A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing mitogenic signals initiated by G protein-coupled receptors

Mol Cell. 2013 Jan 10;49(1):94-108. doi: 10.1016/j.molcel.2012.10.018. Epub 2012 Nov 21.

Abstract

Activating mutations in GNAQ and GNA11, encoding members of the Gα(q) family of G protein α subunits, are the driver oncogenes in uveal melanoma, and mutations in Gq-linked G protein-coupled receptors have been identified recently in numerous human malignancies. How Gα(q) and its coupled receptors transduce mitogenic signals is still unclear because of the complexity of signaling events perturbed upon Gq activation. Using a synthetic-biology approach and a genome-wide RNAi screen, we found that a highly conserved guanine nucleotide exchange factor, Trio, is essential for activating Rho- and Rac-regulated signaling pathways acting on JNK and p38, and thereby transducing proliferative signals from Gα(q) to the nucleus independently of phospholipase C-β. Indeed, whereas many biological responses elicited by Gq depend on the transient activation of second-messenger systems, Gq utilizes a hard-wired protein-protein-interaction-based signaling circuitry to achieve the sustained stimulation of proliferative pathways, thereby controlling normal and aberrant cell growth.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Drosophila / genetics
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Enzyme Activation
  • Female
  • GTP-Binding Protein alpha Subunits / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Gene Knockdown Techniques
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanine Nucleotide Exchange Factors / physiology*
  • Humans
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogens / pharmacology
  • Mitosis*
  • NIH 3T3 Cells
  • Neoplasm Transplantation
  • Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA Interference
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction*
  • Transcription Factor AP-1 / metabolism*
  • rho GTP-Binding Proteins / metabolism*

Substances

  • Drosophila Proteins
  • GNAQ protein, human
  • GTP-Binding Protein alpha Subunits
  • Guanine Nucleotide Exchange Factors
  • Mitogens
  • Receptors, G-Protein-Coupled
  • Transcription Factor AP-1
  • Protein-Serine-Threonine Kinases
  • TRIO protein, human
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • rho GTP-Binding Proteins
  • Clozapine
  • clozapine N-oxide