Contribution of PKC-dependent and -independent processes in temporal ERK regulation by ET-1, PDGF, and EGF in rat myometrial cells.
Endothelin-1 (ET-1), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) stimulated thymidine incorporation with different efficiency (PDGF >> EGF = ET-1) in rat myometrial cells. They also stimulated ERK activation, which culminated at 5 min and then declined to reach a plateau (at 45 min: EGF > 90%, PDGF = 50%, and ET-1 < 10% of maximum). Inhibition and downregulation of PKC demonstrated that ERK activation at 5 min involved PKC delta and -zeta for ET-1 and PKC alpha plus another PKC isoform for PDGF. By contrast, the EGF response did not involve PKC. Stimulation of Ras was more important with EGF than with PDGF, with ET-1 being the weakest activator. The simultaneous incubation of the cells with EGF and ET-1 potentiated the ERK activation at 5 min and mimicked the plateau phase obtained with PDGF. Under these conditions thymidine incorporation was comparable to that induced by PDGF. Taken together, our results indicated that the kinetic profile of ERK activation and its impact on cell proliferation can be modulated by the differential involvement of PKC isoforms and the amplitude of Ras activation.
Robin
Philippe
P
Laboratoire de Signalisation et Régulations Cellulaires, CNRS UMR 8619, Bâtiment 430, Université de Paris-Sud, 91405 Orsay Cedex, France. philippe.robin@bbmpc.u-psud.fr
Boulven
Isaline
I
Bôle-Feysot
Christine
C
Tanfin
Zahra
Z
Leiber
Denis
D
D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009215:Myometrium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000099221:Protein Kinase C zeta
D019332:Endothelin-1; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D044022:Receptor, Endothelin A; D010738:Type C Phospholipases; D018631:ras Proteins; D000099221:Protein Kinase C zeta; C497260:Prkcd protein, rat; C497257:Prkce protein, rat