| Ubiquitination is a dynamic and balanced process that is carried out by a series of ubiquitin-protein conjugating enzymes and deubiquitinating enzymes. Recently, deubiquitinating enzymes have been recognized to play an increasing number of novel roles in biological functions, including protein degradation, cell cycle control, endocytosis and DNA repair.;Our observations reveal the mechanism by which USP8 regulates ErbB receptor signaling and cell cycle progression, and contribute to the further understanding of the functions of substrate specific deubiquitinating enzymes.;USP8 is a novel deubiquitinating enzyme identified as a negative regulator of ErbB receptor signaling and cell growth. However, it remains unclear how USP8 performs the regulating functions. In my thesis, I demonstrate that a neuregulin (NRG) 1-induced protein stability cascade involving USP8 and Nrdp1 mediates the down-regulation of ErbB3 through PI3K pathway. NRG1 stimulation remarkably enhances Nrdp1 stabilization, which in turn leads to the degradation of ErbB3. Furthermore, I provide evidence that USP8 regulates cell cycle progression through the binding to 14-3-3 proteins. USP8 interacts weakly with 14-3-3 proteins during interphase. With the help of nuclear localization sequence (NLS), USP8 can be transported into the nucleus where it deubiquitinates specific substrates to prevent cells from proceeding into mitosis. In contrast, enhancement of 14-3-3 binding during mitosis sequesters USP8 in the cytosol, limits its access to nuclear substrates, and thereby allows the cell cycle to proceed. |
