Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential.
In: Science Signaling, Jg. 12 (2019-02-19), Heft 569, S. N.PAG
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Zugriff:
Structural analysis of the RhoGEF Trio reveals modes of its activation in patients with cancer. 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 Gα q/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 Gα q/11 -Trio-Rho signaling in cells. These findings may lead to targeted therapeutics for patients with uveal melanoma or other Gα q/11 - or Trio-driven tumors. The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gα q/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gα q/11 -coupled G protein–coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gα q/11 binding. Here, we determined the crystal structure of TrioC in its basal state and found that the pleckstrin homology (PH) domain interacts with the Dbl homology (DH) domain in a manner that occludes the Rho GTPase binding site, thereby suggesting the molecular basis of TrioC autoinhibition. Biochemical and biophysical assays revealed that disruption of the autoinhibited conformation destabilized and activated the TrioC module in vitro. Last, mutations in the DH-PH interface found in patients with cancer activated TrioC and, in the context of full-length Trio, led to increased abundance of guanosine triphosphate–bound RhoA (RhoA·GTP) in human cells. These mutations increase mitogenic signaling through the RhoA axis and, therefore, may represent cancer drivers operating in a Gα q/11 -independent manner. [ABSTRACT FROM AUTHOR]
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Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential.
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Autor/in / Beteiligte Person: | Bandekar, Sumit J. ; Arang, Nadia ; Tully, Ena S. ; Tang, Brittany A. ; Barton, Brenna L. ; Li, Sheng ; Gutkind, J. Silvio ; Tesmer, John J. G. |
Zeitschrift: | Science Signaling, Jg. 12 (2019-02-19), Heft 569, S. N.PAG |
Veröffentlichung: | 2019 |
Medientyp: | academicJournal |
ISSN: | 1945-0877 (print) |
DOI: | 10.1126/scisignal.aav2449 |
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