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Origin and evolution of RAS oncoprotein membrane targeting

Antonio García-España1, Mark R Philips2

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

Research Square
|January 30, 2023
PubMed

Insights

The evolution of RAS oncogenes reveals KRAS as the ancestral gene, with duplications generating HRAS, NRAS, and KRASBL. These evolutionary events shaped RAS isoforms, suggesting distinct functions critical for oncoprotein activity.

Area of Science:

  • Evolutionary biology
  • Molecular genetics
  • Cancer research

Background:

  • The RAS oncogene family, including KRAS, HRAS, and NRAS, comprises homologous genes encoding small GTPases.
  • RAS oncoproteins feature a G-domain and a hypervariable region (HVR) for membrane targeting.
  • The evolutionary origins and diversification of RAS isoforms remain underexplored.

Approach:

  • Phylogenetic analysis to trace the evolutionary history of RAS genes.
  • Identification and characterization of gene duplication events and alternative splicing.
  • Comparative genomics to study conserved and divergent features across species.

Key Points:

  • KRAS is the basal oncogene; its duplication yielded HRAS in early vertebrates.
  • Further duplications generated NRAS and KRASBL, with KRAS4A arising from NRAS exon insertion into KRAS.
  • Conserved motifs like polybasic regions (PBR1, PBR2) and modified CaaX motifs suggest functional adaptations in RAS isoforms.

Conclusions:

  • The persistence of four RAS isoforms over 400 million years strongly indicates specialized, differential functions.
  • Evolutionary modifications, including lipid anchor alterations, are critical for RAS oncoprotein activity.
  • Understanding RAS evolution provides insights into oncogenesis and potential therapeutic targets.

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