ArticleCancer cell2019
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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Article in Cancer cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 143 papers.
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143citing papers in PubMed
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143 citing papers in PubMed, 241 citations in OpenAlex.
- Functional genomic screens uncover FERMT2 as a critical regulator of YAP/TAZ-driven tumorigenicity.Cell death and differentiation · 2026Article
- Does the ERBB/EGF Signaling Network Serve as a Nexus for Oncogenic Signals in Uveal Melanoma?Biomolecules · 2026Review
- A Phase II Trial of Defactinib Combined with Avutometinib in Patients with Metastatic Uveal Melanoma.Cancers · 2026Article
- From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease.Clinical and molecular hepatology · 2026Review
- Recent advances in the molecular genetic mechanisms and immune microenvironment of uveal melanoma.Melanoma research · 2026Review
- Estrogen promotes osteogenesis via YAP1-driven activation of ERα orchestrated through TEAD1 binding to the ERα promoter.Journal of molecular histology · 2026Article
- Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction.Nature communications · 2026Article
- Article
- Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction.bioRxiv : the preprint server for biology · 2025Article
- Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression.Nature communications · 2025Article
- Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma.The Journal of biological chemistry · 2025Article
- Focal adhesion kinase inhibition induces membrane accumulation of aquaporin-2 in renal epithelial cells by actin depolymerization and endocytosis inhibition.American journal of physiology. Renal physiology · 2025Article
- Focal adhesion kinase/Src family kinase axis-mediated tyrosine phosphorylation of metabolic enzymes facilitates tumor metastasis.Signal transduction and targeted therapy · 2025Article
- Chromosomal 3p loss and 8q gain drive vasculogenic mimicry via HIF-2α and VE-cadherin activation in uveal melanoma.Cell death and differentiation · 2025Article
- State-of-the-art in Metastatic Uveal Melanoma Treatment: A 2025 Update : How to treat Metastatic Uveal Melanoma in 2025.Current oncology reports · 2025Review
- The guanine nucleotide exchange factor Ric-8A regulates the sensitivity of constitutively active Gαq to the inhibitor YM-254890.The Journal of biological chemistry · 2025Article
- An Agrin-YAP/TAZ Rigidity Sensing Module Drives EGFR-Addicted Lung Tumorigenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma.Cancer cell · 2025Article
- Review
- Loss of NF1 Accelerates Uveal and Intradermal Melanoma Tumorigenesis, and Oncogenic GNAQ Transforms Schwann Cells.Cancer research communications · 2025Article
83 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 7 institutions in 4 countries.
Xiaodong FengMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Nadia ArangMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Damiano Cosimo RigiraccioloMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende 87036, Italy.
Joo Sang LeeCancer Data Science Laboratory, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology & Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA. Electronic address: lee.joosang@gmail.com.
Huwate YeernaMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Zhiyong WangMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Simone LubranoMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Ayush KishoreMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Jonathan A PachterVerastem Oncology, Needham, MA, USA.
Gabriele M KönigMolecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany.
Marcello MaggioliniDepartment of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende 87036, Italy.
Evi KostenisMolecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany.
David D SchlaepferMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Pablo TamayoMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Division of Medical Genetics, UC San Diego School of Medicine, La Jolla, CA 92093, USA.
Qianming ChenState Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China. Electronic address: qmchen@scu.edu.cn.
Eytan RuppinCancer Data Science Laboratory, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology & Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA. Electronic address: eyruppin@gmail.com.
J Silvio GutkindMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: sgutkind@ucsd.edu.
University of California, San Diego · USSichuan University · CNUniversity of Bonn · DEUniversity of Calabria · ITNational Cancer Institute · USUniversity of Maryland, College Park · USVerastem (United States) · US
Funding
VIRAL MALIGNANCYP30CA023100 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DIANE M SIMEONE · 1985 to 2026
$124.9MDiscovery of genetic interactions in cancerZIABC011802 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI RUPPIN, EYTAN · 2018 to 2025
$19.6MGRADUATE TRAINING IN CELLULAR &MOLECULAR PHARMACOLOGYT32GM007752 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BROWN, JOAN HELLER, HANDEL, TRACY M · 1985 to 2023
$13.5MUsing Networks to Seed Hierarchical Whole-cell Models of CancerU54CA209891 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KROGAN, NEVAN J · 2017 to 2021
$10.9MPredoctoral and Postdoctoral Training in Cancer Cell BiologyT32CA067754 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JEAN Y.J. WANG · 1995 to 2026
$6.5MA Rational Systematic Approach to Find Combinations of Pharmacologic and Immune Therapies that Target Identifiable Oncogenic StatesU01CA217885 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI COHEN, EZRA, KAUFMAN, DAN S. · 2017 to 2021
$5.1MRole of Focal Adhesion Kinase In TumorigenesisR01CA102310 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SCHLAEPFER, DAVID D · 2003 to 2019
$5.0MGenePattern and GenePattern Notebook: Integrative 'Omic Analysis for Cancer ResearchU24CA248457 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P., TAMAYO, PABLO · 2020 to 2024
$4.6MNext-generation Functional Genetic Screening of Un-screenable TraitsR01HG009285 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MALI, PRASHANT, TAMAYO, PABLO · 2017 to 2020
$4.2MSupporting and evolving Gene Set Enrichment Analysis and the Molecular Signatures Database for cancer researchU24CA220341 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P., TAMAYO, PABLO · 2018 to 2022
$3.4MGenePattern Notebooks for Cancer ResearchU24CA194107 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P. · 2015 to 2019
$2.8MGPCR - Linked RhoGEFs in Tumor Growth and MetastasisR01CA221289 · NCI · PURDUE UNIVERSITY · PI TESMER, JOHN · 2018 to 2022
$1.9MNCI NIH HHS P30 CA023100NCI NIH HHS R01 CA102310NCI NIH HHS R01 CA221289NCI NIH HHS R33 CA225291NCI NIH HHS T32 CA067754NCI NIH HHS U01 CA217885NCI NIH HHS U24 CA194107NCI NIH HHS U24 CA220341NCI NIH HHS U24 CA248457NCI NIH HHS U54 CA209891NHGRI NIH HHS R01 HG009285NIGMS NIH HHS T32 GM007752
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.
Indexed as
Genes, LethalSignal TransductionAnimalsCell Line, TumorCell ProliferationComputational BiologyFocal Adhesion Kinase 1GTP-Binding Protein alpha Subunits, Gq-G11Hippo Signaling PathwayHumansMelanomaMiceNeoplasm TransplantationPhosphorylationPrognosisProtein Serine-Threonine KinasesFocal Adhesion Kinase 1GNAQ protein, humanGTP-Binding Protein alpha Subunits, Gq-G11Protein Serine-Threonine KinasesPTK2 protein, humanFAKGNA11GNAQG proteinHippoMOB1PTK2signal transductionuveal melanomaYAP
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