DIRAS3 (ARHI) Blocks RAS/MAPK Signaling by Binding Directly to RAS and Disrupting RAS Clusters

Cell Rep. 2019 Dec 10;29(11):3448-3459.e6. doi: 10.1016/j.celrep.2019.11.045.


Oncogenic RAS mutations drive cancers at many sites. Recent reports suggest that RAS dimerization, multimerization, and clustering correlate strongly with activation of RAS signaling. We have found that re-expression of DIRAS3, a RAS-related small GTPase tumor suppressor that is downregulated in multiple cancers, inhibits RAS/mitogen-activated protein kinase (MAPK) signaling by interacting directly with RAS-forming heteromers, disrupting RAS clustering, inhibiting Raf kinase activation, and inhibiting transformation and growth of cancer cells and xenografts. Disruption of K-RAS cluster formation requires the N terminus of DIRAS3 and interaction of both DIRAS3 and K-RAS with the plasma membrane. Interaction of DIRAS3 with both K-RAS and H-RAS suggests a strategy for inhibiting oncogenic RAS function.

Keywords: ARHI; DIRAS3; RAS inhibitor; cluster; dimer; heteromer; ovarian cancer; pancreatic cancer; transformation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3 Cells
  • Animals
  • Carcinogenesis / metabolism*
  • Cell Line, Tumor
  • Female
  • Humans
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Nude
  • Protein Binding
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • raf Kinases / metabolism
  • rho GTP-Binding Proteins / metabolism*


  • DIRAS3 protein, human
  • KRAS protein, human
  • raf Kinases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • rho GTP-Binding Proteins