Cited by 238Hippo pathway signaling and YAP/TAZOcular Oncology and TreatmentsProtein Kinase Regulation and GTPase Signaling

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

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Feng, Xiaodong, Arang, Nadia, Rigiracciolo, Damiano Cosimo, Lee, Joo Sang, Yeerna, Huwate, Wang, Zhiyong, Lubrano, Simone, Kishore, Ayush +9 more·2019·Cancer Cell

Abstract

Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. We show that Gαq activates FAK through TRIO-RhoA non-canonical Gαq-signaling, and genetic ablation or pharmacological inhibition of FAK inhibits UM growth. Analysis of the FAK-regulated transcriptome demonstrated that GNAQ stimulates YAP through FAK. Dissection of the underlying mechanism revealed that FAK regulates YAP by tyrosine phosphorylation of MOB1, inhibiting core Hippo signaling. Our findings establish FAK as a potential therapeutic target for UM and other Gαq-driven pathophysiologies that involve unrestrained YAP function.

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Authors
Feng, X., Arang, N., Rigiracciolo, D. C., Lee, J. S., Yeerna, H., Wang, Z., Lubrano, S., Kishore, A., Pachter, J. A., König, G. M., Maggiolini, M., Kostenis, E., Schlaepfer, D. D., Tamayo, P., Chen, Q., Ruppin, E., & Gutkind, J. S.
Affiliations
  • Sichuan University (CN)
  • University of California San Diego (US)
  • National Institutes of Health (US)
  • Verastem (United States) (US)
  • University of Bonn (DE)
  • University of Calabria (IT)
Corresponding author
  • Lee, Joo Sang
  • Chen, Qianming
  • Ruppin, Eytan
  • Gutkind, J. Silvio
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2019-03
Volume
35
Issue
3
Pages
457-472.e5
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2911710737
Cited by
237
References
71
Citations by year
2026: 14 · 2025: 22 · 2024: 31 · 2023: 40 · 2022: 36 · 2021: 40 · 2020: 37 · 2019: 17
FWCI
17.21
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
Funders
  • NIH (R33CA225291, U01CA217885, P30 CA023100, R01HG009285, 10193SC, CA209891, CA102310, T32GM007752)
  • DGE (1650112, T32CA067754-22)
  • MOE (B14038)
  • National Natural Science Foundation (81672677, 81520108009, 81621062)
  • AIRC (IG 21322)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Ophthalmology › Ocular Oncology and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
uveal melanoma, GNAQ, GNA11, focal adhesion kinase, synthetic lethality, Hippo signaling pathway, YAP, MOB1, tyrosine phosphorylation, therapeutic target
MeSH terms
Hippo Signaling Pathway, Uveal Melanoma, Animals, Genes, Lethal, Humans, Melanoma, Neoplasm Transplantation, Phosphorylation, Prognosis, Uveal Neoplasms, Signal Transduction, Survival Analysis, Protein Serine-Threonine Kinases, Computational Biology, GTP-Binding Protein alpha Subunits, Gq-G11, Cell Line, Tumor, Cell Proliferation, Mice, Focal Adhesion Kinase 1

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