Ras functional proximity proteomics establishes mTORC2 as new direct ras effector

Abstract

Although oncogenic mutations in the three major Ras isoforms, KRAS, HRAS and NRAS, are present in nearly a third of human cancers, therapeutic targeting of Ras remains a challenge due to its structure and complex regulation. However, an in-depth examination of the protein interactome of oncogenic Ras may provide new insights into key regulators, effectors and other mediators of its tumorigenic functions. Previous proteomic analyses have been limited by experimental tools that fail to capture the dynamic, transient nature of Ras cellular interactions. Therefore, in a recent study, we integrated proximity-dependent biotin labeling (BioID) proteomics with CRISPR screening of identified proteins to identify Ras proximal proteins required for Ras-dependent cancer cell growth. Oncogenic Ras was proximal to proteins involved in unexpected biological processes, such as vesicular trafficking and solute transport. Critically, we identified a direct, bona fide interaction between active Ras and the mTOR Complex 2 (mTORC2) that stimulated mTORC2 kinase activity. The oncogenic Ras-mTORC2 interaction resulted in a downstream pro-proliferative transcriptional program and promoted Ras-dependent tumor growth in vivo. Here we provide additional insight into the Ras isoform-specific protein interactomes, highlighting new opportunities for unique tumor-type therapies. Finally, we discuss the active Ras-mTORC2 interaction in detail, providing a more complete understanding of the direct relationship between Ras and mTORC2. Collectively, our findings support a model wherein Ras integrates an expanded array of pro-oncogenic signals to drive tumorigenic processes, including action on mTORC2 as a direct effector of Ras-driven proliferative signals.