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Vol. 60, Issue 2, 363-372, August 2001

Suppression of Cellular Invasion by Activated G-Protein Subunits Galpha o, Galpha i1, Galpha i2, and Galpha i3 and Sequestration of Gbeta gamma

Sandrine Faivre, Karine Régnauld, Erik Bruyneel, Quang-Dé Nguyen, Marc Mareel, Shahin Emami, and Christian Gespach

Institut National de la Santé et de la Recherche Médicale U482, Hôpital Saint-Antoine, Paris, France (S.F., K.R., Q.-D.N., S.E., C.G.); and The Laboratory of Experimental Cancerology, Ghent University, Ghent, Belgium (E.B., M.M.)

It was shown previously that platelet-activating factor receptors (PAF-Rs) inhibit invasiveness of colonic and kidney epithelial cells induced by the src and Met oncogenes via a pertussis toxin-sensitive mechanism. Therefore, Madin-Darby canine kidney (MDCKts.src) cells were stably transfected with constitutively activated forms of Galpha o, Galpha i1, Galpha i2, Galpha i3 (AGalpha o/i), two Gbeta gamma sequestering proteins [C-terminal end of beta -adrenergic receptor kinase (ct-beta ARK) and the Galpha t subunit of retinal G-protein transducin], and Gbeta 1-Ggamma 2 subunits alone or in combination. Cellular invasion induced by src, Met, and leptin was abrogated by the AGalpha o/i, ct-beta ARK, and Galpha t-positive clones, but was induced by coexpression of Gbeta 1gamma 2. In contrast, invasion stimulated by the trefoil factors (TFFs) pS2 and intestinal trefoil factor in MDCKts.src cells or human colonic epithelial cells PCmsrc and HCT8/S11 was insensitive to PAF, AGalpha o, AGalpha i1, and AGalpha i2, but was abolished by AGalpha i3 and the protease-activated receptor-1 (PAR-1) agonist thrombin receptor-activating peptide. Depletion of free Gbeta gamma heterodimers by ct-beta ARK resulted in a remarkable decrease of cellular adhesion and spreading on collagen matrix. Our data demonstrate the following: 1) PAF-Rs impair cellular invasion induced by src, Met, and leptin via the activation of Galpha o and Galpha i1 to -3; 2) invasion induced by TFFs is selectively inhibited by PAR-1 receptors and Galpha i3 activation; and 3) Gbeta gamma dimers are required as positive effectors of invasion pathways induced by oncogenes and epigenetic factors. Thus, redistribution of Galpha o/Galpha i and Gbeta /gamma heterotrimeric G-proteins by PAF-R and PAR-1 exert differential functions on positive and negative signaling pathways involved in cellular invasion and may serve as potential targets for anticancer therapy.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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