RAS variant signalling

Abstract

RAS proteins are small GTPases that regulate signalling networks that control cellular proliferation and survival. They are frequently mutated in cancer and a commonly occurring group of developmental disorders called RASopathies. We discuss recent findings describing how RAS isoforms and different activating mutations differentially contribute to normal and disease-associated biology and the mechanisms that have been proposed to underpin this.

Keywords: RAS; cancer; codon; isoforms; mutation; signalling.

Figure 1.. RAS mutations in cancer.

RAS mutation frequencies for each cancer type are derived from TCGA PanCancer Atlas dataset, release 12.0, comprising 10 122 patient cases. RTK/RAS pathway mutation frequencies comprising data from 85 curated RAS pathway nodes are derived from Sanchez-Vega et al. [2]. Estimated annual RAS mutant patients in the U.S.A. calculated by multiplying the relevant RAS mutation frequencies by the estimated number of new patients per year per cancer type collated from American Cancer Society [63]. Codon mutation pie charts indicate the % of all RAS mutant cases and were collated from the COSMIC database, v85, comprising 53 728 RAS mutant samples [64].

Figure 2.. Sequence features of RAS isoforms.

The G-domain of RAS comprises the effector and allosteric lobes. The main area of sequence divergence (blue) between isoforms is in the HVR with limited divergence also in the allosteric lobe clustered around residues associated with nucleotide and membrane binding. Residues mutated in cancer (red) and RASopathies (underlined) are highlighted. Wild-type KRAS 3D structure (PDB: 4OBE; residues 1–169) showing relative positioning of Switch domains versus membrane-binding residues regulating G-domain orientation (orange), D154 residue required for dimerisation (pink) and putative dimerisation interface on α4–α5 helices (cyan).