Decoding RAS isoform and codon-specific signalling

Abstract

RAS proteins are key signalling hubs that are oncogenically mutated in 30% of all cancer cases. Three genes encode almost identical isoforms that are ubiquitously expressed, but are not functionally redundant. The network responses associated with each isoform and individual oncogenic mutations remain to be fully characterized. In the present article, we review recent data defining the differences between the RAS isoforms and their most commonly mutated codons and discuss the underlying mechanisms.

Figure 1. RAS activation and signalling

RAS cycling between the inactive GDP-bound and the active GTP-bound conformations is controlled by GEFs and GAPs. GTP-bound RAS can interact with more than 20 effectors that control many cellular functions. AF6, ALL-1-fusion partner in chromosome 6; ERK, extracellular-signal-regulated kinase; MEK, MAPK/ERK kinase; RASSF, RAS-association domain family.

Figure 2. Relative RAS isoform protein abundance in a panel of cancer cell lines

KRAS is the most abundant isoform in the majority of cell lines, whereas HRAS typically represents ≤20% of total RAS in most cell lines. Data taken from [43].

Figure 3. RAS isoform codon mutation bias in human cancers

(A) A survey of RAS mutations across all cancers reveals that KRAS favours mutation at codon 12, whereas NRAS is typically mutated at codon 61. (B) Analysis of individual tumour types with ≥20 mutations of each isoform reveals similar codon biases. Data from Sanger COSMIC (Catalog of Somatic Mutations in Cancer) version 52 dataset and collated in [8].