Understanding how the stability of tumor suppressor PTEN is regulated

Ubiquitin is a small regulatory protein, which is used to control the function of other proteins when it is directly attached to them. The addition of ubiquitin, termed ubiquitination, can affect the turnover of proteins by increasing their degradation via the proteosome, or affect their cellular location, activity or interactions with other proteins. As its name suggests, the ubiquitin system appears to contribute to the regulation of most proteins in eukaryotic cells, therefore influencing diverse areas of physiology and pathology. The lipid and protein tyrosine phosphatase, PTEN is one of the most frequently mutated tumor suppressors in human cancer. Evidence suggests that even subtle reductions in the levels of PTEN could be a determining force in inducing abnormal cellular and tissue outcomes. Thus, understanding how PTEN stability is regulated is of great potential clinical importance. It has been known for some years that PTEN can be ubiquitinated and that this appears to target PTEN for destruction. It is known that there are several different sites on PTEN at which ubiquitin can be added, however, the detailed mechanisms by which this regulates PTEN are still not clear. My project aims to understand the molecular details of how PTEN is regulated by ubiquitination. In the talk, I will discuss some data which shows how ubiquitination at various lysine residues on PTEN could regulate its stability and show that a ubiquitination site that has not been studied before has a strong effect on PTEN stability. Since even small changes in PTEN abundance can have significant effects on tumour formation, this may have a significant effect on PTEN’s functions to block cancer.