Research article
Transformation by a nucleotide-activated P2Y receptor is mediated by activation of Gαi, Gαq and Rho-dependent signaling pathways
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* Corresponding author: Irene E Zohn izohn@cnmcresearch.org
1 Linebergher Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
2 Department of Pharmacology, Chapel Hill, NC 27599, USA
3 Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA
4 Department of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine, Washington DC 20037, USA
Journal of Molecular Signaling 2010, 5:11 doi:10.1186/1750-2187-5-11
Published: 23 July 2010Abstract
Background
Nucleotide-actived P2Y receptors play critical roles in the growth of tumor cells by regulating cellular proliferation, differentiation and survival.
Results
Here we demonstrate that an avian P2Y purinoceptor (tP2YR) with unique pharmacological and signal transduction properties induces morphologic and growth transformation of rodent fibroblasts. tP2YR induced a transformed phenotype similar to the mas oncogene, a G protein-coupled receptor which causes transformation by activation of Rac-dependent pathways. tP2YR-transformed cells exhibited increased steady-state activation of Rac1 and RhoA. Like activated Rho GTPases, tP2YR cooperated with activated Raf and caused synergistic transformation of NIH3T3 cells. Our data indicate that the ability of tP2YR to cause transformation is due to its unique ability among purinergic receptors to simultaneously activate Gαq and Gαi. Co-expression of constitutively activated mutants of these two Gα subunits caused the same transformed phenotype as tP2YR and Mas. Furthermore, transformation by both tP2YR and Mas was blocked by pharmacological inhibition of GαI by pertussis toxin (PTX) indicating an essential role for Gαi in transformation by these G-protein coupled receptors.
Conclusions
Our data suggest that coordinated activation of Gαq and Gαi may link the tP2YR and possibility the Mas oncogene with signaling pathways resulting in activation of Rho family proteins to promote cellular transformation.