TGF-beta isoforms differentially attenuate EGF mitogenicity and receptor activity in fetal lung mesenchymal cells.
To evaluate signaling interactions, combinations of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) isoforms were applied to primary fetal mouse lung mesenchymal cells isolated at 16 days of gestation. The three isoforms of TGF-beta had similar mitogenic potentials, as assessed by thymidine incorporation (half-maximal effective concentration approximately 2 ng/ml). However, combined exposure to EGF and TGF-beta yielded an isoform-dependent attenuation of EGF-induced mitogenesis. Combinations of 20 ng/ml EGF and 2 ng TGF-beta 1, TGF-beta 2, or TGF-beta 3 resulted in thymidine incorporation values 0.76, 0.74, and 0.86 times that of EGF alone, respectively; attenuation of EGF mitogenicity, interactions between EGF and TGF-beta isoforms, and differences between isoforms were all statistically significant by analysis of variance. Treatment with TGF-beta isoforms significantly reduced EGF-induced receptor angiotensin II substrate phosphorylation. TGF-beta isoform-specific signaling also significantly attenuated EGF-induced phosphorylation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 2. These results suggest that isoform-specific TGF-beta signaling modulates the EGF signal transduction pathway upstream of MAP kinase.
Lee
M
M
Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, USA.
Hwang
C
C
Lee
J
J
Slavkin
H
H
Warburton
D
D
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005333:Fetus / Q000166:cytology / Q000378:metabolism*; D007536:Isomerism; D008168:Lung / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D051379:Mice / Q000196:embryology; D008934:Mitogens / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D008934:Mitogens; D016212:Transforming Growth Factor beta; D014443:Tyrosine; D004815:Epidermal Growth Factor; D010770:Phosphotransferases; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013936:Thymidine