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Original Article

Elastin Peptides Activate Extracellular Signal-Regulated Kinase 1/2 via a Ras-Independent Mechanism Requiring Both p110/Raf-1 and Protein Kinase A/B-Raf Signaling in Human Skin Fibroblasts

Laboratory of Biochemistry, Unité Mixte Recherche Centre National de la Recherche Scientifique 6198, IFR53 Biomolécules, Faculty of Sciences, University of Reims Champagne-Ardenne, Moulin de la Housse, Reims, France (L.Du., E.L., R.D., B.R., C.B., F.D., W.H., L.M., L.De.); and EA 2070, IFR53 Biomolécules, Faculty of Pharmacy, University of Reims Champagne-Ardenne, Reims, France (R.D.)

Abstract

Elastin peptides (EPs) produced during cancer progression bind to the elastin binding protein (EBP) found at the surface of dermal fibroblasts, leading to the expression of collagenase-1 gene. The production of this enzyme involved in stromal reaction is caused by the sustained activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway via cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K). However, the mechanism of these signaling events remains unknown. We show that -elastin (E), a commonly used EP, induces maximum phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)1/2 and ERK1/2 after 30 min. The simultaneous inhibition of PKA and PI3K, by N-(2-(p-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (H89) and 2-(4-morpholynil)-8-phenyl-4H-1-bemzopyran-4-one (LY294002), respectively, blocked MEK1/2 and ERK1/2 phosphorylation, as did lactose, an EBP antagonist. E induced Raf-1 phosphorylation and activation in a PI3K-dependent manner. In our system, the PI3K p110 is expressed and activated by -derived subunits from a pertussis toxin-sensitive G protein after fibroblast stimulation. Pertussis toxin also blocks the Raf-1/MEK1/2/ERK1/2 phosphorylation cascade. In addition, we found that B-Raf is expressed in dermal fibroblasts and activated in a PKA-dependent manner after E treatment, thereby integrating PKA signals to MEK1/2. It is noteworthy that Ras involvement was excluded because ERK1/2 activation by E was not blocked in RasN17-transfected fibroblasts. Together, our results identify a novel Ras-independent ERK1/2 activation system in which p110/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Thus, p110 and B-Raf seem to be important modulators of dermal fibroblasts physiology and should now qualify as therapeutic targets in strategies aiming at limiting elastin degradation contribution to cancer progression.

Address correspondence to: Dr. Laurent Debelle, Université de Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Laboratoire de Biochimie, UMR CNRS 6198, IFR53 Biomolécules, Moulin de la Housse, BP 1039, 51687 REIMS Cedex 2, France. E-mail: laurent.debelle{at}univ-reims.fr

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