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Induction and Analysis of Epithelial to Mesenchymal Transition
10:37

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Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun

Maria Julia Marinissen1, Joan-Marc Servitja, Stefan Offermanns

  • 1Oral and Pharyngeal Cancer Branch, NIDCR/National Institutes of Health, Building 30, Room 211, 9000 Rockville Pike, Bethesda, MD 20892-4330, USA.

The Journal of Biological Chemistry
|September 5, 2003
PubMed

Insights

Protease-activated receptor-1 (PAR-1) signaling through Galphaq and Galpha13 G proteins is crucial for inducing c-jun expression and cell transformation, while Galpha-i signaling alone activates ERK but does not transform cells.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • G protein-coupled receptors (GPCRs) play a role in cell growth, but their transforming potential mechanisms are not fully understood.
  • Thrombin and its receptor, protease-activated receptor-1 (PAR-1), are known mitogens with focus-forming activity.

Purpose of the Study:

  • To dissect the molecular mechanisms by which PAR-1 signaling, through specific G protein alpha subunits (Galphai, Galphaq/11, Galpha12/13), initiates transcriptional events leading to cell transformation.
  • To identify the key signaling pathways and transcription factors involved in PAR-1-mediated cell transformation.

Main Methods:

  • Utilized NIH 3T3 cells with endogenous and transfected PAR-1.
  • Employed ectopic expression of muscarinic receptors coupled to Galphaq and Galphai.
  • Used chimeric G protein alpha subunits and murine fibroblasts deficient in Galphaq/11 and Galpha12/13.

Main Results:

  • While Galphai coupling is sufficient for ERK activation, coupling to Galphaq and/or Galpha13 is essential for c-jun expression and cell transformation.
  • Galphaq and Galpha13 initiate MAPK cascades (JNK, p38, ERK5), regulating transcription factors controlling the c-jun promoter.
  • c-Jun and its regulating kinases are integral to the PAR-1 transforming pathway.

Conclusions:

  • PAR-1-mediated cell transformation is dependent on Galphaq and Galpha13 signaling pathways.
  • The JNK, p38, and ERK5 MAPK cascades, along with c-Jun, are critical components of this transforming pathway.

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