| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
subunit signaling by PAR-1 receptors in cellular invasion
INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France;
*
The Laboratory of Experimental Cancerology, Ghent University Hospital, B-9000 Ghent, Belgium;
Asahi Chemical Industry Company, Samejima, Fuji, Shizuoka 416-0934, Japan; and
Chiba University, Department of Biology, 1-33 Yayoicho, Inageku, Chiba, Chiba 263-8522, Japan
1Correspondence: INSERM Unit U482, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France. E-mail: gespach{at}st-antoine.inserm.fr
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 G
o/Gi. We provide pharmacological and biochemical evidence that in the presence of PTx, PAR-1 induced cellular invasion through G12/G13- and RhoA/Rho kinase (ROCK) -dependent signaling. However, inhibition of the endogenous small GTPase RhoA by the C3 exoenzyme, dominant-negative N19-RhoA, activated G26V-RhoD, and activators of the nitric oxide/cGMP pathways conferred invasive activity to PAR-1 via a signaling cascade using Gq, phospholipase C (PLC), Ca2+/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 Go/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 G subunit signaling by PAR-1 receptors in cellular invasion.
Key Words: colon cancer progression • metastatic potential • guanylate cyclases • src • rac • myosin light chain kinase • guanylin • cGMP
This article has been cited by other articles:
|
|
 |
|
  G. P. Prevost, M. O. Lonchampt, S. Holbeck, S. Attoub, D. Zaharevitz, M. Alley, J. Wright, M. C. Brezak, H. Coulomb, A. Savola, et al. Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric G{alpha}/G{beta}{gamma} Protein Complex. Cancer Res., September 15, 2006; 66(18): 9227 - 9234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Souaze, V. Viardot-Foucault, N. Roullet, M. Toy-Miou-Leong, A. Gompel, E. Bruyneel, E. Comperat, M. C Faux, M. Mareel, W. Rostene, et al. Neurotensin receptor 1 gene activation by the Tcf/{beta}-catenin pathway is an early event in human colonic adenomas Carcinogenesis, April 1, 2006; 27(4): 708 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Steinhoff, J. Buddenkotte, V. Shpacovitch, A. Rattenholl, C. Moormann, N. Vergnolle, T. A. Luger, and M. D. Hollenberg Proteinase-Activated Receptors: Transducers of Proteinase-Mediated Signaling in Inflammation and Immune Response Endocr. Rev., February 1, 2005; 26(1): 1 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hazarika, M. F. McCarty, V. G. Prieto, S. George, D. Babu, D. Koul, M. Bar-Eli, and M. Duvic Up-regulation of Flotillin-2 Is Associated with Melanoma Progression and Modulates Expression of the Thrombin Receptor Protease Activated Receptor 1 Cancer Res., October 15, 2004; 64(20): 7361 - 7369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. Zharikov, K. Y. Krotova, L. Belayev, and E. R. Block Pertussis toxin activates L-arginine uptake in pulmonary endothelial cells through downregulation of PKC-{alpha} activity Am J Physiol Lung Cell Mol Physiol, May 1, 2004; 286(5): L974 - L983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ge, Y. Ly, M. Hollenberg, and K. DeFea A {beta}-Arrestin-dependent Scaffold Is Associated with Prolonged MAPK Activation in Pseudopodia during Protease-activated Receptor-2-induced Chemotaxis J. Biol. Chem., September 5, 2003; 278(36): 34418 - 34426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Kang, S. Y. Choi, M. K. Cho, C. H. Lee, and S. G. Kim Thrombin Induces Nitric-oxide Synthase via Galpha 12/13-coupled Protein Kinase C-dependent I-kappa Balpha Phosphorylation and JNK-mediated I-kappa Balpha Degradation J. Biol. Chem., May 2, 2003; 278(19): 17368 - 17378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mareel and A. Leroy Clinical, Cellular, and Molecular Aspects of Cancer Invasion Physiol Rev, April 1, 2003; 83(2): 337 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Attoub, C. Rivat, S. Rodrigues, S. Van Bocxlaer, M. Bedin, E. Bruyneel, C. Louvet, M. Kornprobst, T. Andre, M. Mareel, et al. The c-kit Tyrosine Kinase Inhibitor STI571 for Colorectal Cancer Therapy Cancer Res., September 1, 2002; 62(17): 4879 - 4883. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
