Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2

Abstract

The epidermal growth factor receptor (EGFR) is activated by a variety of ligands including EGF and transforming growth factor-alpha (TGFa), whereas no ligand for the homologous ErbB2 oncoprotein has yet been identi®ed. Here we use both an ErbB2 phosphoantibody (aPY 1222 ) and an activation-speci®c EGFR antibody to show that low concentrations of EGF induce more e cient tyrosine phosphorylation of ErbB2 in A431 cells than does equimolar TGFa, while EGFR is more potently activated by TGFa. Co-precipitation studies con®rm that heterodimerization of activated EGFR and transphosphorylated ErbB2 is readily induced by EGF but not TGFa. EGFR downregulation is also more e ciently induced by EGF, suggesting that liganddependent modi®cation of ErbB2 may be required to terminate EGFR signalling in cells expressing both receptor types. These ®ndings indicate that EGF and TGFa di er in their abilities to induce tyrosine phosphorylation and heterodimerization of ErbB2, and raise the possibility that ErbB2 exerts its oncogenic e ect in part by impairing TGFa-dependent EGFR downregulation.

The relative role of ErbB1–4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells

“…In comparison, A431 SCCs expressed higher levels of ErbB1 consistent with previous reports (Gamett et al, 1995;Gulliford et al, 1997;Riese and Stern, 1998); the relative expression levels of ErbB2 and ErbB3 proteins were similar to those in MDA cells. In both cell lines ErbB4 protein was not detected by immunoprecipitation ( Figure 1).…”

“…Therefore, comparing expression levels of di erent ErbB receptors in a given cell line is less reliable than the relative quantitation of the same ErbB receptor in di erent cell lines. Another consideration is that the relative expression levels of ErbB proteins may depend on culture conditions and the duration of continuous culture (Gulliford et al, 1997;Todd et al, 1999). Despite these caveats our ®ndings support the concept that in autocrine growth regulated carcinoma cells at least one of the ErbB receptors with GF binding speci®city and an active kinase domain, such as ErbB1 or ErbB4, are dominantly expressed.…”

“…These results were consistent with the relative inhibitor selectivity of AG825 for ErbB2. Furthermore, these results demonstrated that inhibiting ErbB2 resulted in a compensatory activation of ErbB1 suggesting a possible negative modulating role for ErbB2 on ErbB1 function (Gulliford et al, 1997).…”

Active signaling by Neu in transgenic mice

“…Selective pressure for mutational activation may occur with greater frequency when other mechanisms of activation are not readily available. It has also been reported that TGFa is a less ecient transactivator of Neu than is EGF (Gulliford et al, 1997).…”

Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells

“…In addition, we have shown that the functionally distinct EGFR ligands, EGF and transforming growth factor-alpha (TGFa), exert differing effects on EGFR downregulation and hence on the duration of ErbB2 co-activation: high concentrations of EGF initially cause prolonged EGFR activation associated with ErbB2 heterodimerisation, followed by eventual EGFR downregulation and signal cessation; whereas TGFa fails to downregulate EGFR, leading to sustained signalling (Gulliford et al, 1997;Ouyang et al, 1999a). The possibility is thus raised that ErbB2 could mimic the tumorigenic effects of TGFa in cancer cells by its similar ability to prolong EGFR signalling.…”