Alterations in RAS interactome triggered by ubiquitination

Ubiquitination is one of the most prominent post-translational modifications in all eukaryotic systems. For decades, ubiquitination was mainly considered as a tag directing substrate proteins to proteasomal degradation. However, it has become more and more clear that ubiquitination can alter functioning of the target protein in many ways depending on the type of ubiquitin conjugation and target site of ubiquitination. In this project, we will focus on the reversible mono-ubiquitination of the RAS GTPases, signaling proteins crucial for maintaining cellular homeostasis and dysfunction of which leads to multiple human pathologies. Our preliminary results indicate that mono-ubiquitination controls RAS activity and signaling by perturbing its interaction network, thereby representing a novel mechanism of RAS regulation. In this project, we aim to develop new tools to study mono-ubiquitinated proteins and unravel general principles of the interactome alterations driven by mono-ubiquitination. Cracking the code of RAS mono-ubiquitination will uncover a novel regulatory mechanism of RAS signaling.