The role of RAS ubiquitination in cancer development and progression.

The RAS GTPases are among the most commonly mutated oncoproteins in human cancers. We and others recently demonstrated a crucial role of reversible ubiquitination in regulation of the RAS GTPases. The primary objective of the proposed study is to understand the contribution of RAS ubiquitination in RAS-mediated tumorigenesis. Using a quantitative proteomic analysis of the ubiquitinated RAS interactome, we will assess how ubiquitination affects the RAS signaling pathway. By utilizing a targeted MAPPIT-based approach, we plan to identify enzymes controlling RAS ubiquitination. Finally, we will elucidate the roles of the validated enzymes in cancer development and progression by using in vitro models of human cell transformation and in vivo mouse models of melanoma. The results of these studies will not only advance our understanding of RAS signaling in cancer initiation and maintenance but also could lead to novel therapeutic strategies for treatment of RAS mutated tumors.