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Lysosomal proteases are mainly responsible for the degradation of proteins taken up from the cell surface and are involved in 20% of normal protein turnover. Therefore, a nonlysosomal proteolytic enzyme complex, the proteasome, degrades most cellular proteins. Proteasomes, which are localized in both the cytosol and nucleus, represent up to 1% of all cellular proteins in eukaryotes. 1 It specifically degrades cytoplasmic and nuclear proteins previously tagged with Ub in an adenosine triphosphate (ATP)-dependent manner. The Ub-proteasome pathway (UPP) is involved in processing and functional modifications of proteins implicated in essential cellular processes, 2 such as survival, function, and cell cycling of normal cells. Indeed, intracellular proteolysis is necessary for physiological regulation of transcription, cell cycle, antigen processing, and signal transduction. 3 Thus, a deregulation may contribute to tumor progression, neurodegenerative or autoimmune diseases, drug resistance, and metabolic disorders that have been clearly demonstrated in humans, 4–7 making this catalytic process inhibition a selective therapeutic target in cancer. Here we will focus on the role of kinases and protein phosphorylation/dephosphorylation turnovers in ubiquitination targeting proteins as well as the action of the proteasome inhibitors on signal transduction pathways.