Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2.
The epidermal growth factor receptor (EGFR) is activated by a variety of ligands including EGF and transforming growth factor-alpha (TGFalpha), whereas no ligand for the homologous ErbB2 oncoprotein has yet been identified. Here we use both an ErbB2 phosphoantibody (aPY1222) and an activation-specific EGFR antibody to show that low concentrations of EGF induce more efficient tyrosine phosphorylation of ErbB2 in A431 cells than does equimolar TGFalpha, while EGFR is more potently activated by TGFalpha. Co-precipitation studies confirm that heterodimerization of activated EGFR and transphosphorylated ErbB2 is readily induced by EGF but not TGFalpha. EGFR downregulation is also more efficiently induced by EGF, suggesting that ligand-dependent modification of ErbB2 may be required to terminate EGFR signalling in cells expressing both receptor types. These findings indicate that EGF and TGFalpha differ in their abilities to induce tyrosine phosphorylation and heterodimerization of ErbB2, and raise the possibility that ErbB2 exerts its oncogenic effect in part by impairing TGFalpha-dependent EGFR downregulation.
Gulliford
T J
TJ
Division of Medicine, Imperial College School of Medicine, Charing Cross Hospital, London, UK.
Huang
G C
GC
Ouyang
X
X
Epstein
R J
RJ
D000906:Antibodies; D000918:Antibody Specificity; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D010766:Phosphorylation; D011233:Precipitin Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
D000906:Antibodies; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; D016211:Transforming Growth Factor alpha; D014443:Tyrosine