RAS proteins, which act as binary molecular switches, are implicated in approximately 20% of all cancer cases and are known to play a critical role in the initiation and progression of some of the deadliest cancers, such as lung, colon, and pancreatic cancers. When RAS proteins are in the GTP-bound state, they interact with various effector proteins, such as RAF Kinase, PI 3-Kinase, and RalGDS, leading to the activation of multiple signaling pathways in the cell. Our recent structural studies, including investigations into the KRAS-SIN1 (RBD-PH domain), KRAS-RAF1 (RBD-CRD), and SHOC2-MRAS-PP1C complex, have provided new insights into the vital role played by the switch-II and interswitch regions in the interaction between RAS and downstream effectors and regulators. These findings extend beyond the earlier observations that the switch-I region of RAS proteins alone plays a more significant role in RAS-effector interactions. Furthermore, research into the KRAS4a-SIN1 complex and the reported interaction between KRAS4a and hexokinase have given us a glimpse into the isoform-specific RAS-effector interaction. Finally, the investigation of the SHOC2-MRAS-PP1C complex has also revealed the crucial role played by other members of the RAS subfamily, such as MRAS, in RAF activation by canonical RAS isoforms. Collectively, these studies have shed new light on the mechanisms by which RAS interacts with downstream effectors and regulators.

Citation Format: Dhirendra K. Simanshu. Uncovering new structural insights into RAS interactions with effectors and regulators [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 IA05.