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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.
Feng, Xiaodong; Arang, Nadia; Rigiracciolo, Damiano Cosimo; Lee, Joo Sang; Yeerna, Huwate; Wang, Zhiyong; Lubrano, Simone; Kishore, Ayush; Pachter, Jonathan A; König, Gabriele M; Maggiolini, Marcello; Kostenis, Evi; Schlaepfer, David D; Tamayo, Pablo; Chen, Qianming; Ruppin, Eytan; Gutkind, J Silvio.
Afiliação
  • Feng X; Moores 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.
  • Arang N; Moores 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.
  • Rigiracciolo DC; Moores 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.
  • Lee JS; Cancer 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.
  • Yeerna H; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Wang Z; Moores 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.
  • Lubrano S; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Kishore A; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Pachter JA; Verastem Oncology, Needham, MA, USA.
  • König GM; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany.
  • Maggiolini M; Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende 87036, Italy.
  • Kostenis E; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany.
  • Schlaepfer DD; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Tamayo P; Moores 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.
  • Chen Q; State 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.
  • Ruppin E; Cancer 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.
  • Gutkind JS; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: sgutkind@ucsd.edu.
Cancer Cell ; 35(3): 457-472.e5, 2019 03 18.
Article em En | MEDLINE | ID: mdl-30773340
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Uveais / Transdução de Sinais / Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP / Quinase 1 de Adesão Focal / Genes Letais / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Uveais / Transdução de Sinais / Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP / Quinase 1 de Adesão Focal / Genes Letais / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article