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A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK
Open accessAbstract
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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“On the other hand, FAK was reported to positively regulate YAP activity through tyrosine phosphorylation of the YAP upstream modulator MOB1, then dissociating the MOB1/LATS complex.[ 31, 32 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [31]
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“FAK is known to activate and accumulate YAP in cell nucleus through its regulation of the MOB1/LATS1/2 complex, which is an upstream biomarker of YAP signaling[ 31, 32 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [31]
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Metadata
- 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
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 35
- Issue
- 3
- Pages
- 457-472.e5
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC6737937
- 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
- bronze
- doi.org
- Licence
- 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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