Proteins in cells are regulated in their abundance, and sometimes need to be removed entirely. A major challenge for cell biology is to understand how these processes are controlled. Proteins are also subject to quality control, with abnormal or misfolded proteins being degraded. Such mechanisms protect cells from the damage caused by misfolded proteins, and are closely related to those used for specific regulatory purposes where proteins need to be removed, such as the downregulation of signalling receptors. We wish to understand how proteins are recognised and destroyed, and how these processes can be regulated. The key event is ubiquitination, and we have focussed on the HECT family of ubiquitin ligases in mammalian cells. In particular, we have devised both peptide-based specific inhibitors of HECT ligases, and a small molecule, heclin, that inhibits most if not all HECT ligases (but not the more numerous ubiquitin ligases of the RING type) in tissue culture cells. This provides a useful tool to evaluate the contribution of HECT ligases to ubiquitination both of specific proteins and also bulk proteins following thermal or other stress. We have shown that a particular HECT ligase, WWP2, which is frequently absent in ovarian cancer cells, is activated by Wnt signalling and controls the level of a Wnt signalling component, but also ubiquitinates Notch and down-regulates Notch signalling. The mechanism is related to that which we previously described by which other HECT ligase regulators, Ndfip1 and Ndfip2, modulate epidermal growth factor signalling pathways. Such regulation of HECT ligases may thus be relevant to growth control in a variety of cells. We are also studying the ubiquitination of alpha synuclein, the protein that forms abnormal and ultimately toxic filaments in Parkinson’s disease. This is an example of a disease that results from the failure of quality control mechanisms, and we wish to understand why this happens.