This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Darmoul, D. Articles by Laburthe, M. Search for Related Content PubMed PubMed Citation Articles by Darmoul, D. Articles by Laburthe, M.

---

Signaling and Regulation

Activation of Proteinase-Activated Receptor 1 Promotes Human Colon Cancer Cell Proliferation Through Epidermal Growth Factor Receptor Transactivation

¹ Neuroendocrinologie et Biologie Cellulaire Digestives, Institut National de la Sante et de la Recherche Medicale, Paris, France and ² UMR 626, Faculté de Médecine Timone, Marseille, France

Requests for reprints: Dalila Darmoul, Neuroendocrinologie et Biologie Cellulaire Digestives, Institut National de la Sante et de la Recherche Medicale U410, Faculté de Médecine Xavier Bichat, 75018 Paris, France. Phone: 33-1-44-85-61-30; Fax: 33-1-42-28-87-65. E-mail: darmoul{at}bichat.inserm.fr

Serine proteases are now considered as crucial contributors to the development of human colon cancer. We have shown recently that thrombin is a potent growth factor for colon cancer cells through activation of the aberrantly expressed protease-activated receptor 1 (PAR1). Here, we analyzed the signaling pathways downstream of PAR1 activation, which lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events on activation of PAR1 by thrombin or specific activating peptide: (a) a matrix metalloproteinase–dependent release of transforming growth factor- (TGF-) as shown with TGF- blocking antibodies and measurement of TGF- in culture medium; (b) TGF--mediated activation of epidermal growth factor receptor (EGFR) and subsequent EGFR phosphorylation; and (c) activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and subsequent cell proliferation. The links between these events are shown by the fact that stimulation of cell proliferation and ERK1/2 on activation of PAR1 is reversed by the MMP inhibitor batimastat, TGF- neutralizing antibodies, EGFR ligand binding domain blocking antibodies, and the EGFR tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGFR seems to be a major mechanism whereby activation of PAR1 results in colon cancer cell growth. Finally, PAR1 activation induces Src phosphorylation, which is reversed by using the Src tyrosine kinase inhibitor PP2, suggesting that Src activation plays a permissive role for PAR1-mediated ERK1/2 activation and cell proliferation probably acting downstream of the EGFR. These data explain how thrombin exerts robust trophic action on colon cancer cells and underline the critical role of EGFR transactivation.

This article has been cited by other articles:

				T. Voisin, A. El Firar, C. Rouyer-Fessard, V. Gratio, and M. Laburthe A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism FASEB J, June 1, 2008; 22(6): 1993 - 2002. [Abstract] [Full Text] [PDF]

				A. Siegbahn, M. Johnell, A. Nordin, M. Aberg, and T. Velling TF/FVIIa Transactivate PDGFR to Regulate PDGF-BB Induced Chemotaxis in Different Cell Types: Involvement of Src And PLC Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 135 - 141. [Abstract] [Full Text] [PDF]

				M. Hurtado, J. J. Lozano, E. Castellanos, L. A Lopez-Fernandez, K. Harshman, C. Martinez-A, A. R Ortiz, T. M Thomson, and R. Paciucci Activation of the epidermal growth factor signalling pathway by tissue plasminogen activator in pancreas cancer cells Gut, September 1, 2007; 56(9): 1266 - 1274. [Abstract] [Full Text] [PDF]

				D. F. McCole, A. Truong, M. Bunz, and K. E. Barrett Consequences of Direct Versus Indirect Activation of Epidermal Growth Factor Receptor in Intestinal Epithelial Cells Are Dictated by Protein-tyrosine Phosphatase 1B J. Biol. Chem., May 4, 2007; 282(18): 13303 - 13315. [Abstract] [Full Text] [PDF]