCK II, priming it for super-activation by association with phosphorylated NPM-T199 [50]. "
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    • "Reduced mRNA levels of RhoE further correlate with disease progression in breast and prostate cancer, possibly due to increased ROCK I activity (Pinner and Sahai 2008; Belgiovine et al. 2010). Similarly, morgana/chp-1 and nucleophosmin/B23 (NPM/ B23) compete for binding on ROCK II, thereby regulating ROCK II activity, centrosome duplication, and neoplastic transformation (Ma Z et al. 2006; Ferretti et al. 2010). Downregulation of endogenous ROCK inhibitors in cancer could potentiate more aggressive migratory and invasive behavior. "
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    • "NPM was reported to have the ability to control centrosome duplication in association with ROCK2 (Ma et al., 2006b), a member of the Rho-associated, coiled-coil containing protein kinase family that is frequently overexpressed in cancer (Nishimura et al., 2003). After NPM phosphorylation by CDK2–cyclin E, the binding between NPM and ROCK2 increases and ROCK2 is activated at centrosomes, leading to centrosome duplication (Ma et al., 2006b). In ROCK2 activation, the binding of Rho small GTPase to the auto-inhibitory region is also required (Kanai et al., 2010). "

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