%0 Journal Article
%T Targeting nucleotide exchange to inhibit constitutively active G protein ¦Á subunits in cancer cells
%J -
%D 2018
%R 10.1126/scisignal.aao6852
%X Constitutively active G protein ¦Á subunits cause cancer, cholera, Sturge-Weber syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active G¦Á subunits in these disorders has yet to be achieved. We found that constitutively active G¦Áq in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate¨Cfor¨Cguanosine triphosphate (GDP/GTP) exchange to trap constitutively active G¦Áq in inactive, GDP-bound G¦Á¦Â¦Ã heterotrimers. Allosteric inhibition of other G¦Á subunits was achieved by the introduction of an FR-binding site. In UM cells driven by constitutively active G¦Áq, FR inhibited second messenger signaling, arrested cell proliferation, reinstated melanocytic differentiation, and stimulated apoptosis. In contrast, FR had no effect on BRAF-driven UM cells. FR promoted UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)¨Cmediated gene silencing, a heretofore unrecognized effector system of constitutively active G¦Áq in UM. Constitutively active G¦Áq and PRC2 therefore provide therapeutic targets for UM. The development of FR analogs specific for other G¦Á subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active G¦Á subunits or multiple G protein¨Ccoupled receptors (GPCRs) where targeting a single receptor is ineffective
%U http://stke.sciencemag.org/content/11/546/eaao6852