Abstract
Numerous epidermal growth factor (EGF)-related peptide binding members of the ErbB family of receptor tyrosine kinases have been described. While several EGF agonists bind and activate ErbB-1/EGF receptor, neu differentiation factor (NDF) functions as a ligand for ErbB-3 and ErbB-4. However, it is currently unknown which specific subsets of ErbB receptors become activated in response to each of these ligands. The present study addresses this issue using the T47D breast tumor cell line, which expresses moderate levels of all the presently known ErbB receptors. We show that all the EGF agonists, but not NDF, stimulated tyrosine phosphorylation of ErbB-1. In contrast, all the EGF-related factors except amphiregulin were able to induce tyrosine phosphorylation of ErbB-2. The ability to induce tyrosine phosphorylation of ErbB-3 varied dramatically among the different EGF-related peptides. While EGF, transforming growth factor (TGF)-alpha, and amphiregulin only had a moderate effect, NDF dramatically increased the ErbB-3 phosphotyrosine content. Most notably, heparin binding EGF-related growth factor (HB-EGF) and betacellulin (BTC) were more effective than other EGF agonists. Consequently, only NDF, HB-EGF, and BTC significantly stimulated association of phosphatidylinositol kinase activity with ErbB-3. Among the EGF agonists, HB-EGF induced a low level of ErbB-4 tyrosine phosphorylation, while BTC was as efficient as NDF in activating ErbB-4. The BTC activation of ErbB-4 appears to be independent of ErbB-1, as shown by pretreatment of cells with an antibody that inhibits binding of EGF agonists to ErbB-1. As a result of the differential activation of ErbB receptors, most of the EGF-related growth factors had distinguishable biological activities on cultured mammary epithelial cell lines.
Highlights
Phosphotyrosine binding domain containing proteins and allow for the modulation of intracellular signaling pathways [2, 3]
T47D cells were treated with epidermal growth factor (EGF), transforming growth factor (TGF)␣, heparin-binding EGF-like growth factor (HB-EGF), AR, BTC, or neu differentiation factor (NDF), and ErbB-1 was immunoprecipitated and analyzed for its phosphotyrosine content by Western blotting with a specific antibody (Fig. 1A)
With the exception of AR, the EGF agonists, as well as NDF, induced tyrosine phosphorylation of ErbB-2 to a similar extent, presumably due to the ability of both EGF- and NDF-receptors to heterodimerize with this receptor (Fig. 1B)
Summary
Phosphotyrosine binding domain containing proteins and allow for the modulation of intracellular signaling pathways [2, 3]. A large number of RTK subclasses has been described, among which the type I/ErbB family of RTKs is of particular interest due to their frequent involvement in human cancer Four members of this family are currently known: epidermal growth factor (EGF) receptor/ErbB-1, ErbB-2, ErbB-3, and ErbB-4 (4 –7). Regulation of ErbB receptor activity appears to be very complex since a large number of ErbB ligands have been described. All of these peptides are derived from transmembrane precursors and are cleaved to give rise to the mature, soluble ligands. In view of the large number of ErbB ligands and the extensive cross-talk occurring between ErbB receptors, the knowledge about functional differences in the signaling capacities of EGF-related peptides has remained fragmentary. The present study was designed as a comparative analysis of all the currently available EGF-related growth factors with respect to activation of ErbB receptors and biological activity
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