Figure 3. Responding to centrosome defects.

Pathways activated by centrosome loss (bottom) and centrosome amplification (top). Centrosome loss leads to 53BP1 and USP28-dependent stabilization of p53, which in turn promotes either cell death or cell cycle arrest^{133,136–138}. An increased duration of mitosis also activates p53 through the same pathway. Centrosome amplification leads to hyper-activation of Rac1 and a corresponding decline in RhoA-GTP. RhoA-GTP activates the LATS2 kinase, which stabilizes p53 through inhibition of MDM2. In addition, LATS2 phosphorylates and inactivates the transcription factor YAP to inhibit proliferation¹⁴⁸. In an alternative pathway, supernumerary centrosomes promote activation of the PIDDosome, which leads to activation of Caspase-2¹⁴⁹. Active Caspase-2 cleaves MDM2 and thereby stabilizes p53²⁰⁸.