Role of NRas ubiquitination in control of melanoma development and progression.

Melanoma is one of the most aggressive skin cancers. The 15–20% of all melanomas harbors activating NRas mutations. At present, little progress has been made in developing targeted therapy strategies for NRas mutant melanoma, thus a better understanding of the Ras pathway is an urgent need for establishing new treatment strategies. We and others have recently demonstrated that ubiquitination of the Ras family members dramatically affects their functioning. Notably, ubiquitination of KRas affects its tumorigenic properties. This strongly highlights the importance of ubiquitination in control of the Ras signaling. The main goal of my proposal is to understand the role of NRas ubiquitination in melanoma development and progression. I plan to examine NRas ubiquitination status in normal melanocytes and melanoma cell lines, and assess how NRas ubiquitination affects its ability to regulate the downstream signaling and affect tumorigenic transformation. As a next step, I will identify and validate enzymes controlling NRas ubiquitination. Finally, I will search for the alterations of the identified enzymes in melanoma samples and elucidate their roles in melanoma development by using in vitro models of melanocytes transformation and in vivo mouse models of melanoma. The results of these studies will not only advance our understanding of the Ras signaling in melanoma development and progression, but also could lead to novel therapeutic strategies.