RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells

Sci Rep. 2018 Jan 12;8(1):653. doi: 10.1038/s41598-017-18851-4.


Analysis of 501 melanoma exomes revealed RGS7, which encodes a GTPase-accelerating protein (GAP), to be a tumor-suppressor gene. RGS7 was mutated in 11% of melanomas and was found to harbor three recurrent mutations (p.R44C, p.E383K and p.R416Q). Structural modeling of the most common recurrent mutation of the three (p.R44C) predicted that it destabilizes the protein due to the loss of an H-bond and salt bridge network between the mutated position and the serine and aspartic acid residues at positions 58 as 61, respectively. We experimentally confirmed this prediction showing that the p.R44C mutant protein is indeed destabilized. We further show RGS7 p.R44C has weaker catalytic activity for its substrate Gαo, thus providing a dual mechanism for its loss of function. Both of these effects are expected to contribute to loss of function of RGS7 resulting in increased anchorage-independent growth, migration and invasion of melanoma cells. By mutating position 56 in the R44C mutant from valine to cysteine, thereby enabling the formation of a disulfide bridge between the two mutated positions, we slightly increased the catalytic activity and reinstated protein stability, leading to the rescue of RGS7's function as a tumor suppressor. Our findings identify RGS7 as a novel melanoma driver and point to the clinical relevance of using strategies to stabilize the protein and, thereby, restore its function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disulfides / chemistry
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Humans
  • Hydrogen Bonding
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Models, Molecular
  • Mutation*
  • Neoplasm Invasiveness
  • Protein Conformation
  • Protein Stability
  • RGS Proteins / chemistry*
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*


  • Disulfides
  • RGS Proteins
  • RGS7 protein, human
  • GTP-Binding Protein alpha Subunits, Gi-Go