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

Jose P Vaqué; Robert T Dorsam; Xiaodong Feng; Ramiro Iglesias-Bartolome; David J Forsthoefel; Qianming Chen; Anne Debant; Mark A Seeger; Bruce R Ksander; Hidemi Teramoto; J Silvio Gutkind

doi:10.1016/j.molcel.2012.10.018

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.

Authors

Jose P Vaqué¹, Robert T Dorsam, Xiaodong Feng, Ramiro Iglesias-Bartolome, David J Forsthoefel, Qianming Chen, Anne Debant, Mark A Seeger, Bruce R Ksander, Hidemi Teramoto, J Silvio Gutkind

Affiliation

¹ Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.

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

Grants and funding

ZIA DE000551-21/ImNIH/Intramural NIH HHS/United States