How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. We consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity. There are two major pathways in oncogenic Ras-driven proliferation: MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. All membrane-anchored, proximally located, oncogenic Ras isoforms can promote Raf dimerization and fully activate MAPK signaling. So why the differential statistics of oncogenic isoforms in distinct cancers and what makes KRas so highly oncogenic? Many cell-specific factors may be at play, including higher KRAS mRNA levels. As a key factor, we suggest that because only KRas4B binds calmodulin, only KRas can fully activate PI3Kα/Akt signaling. We further propose that nanoclustering (or Ras dimerization) is not essential for all oncogenic Ras pathways, that nanoclustering can explain the challenging question of why especially wild-type KRas can inhibit its oncogenic variant, and more.

Regulatory mechanisms of Ras signaling at the membrane

2019 Spring National Meeting

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