Cellular communication and the link between the extracellular and intracellular environments are in part mediated by signalling events from plasma membrane proteins. Their tight regulation by a diverse array of post-translational modifications (PTM) is essential to maintain the cellular integrity. Understanding these modifications would help with understanding cancer cell progression. Dystroglycan is one of the plasma membrane proteins with both structural and signalling properties, and is a core component of the dystrophin associated protein complex (DAPC). The nuclear localisation of dystroglycan and some DAPC members suggests similar roles to those observed in the plasma membrane. Dystroglycan is composed of an alpha and beta subunits that are modified by different PTM. The altered glycosylation of alpha and the phosphorylation of Y890 in beta, are triggering factors for the instability of dystroglycan leading to the disruption of the DAP complex. In cancer studies, it has recently been indicated that in addition to the above-mentioned PTM, other signalling events such as additional phosphorylation sites and ubiquitination, could mediate the rapid turnover of dystroglycan from the plasma membrane and from the nucleus. Here we show that beta-dystroglycan is susceptible to additional phosphorylation, and we were able to demonstrate its multiple ubiquitination. Further experiments revealed that beta-dystroglycan is subject to intramembrane proteolytic events induced by increased cellular density and PDBu treatment. Interestingly, we observed the translocation of beta- dystroglycan to the nucleus due to high cell density growth. By enzymatic inhibition studies we were able to identify gamma-secretase and furin as the enzymes responsible for the shedding of beta-dystroglycan from both the plasma membrane and nuclear envelope. Interestingly, we observed the preferential nuclear translocation and degradation by the proteasome of the cytoplasmic fragment of beta-dystroglycan. An interactome analysis by mass spectrometry techniques revealed that beta-dystroglycan interacts with components of the ubiquitin-proteasome system, the cell-cycle, and the nucleus. This all together suggests that, the regulated intramembrane proteolysis mediated by ubiquitination and phosphorylation PTM of beta-dystroglycan triggers downstream nuclear signalling events. These findings provide more ideas of the mechanisms implicated in the regulation of beta-dystroglycan and importantly, of some nuclear processes wherein beta-dystroglycan is involved. These insights may have further implications in the understanding of the progression of cancer and the development of useful therapies.