The experimental power of FR900359 to study Gq-regulated biological processes

Nat Commun. 2015 Dec 14;6:10156. doi: 10.1038/ncomms10156.

Abstract

Despite the discovery of heterotrimeric αβγ G proteins ∼25 years ago, their selective perturbation by cell-permeable inhibitors remains a fundamental challenge. Here we report that the plant-derived depsipeptide FR900359 (FR) is ideally suited to this task. Using a multifaceted approach we systematically characterize FR as a selective inhibitor of Gq/11/14 over all other mammalian Gα isoforms and elaborate its molecular mechanism of action. We also use FR to investigate whether inhibition of Gq proteins is an effective post-receptor strategy to target oncogenic signalling, using melanoma as a model system. FR suppresses many of the hallmark features that are central to the malignancy of melanoma cells, thereby providing new opportunities for therapeutic intervention. Just as pertussis toxin is used extensively to probe and inhibit the signalling of Gi/o proteins, we anticipate that FR will at least be its equivalent for investigating the biological relevance of Gq.

Publication types

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

MeSH terms

  • Animals
  • Ardisia / chemistry
  • Cell Line, Tumor
  • Depsipeptides / chemistry
  • Depsipeptides / pharmacology*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Melanoma / metabolism
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Protein Isoforms
  • Signal Transduction
  • Tail / blood supply
  • Vasoconstriction / drug effects

Substances

  • Depsipeptides
  • FR900359
  • Protein Isoforms
  • GTP-Binding Protein alpha Subunits, Gq-G11