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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.

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机构: [1]Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA [2]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China [3]Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA [4]Cancer Data Science Laboratory, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA [5]Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany [6]Verastem Oncology, Needham, MA, USA [7]Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende 87036, Italy [8]Center for Bioinformatics and Computational Biology & Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA [9]Division of Medical Genetics, UC San Diego School of Medicine, La Jolla, CA 92093, USA
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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. Copyright © 2019 Elsevier Inc. All rights reserved.

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出版当年[2019]版:
大类 | 1 区 医学
小类 | 1 区 肿瘤学 1 区 细胞生物学
最新[2023]版:
大类 | 1 区 医学
小类 | 1 区 细胞生物学 1 区 肿瘤学
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第一作者机构: [1]Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA [2]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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通讯机构: [4]Cancer Data Science Laboratory, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA [8]Center for Bioinformatics and Computational Biology & Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA
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