A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK

Abstract

Highlights d Innovative bioinformatics pipeline reveals FAK as candidate synthetic lethal with Gaq d FAK is a central mediator of the GNAQ-driven oncogenic signaling circuitry d FAK activates YAP by MOB1 phosphorylation resulting in Hippo pathway inhibition d FAK represents a potential precision therapeutic target for uveal melanoma treatment

STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation

“…7A), we observed that the MAP4K4 knockdown signature associated significantly with a number of YAP1 genesets derived from the literature as well as those we have generated by ectopic expression of wild-type or mutant YAP1 in immortalized human mammary epithelial cell (YAP1 UP, YAP1 mt UP) ( Fig. 8C) (p-value<0.0001) (Zhao et al 2008, Cordenonsi et al 2011, Yu et al 2012, Hiemer et al 2015, Feng et al 2019). Furthermore, when we compared the MAP4K4 knockdown signature with gene dependency data from Project Achilles, a large-scale project involving genome scale loss-of-function fitness screens performed in hundreds of cancer cell lines (Aguirre et al 2016, Meyers et al 2017, Tsherniak et al 2017, we observed significant association with dependency profiles of TAZ1 and TEAD1 (IC= -0.447, -0.512, p-value= 0.0001, 0.0001, respectively), which are both Hippo pathway effector molecules (Fig.…”

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

“…This indicated that the majority of GPCR signaling likely promotes Yap nuclear accumulation and transcriptional activity. Subsequent studies corroborated the Yap-activating role of S1P (Miller et al, 2012), and identified activating mutations in G-protein subunits in cancer (Cai & Xu, 2013;Feng et al, 2014Feng et al, , 2019Jang et al, 2012;Van Raamsdonk et al, 2009;F. X. Yu et al, 2014).…”

“…This indicated that the majority of GPCR signaling likely promotes Yap nuclear accumulation and transcriptional activity. Subsequent studies corroborated the Yap‐activating role of S1P (Miller et al, ), and identified activating mutations in G‐protein subunits in cancer (Cai & Xu, ; Feng et al, , ; Jang et al, ; Van Raamsdonk et al, ; F. X. Yu et al, ). Thus, GPCR signaling is a significant regulator of Hippo signaling, typically associated with Yap nuclear accumulation and transcriptional activity.…”

Uveal melanoma cells use ameboid and mesenchymal mechanisms of cell motility crossing the endothelium

“…BAP1 is a histone deubiquitinase recruited to promoters of genes [16], and we found that several actin cytoskeleton regulator genes are targeted by BAP1 in UM cells [16]. In parallel, constitutively active Gq/11, the oncogenic driver of UM, activates the dual nucleotide exchange factor TRIO, which in turn activates the Rho-like small GTPases RhoA and Rac1 [17] that regulate the actin cytoskeleton during cell migration [18,19]. We hypothesize that regulation of actin-based processes, downstream of BAP1 and Gq/11, and via the RhoA and Rac1 pathways, controls the migration of UM cells.…”