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Origin and Evolution of RAS Membrane Targeting

Oncogene volume 42, pages 1741–1750 (2023)Cite this article

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Abstract

KRAS, HRAS and NRAS proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS proteins consist of a globular G-domain (aa1-166) and a 22-23 aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionary origins of the RAS isoforms, their HVRs and alternative splicing of the KRAS locus has not been explored. We found that KRAS is basal to the RAS proto-oncogene family and its duplication generated HRAS in the common ancestor of vertebrates. In a second round of duplication HRAS generated NRAS and KRAS generated an additional RAS gene we have designated KRASBL, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4th exon of NRAS into the 3rd intron of KRAS. We found evolutionary conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS protein function. The persistence of four RAS isoforms through >400 million years of evolution argues strongly for differential function.

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Fig. 1: Membrane targeting motifs and gene structure of human RAS proteins.
Fig. 2: Eukaryotic RAS protein C-terminal alignment and HVR targeting motifs.
Fig. 3: Conservation of intron/exon gene structures.
Fig. 4: The switch-I and -II regions of eukaryotic RAS proteins are strictly conserved over 1480 MY.
Fig. 5: Vertebrate RAS protein expansion.

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Data availability

All data analyzed in this report are publicly available from NCBI (https://www.ncbi.nlm.nih.gov), Ensembl (http://www.ensembl.org/) and SIMRBASE (https://genomes.stowers.org). The data utilized are provided in Suppl. File 1.

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Acknowledgements

We thank Sebastien Santini (CNRS/AMU IGS UMR7256) and the PACA Bioinfo platform for the availability and management of the phylogeny.fr website.

Funding

Funding was provided to M.R.P. (NIH R35CA253178).

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  1. Bionos Biotech SL; Biopolo Hospital La Fe, Valencia, Spain

    Antonio García-España

  2. Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA

    Mark R. Philips

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AGE mined genomic databases and performed alignment and phylogenetic analysis which was put into the context of RAS membrane targeting by MRP and AGE wrote the manuscript together.

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Correspondence to Mark R. Philips.

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García-España, A., Philips, M.R. Origin and Evolution of RAS Membrane Targeting. Oncogene 42, 1741–1750 (2023). https://doi.org/10.1038/s41388-023-02672-z

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