Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry

Xiaodong Feng; Maria Sol Degese; Ramiro Iglesias-Bartolome; Jose P Vaque; Alfredo A Molinolo; Murilo Rodrigues; M Raza Zaidi; Bruce R Ksander; Glenn Merlino; Akrit Sodhi; Qianming Chen; J Silvio Gutkind

doi:10.1016/j.ccr.2014.04.016

Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry

Cancer Cell. 2014 Jun 16;25(6):831-45. doi: 10.1016/j.ccr.2014.04.016. Epub 2014 May 29.

Authors

Affiliations

¹ 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.
² Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
³ Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
⁴ Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
⁵ Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
⁶ Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
⁷ State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: qmchen@scu.edu.cn.
⁸ 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.

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.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
Cell Cycle Proteins
Cell Growth Processes / physiology
Cell Line, Tumor
Female
GTP Phosphohydrolases / genetics
GTP Phosphohydrolases / metabolism*
GTP-Binding Protein alpha Subunits / genetics*
GTP-Binding Protein alpha Subunits / metabolism
GTP-Binding Protein alpha Subunits, Gq-G11
Gene Knockdown Techniques
HEK293 Cells
Heterografts
Hippo Signaling Pathway
Humans
Melanoma / enzymology
Melanoma / genetics*
Melanoma / metabolism
Melanoma, Cutaneous Malignant
Mice
Mice, Inbred NOD
Mutation
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction
Skin Neoplasms
Transcription Factors / genetics*
Transcription Factors / metabolism
Transfection
Uveal Neoplasms / enzymology
Uveal Neoplasms / genetics*
Uveal Neoplasms / metabolism
rho GTP-Binding Proteins / genetics
rho GTP-Binding Proteins / metabolism

Substances

Cell Cycle Proteins
GNA11 protein, human
GNAQ protein, human
GTP-Binding Protein alpha Subunits
Nuclear Proteins
Transcription Factors
YY1AP1 protein, human
Protein Serine-Threonine Kinases
GTP Phosphohydrolases
GTP-Binding Protein alpha Subunits, Gq-G11
rho GTP-Binding Proteins

Supplementary concepts

Uveal melanoma

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding