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

Carol B. Martin, Gwendolyn M. Mahon, Mark B. Klinger, Robert J. Kay, Marc Symons, Channing J. Der, Ian P. Whitehead

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1953-1963
Number of pages11
JournalOncogene
Volume20
Issue number16
DOIs
StatePublished - Apr 12 2001

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Cancer Research

Keywords

  • PAR-1
  • RhoA
  • Thrombin
  • Transformation

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