The differential activation of phosphatidylinositol-3 kinase and mitogen-activated protein kinases by PDGF-AA and IGF-I might explain the synergistic effect of the two growth factors on the proliferation of AKR-2B fibroblasts.
AKR-2B mouse fibroblasts express similar numbers of alpha- or beta-type PDGF receptors on their surface. Previous studies showed that PDGF-AA alone was unable to stimulate cell proliferation. Simultaneous addition together with insulin-like growth factor I (IGF-I), itself also inactive, led to a significant proliferation of the cells. In an effort to explain this synergism of the two growth factors we describe here the effects of the isoforms PDGF-AA or -BB and insulin-like growth factor I on three distinct signaling pathways, i.e., polyphosphoinositol turnover and [Ca2+]i increase, phosphatidylinositol-3 kinase, and mitogen-activated protein kinases. Whereas PDGF-BB effectively stimulated all three events, PDGF-AA failed to stimulate the phosphatidylinositol-3 kinase activity, but stimulated the mitogen-activated protein kinase to a maximum extent. In contrast IGF-I had no effect on mitogen-activated kinase but strongly stimulated phosphatidylinositol-3 kinase activity.
Department of Physiological Chemistry, Theodor-Boveri-Institute, University of Würzburg, Germany.
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TA
Karenberg
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Fenn
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Sachinidis
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Hoppe
D000818:Animals; D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004357:Drug Synergism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007295:Inositol Phosphates / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008806:Mice, Inbred AKR; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D007295:Inositol Phosphates; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium