Response to transforming growth factor alpha (TGFalpha) and epidermal growth factor (EGF) in hepatocytes: lower EGF receptor affinity of TGFalpha is associated with more sustained activation of p42/p44 mitogen-activated protein kinase and greater efficacy in stimulation of DNA synthesis.
The epidermal growth factor (EGF) receptor mediates the effects of both EGF and transforming growth factor alpha (TGFalpha). Recent data suggested that EGF acts as a partial agonist/antagonist in hepatocytes, TGFalpha exerting a larger maximal stimulation of DNA synthesis than EGF. To further study the mechanisms involved in mediating the different effects of EGF and TGFalpha, we have examined receptor binding of the two growth factors and their action on the p42/p44 mitogen-activated protein (MAP) kinase activity in hepatocytes. Single-ligand concentration curves and competition experiments showed that the binding affinity to a common population of surface binding sites was about 20-fold lower for TGFalpha than for EGF. MAP kinase activity responded to EGF and TGFalpha with different kinetics. While the two agents produced almost identical acute (5 min) stimulation (peak about fivefold), TGFalpha produced a more sustained MAP kinase activity than EGF. The difference between EGF and TGFalpha was still detectable 24 h after growth factor addition. The results show that in hepatocytes a lower receptor affinity of TGFalpha, as compared to EGF, is associated with a more sustained activation of the MAP kinase and a greater efficacy in the stimulation of DNA synthesis. This suggests that differential interaction of these two agents with the EGF receptor results in differences in the downstream events elicited at a given level of receptor occupancy. The data also are compatible with a role of a prolonged MAP kinase activity in the mitogenic effects of EGF and TGFalpha.
Thoresen
G H
GH
Department of Pharmacology, Faculty of Medicine, University of Oslo, Norway. hege.thoresen@labmed.uio.no
Guren
T K
TK
Sandnes
D
D
Peak
M
M
Agius
L
L
Christoffersen
T
T
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*
D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D004247:DNA; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases