Research ArticleBiochemistry

Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential

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Science Signaling  19 Feb 2019:
Vol. 12, Issue 569, eaav2449
DOI: 10.1126/scisignal.aav2449

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Tumorigenic Trio

Rho guanine nucleotide exchange factors (RhoGEFs) activate the Rho family of small GTPases that regulate cell migration and gene expression in normal development, as well as disease, including some cancers. In many uveal melanomas, the RhoGEF Trio mediates signaling from oncogenic Gαq/11 proteins, which drives tumor progression. Bandekar et al. investigated the structural regulation of Trio and showed that mutations found in patients relieve its autoinhibitory conformation, thereby enabling sustained Gαq/11-Trio-Rho signaling in cells. These findings may lead to targeted therapeutics for patients with uveal melanoma or other Gαq/11- or Trio-driven tumors.