Post-translational modifications on proteins, such as reversible ubiquitylation and phosphorylation, are fundamental to controlling cellular signalling through regulation of protein stability and function. Reversible ubiquitylation is controlled by E3 ubiquitin ligases and deubiquitylases, while phosphorylation is controlled by protein kinases and phosphatases. Abnormal protein abundance or function in cells is often a hallmark of many human diseases, such as neurodegenerative diseases and cancer. Therefore, by targeting intracellular proteins of interest (POIs) with desired post-translational modifications, we can fundamentally alter their abundance and/or function and rewire cell signalling. The Sapkota lab has developed the Affinity-directed PROtein Missile (AdPROM) system through which we have been able to target the degradation of endogenous proteins (Fulcher et al, 2017; Roth et al, 2020; Simpson et al, 2020), uncover novel degradation-capable E3 ubiquitin ligases, and redirect protein kinases and phosphatases to new protein substrates. This project will enable the prospective PhD candidate to develop AdPROM and small molecule toolkit (such as PROTACs and Phosphatase-targeting chimeras) that serve to redirect endogenous E3 ubiquitin ligase and protein phosphatase activities to unique disease-relevant protein targets and assess the consequences of desired modifications on physiological protein function. The successful PhD candidate will employ cutting-edge CRISPR/Cas9 genome editing, microscopy and mass-spectrometry technologies as well as state-of-the-art blend of molecular, biochemical, chemical and cell biology methodologies.