title: Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.
abstract: Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼ 83% and ∼ 6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Feng
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Maria Sol
authors.initials: MS
authors.lastname: Degese
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Iglesias-Bartolome
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Jose P
authors.initials: JP
authors.lastname: Vaque
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Murilo
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: M Raza
authors.initials: MR
authors.lastname: Zaidi
authors.affiliation: Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Akrit
authors.initials: A
authors.lastname: Sodhi
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: qmchen@scu.edu.cn.
authors.forename: Qianming
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA. Electronic address: sg39v@nih.gov.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics* / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D064593:Heterografts; D000090683:Hippo Signaling Pathway; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014604:Uveal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000096142:Cutaneous Malignant Melanoma; D000098943:Uveal Melanoma
chemical_list: D018797:Cell Cycle Proteins; C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D017346:Protein Serine-Threonine Kinases; D020558:GTP Phosphohydrolases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020741:rho GTP-Binding Proteins