A comparison of epidermal growth factor receptor-mediated mitogenic signaling in response to transforming growth factor alpha and epidermal growth factor in cultured fetal rat hepatocytes.
We compared the ability of Epidermal Growth Factor (EGF) and Transforming Growth Factor alpha (TGF alpha) to transduce a mitogenic signal via their common receptor, the EGF receptor, in primary cultures of fetal rat hepatocytes. Mitogenic potency, measured as DNA synthesis, was similar in response to EGF and TGF alpha although signal initiation, measured as EGF receptor tyrosine phosphorylation, was more than 3-fold higher in response to EGF compared to TGF alpha. Downstream signal transduction events including Shc tyrosine phosphorylation, Shc/Grb2 complex formation and MAP kinase activation were similar in response to EGF and TGF alpha, thus indicating a dissociation between potency for receptor activation versus signal propagation. These data suggest that TGF alpha may preferentially activate an EGF receptor population linked to the Ras/MAP kinase pathway. In contrast, EGF shows no such selectivity, thereby reducing the mitogenic potency of EGF relative to its ability to activate the EGF receptor.
Lipeski
L E
LE
Division of Pediatric Endocrinology and Metabolism, Rhode Island Hospital, Providence, USA.
Boylan
J M
JM
Gruppuso
P A
PA
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000196:embryology*; D008934:Mitogens / Q000494:pharmacology; D010766:Phosphorylation; D011247:Pregnancy; D011506:Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D008934:Mitogens; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016211:Transforming Growth Factor alpha; D014443:Tyrosine; D004815:Epidermal Growth Factor; D004247:DNA; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013936:Thymidine