LAUSR

The RAS pathway is the most frequently activated signaling node in human cancer. Nevertheless, the mechanisms leading to the hyperactivation of wild-type RAS in human pathologies have not been fully elucidated. The GTPase activity of RAS proteins is tightly controlled through a series of post-transcriptional mechanisms, which are commonly distorted in the context of cancer. Here, we explored the functional role of KRAS and NRAS ubiquitination at lysine 128 (K128), which is the most abundant post-translational modification of the RAS proto-oncogenes. Our data indicate that RAS ubiquitination at K128 promotes GTP hydrolysis and impedes downstream signaling via a bimodal mechanism. Ubiquitination at K128 not only destabilizes the active RAS clusters at the plasma membrane but also facilitates the interaction of RAS with RAS GTPase-activating proteins. Understanding the complexities of RAS biology may be translated into novel therapeutic approaches to defeating RAS-driven cancers. Citation Format: Wout Magits, Mikhail Steklov, Benoit Lechat, Ruth Nussinov, Anna Sablina. A bimodal mechanism of RAS inactivation by monoubiquitination [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR04.