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The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways

Oncogene volume 20, pages 1953–1963 (2001)Cite this article

Abstract

We utilized a cDNA expression library derived from the B6SutA1 mouse myeloid progenitor cell line to search for novel oncogenes that promote growth transformation of NIH3T3 cells. A 2.2 kb transforming cDNA was recovered that encodes the wild type thrombin-stimulated G protein-coupled receptor PAR-1. In addition to its potent focus forming activity, constitutive overexpression of PAR-1 in NIH3T3 cells promoted the loss of anchorage- and serum-dependent growth. Although inhibitors of thrombin failed to block PAR-1 transforming activity, a PAR-1 mutant that cannot be cleaved by thrombin was nontransforming. Since the foci of transformed cells induced by PAR-1 bear a striking resemblance to those induced by activated RhoA, we determined if PAR-1 transformation was due to the aberrant activation of a specific Rho family member. Like RhoA, PAR-1 cooperated with activated Raf-1 and caused synergistic enhancement of transforming activity, induced stress fibers when microinjected into porcine aortic endothelial cells, stimulated the activity of the serum response factor and NF-κB transcription factors, and PAR-1 transformation was blocked by co-expression of dominant negative RhoA. Finally, PAR-1 transforming activity was blocked by pertussis toxin and by co-expression of the RGS domain of Lsc, implicating Gαi and Gα12/Gα13 subunits, respectively, as mediators of PAR-1 transformation. Taken together, these observations suggest that PAR-1 growth transformation is mediated, in part, by activation of RhoA.

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Acknowledgements

We thank Misha Rand for assistance in figure and manuscript preparation. This work was supported by Public Health Service grants CA42978, CA55008, CA63071 (CJ Der) and CA77493 (IP Whitehead) from the National Cancer Institute, and by a grant from the Medical Research Council of Canada (RJ Kay).

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Authors and Affiliations

  1. Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7295, NC, USA

    Carol B Martin & Channing J Der

  2. Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, Newark, 07103-2714, New Jersey, NJ, USA

    Gwendolyn M Mahon & Ian P Whitehead

  3. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z-4E6, Canada

    Mark B Klinger & Robert J Kay

  4. Laboratory of Molecular Oncology, Picower Institute of Medical Research, New York, 11030, Manhasset, NY, USA

    Marc Symons

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Martin, C., Mahon, G., Klinger, M. et al. The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways. Oncogene 20, 1953–1963 (2001). https://doi.org/10.1038/sj.onc.1204281

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