Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun expression to induce cell transformation.
Although the ability of G protein-coupled receptors to stimulate normal and aberrant cell growth has been intensely investigated, the precise nature of the molecular mechanisms underlying their transforming potential are still not fully understood. In this study, we have taken advantage of the potent mitogenic effect of thrombin and the focus-forming activity of one of its receptors, protease-activated receptor-1, to dissect how this receptor coupled to Galphai, Galphaq/11, and Galpha12/13 transduces signals from the membrane to the nucleus to initiate transcriptional events involved in cell transformation. Using endogenous and transfected thrombin receptors in NIH 3T3 cells, ectopic expression of muscarinic receptors coupled to Galphaq and Galphai, and chimeric G protein alpha subunits and murine fibroblasts deficient in Galphaq/11, and Galpha12/13, we show here that, although coupling to Galphai is sufficient to induce ERK activation, the ability to couple to Galphaq and/or Galpha13 is necessary to induce c-jun expression and cell transformation. Furthermore, we show that Galphaq and Galpha13 can initiate the activation of MAPK cascades, including JNK, p38, and ERK5, which in turn regulate the activity of transcription factors controlling expression from the c-jun promoter. We also present evidence that c-Jun and the kinases regulating its expression are integral components of the transforming pathway initiated by protease-activated receptor-1.
Marinissen
Maria Julia
MJ
Oral and Pharyngeal Cancer Branch, NIDCR/National Institutes of Health, Building 30, Room 211, 9000 Rockville Pike, Bethesda, MD 20892-4330, USA.
Servitja
Joan-Marc
JM
Offermanns
Stefan
S
Simon
Melvin I
MI
Gutkind
J Silvio
JS
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism; D014158:Transcription, Genetic
D044463:Receptor, PAR-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11