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RhoA‐ and RhoD‐dependent regulatory switch of Gα subunit signaling by PAR‐1 receptors in cellular invasion
Author(s) -
Nguyen Quang-Dé,
Faivre Sandrine,
Bruyneel Erik,
Rivat Christine,
Seto Minoru,
Endo Takeshi,
Mareel Marc,
Emami Shahin,
Gespach Christian
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0525com
Subject(s) - rhoa , microbiology and biotechnology , biology , signal transduction , rac1 , rac gtp binding proteins , gtpase , myosin light chain kinase , phosphorylation
Thrombin and proteinase‐activated receptors (PAR) specifically regulate several functions that markedly enhance the transformation phenotype such as inflammation, cell proliferation, tumor growth, and metastasis. We recently reported that thrombin inhibits cellular invasion induced by src, hepatocyte growth factor (HGF), and leptin in kidney and colonic epithelial cells via predominant activation of the pertussis toxin (PTx) ‐sensitive G‐proteins Gαo/Gαi. We provide pharmacological and biochemical evidence that in the presence of PTx, PAR‐1 induced cellular invasion through Gα12/Gα13‐ and RhoA/Rho kinase (ROCK) ‐dependent signaling. However, inhibition of the endogenous small GTPase RhoA by the C3 exoenzyme, dominant‐negative N19‐RhoA, activated G26VRhoD, and activators of the nitric oxide/cGMP pathways conferred invasive activity to PAR‐1 via a signaling cascade using Gαq, phospholipase C (PLC), Ca 2+ / calmodulin myosin light chain kinase (CaM‐MLCK), and phosphorylation of MLC. We found that cellular invasion induced by the src oncogene is abrogated by inhibitors of the RhoA/ROCK pathway and is independent of PLC/CaM‐MLCK signaling. Our data demonstrate that the RhoA and RhoD small GTPases are acting as a molecular switch of cellular invasion and reveal a novel critical mechanism by which PAR‐1 bypass Gαo/i and RhoA inhibition via differential coupling to heterotrimeric G‐proteins linked to divergent or convergent biological responses. Our data also indicate that Rho GTPases and ROCK mediate a src‐dependent invasion signal in kidney and colonic cancer cells. We conclude that dynamic regulation of Rho GTPases activation and inactivation by oncogenes, growth factors, cGMP‐inducing agents, and adhesion molecules can initiate convergent invasion signals controlled by the thrombin PAR‐1 in cancer cells.—Nguyen, Q.‐D., Faivre, S., Bruyneel, E., Rivat, C., Seto, M., Endo, T., Mareel, M., Emami, S., Gespach, C. RhoA‐ and RhoD‐dependent regulatory switch of Gα subunit signaling by PAR‐1 receptors in cellular invasion. FASEB J. 16, 565–576 (2002)