Abstract IA08: Lipid dependence of KRAS plasma membrane interactions

Abstract

Abstract RAS proteins must localize to the plasma membrane (PM) in order to function. We have examined how different RAS PM anchors select and assemble highly specific phospholipids into signaling platforms called nanoclusters, how these transient lipid assemblies impact signal transmission, and in consequence how the lipid composition of the PM can operate as high-level regulator of RAS signal transmission. For example, the KRAS polybasic domain (PBD)-farnesyl membrane anchor exhibits exquisite specificity for phosphatidylserine (PtdSer) over other anionic phospholipids by virtue of defined structural dynamics of the C-terminal polybasic domain and farnesyl group. This specificity extends to PtdSer with specific combinations of lipid side chains. PtdSer binding is therefore essential for stable KRAS PM binding and the spatial organization of KRAS into nanoclusters. These and complementary results with RAC1 highlight the critical role of specific anionic PM lipids in the biologic function of small GTPases. In this context for KRAS we have now shown that the PM levels and lateral availability of PtdSer are critically dependent on sphingomyelin metabolism such that multiple perturbations of sphingomyelin content or distribution, or endolysosmal lipid trafficking, profoundly affect KRAS plasma membrane localization, nanoclustering, and function. Concordantly, directly targeting the molecular machinery that maintains PtdSer on the PM also abrogates KRAS function in multiple pancreatic cancer cell lines. These new observations suggest multiple new potential therapeutic targets to abrogate oncogenic KRAS signaling, which we are evaluating in model systems. Citation Format: John F. Hancock. Lipid dependence of KRAS plasma membrane interactions [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA08.