Hippo-Independent Activation of YAP by the GNAQ Uveal Melanoma Oncogene through a Trio-Regulated Rho GTPase Signaling Circuitry

Abstract

Summary Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ~83% and ~6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional co-activator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of PLCβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, the first described GNAQ/GNA11-initiated human malignancy.

RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

“…Finally, in vivo, lung tumors observed in transgenic RhoB-deficient mice exhibited increased nuclear YAP. An opposite effect for RhoA and Rac was recently suggested, favoring YAP activation (36,43). Thus, if control of YAP nuclear entrance was first linked to the promigratory RhoA/Rac proteins, we unravel here how RASSF1A and RhoB could act as cell migration and metastasis suppressors, by opposing to YAP nuclear entrance.…”

“…In line with such data, we report here that RASSF1A knockdown promotes a nuclear accumulation of active YAP. A regulation of YAP has been previously reported through a Trio-Rho/Rac signaling circuitry, downstream Gaq activation (36). ECM rigidity and mechanical stress were also shown to regulate YAP transcriptional activity, via the tension the actomyosin cytoskeleton (37), and a Rho GTPase activity (6).…”

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

“…Our results thus suggest that SFKs promote the proliferation of crypt IECs by activating Rac, which in turn upregulates the abundance of YAP. The Rho family GTPases Rac and Rho are thought to contribute to YAP activation by oncogenic mutants of GNAQ in a manner dependent on actin polymerization (46). Phosphorylation of YAP at Tyr 357 by c-Src increases the stability of the protein, and this action of c-Src has been implicated in the promotion of IEC proliferation (47).…”

Cellular functions of the ADF/cofilin family at a glance

“…Cells from these uveal melanomas have reduced levels of cofilin activity, which promote actin cytoskeleton stability and activation of YAP. YAP activation is sensitive to inhibition of either contractility or actin polymerization in this context as well (Feng et al, 2014).…”