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.

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
  • Humans
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Melanoma / metabolism
  • 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
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • GTP Phosphohydrolases
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • rho GTP-Binding Proteins

Supplementary concepts

  • Melanoma, Cutaneous Malignant
  • Uveal melanoma