Development of Strategies to Manipulate ErbB Receptor Heterodimerization from a Quantitative Analysis of Receptor/Ligand Relationships

摘要

Members of the erbB family of receptor tyrosine kinases include the epidermal growth factor (EGF) receptor and erbB2 (also known as HER-2/Neu) that is found overexpressed in many human breast cancer cases. The aim of our studies is to understand the mechanism by which growth factors activate these receptors. If this mechanism can be understood in detail, it should be possible to design approaches to block inappropriate receptor activation, which occurs in many breast cancers. While EGF activates erbB 1 (the EGF receptor) by directly inducing its homodimerization, the same growth factor activates erbB2 by inducing the formation of hetero-oligomeric complexes between erbB 1 and erbB2. We have shown that the isolated extracellular domain of erbB 1 is sufficient for EGF-induced homodimerization of that receptor. By contrast, isolated extracellular domains are not sufficient to recapitulate the hetero- oligomerization of erbB receptors that has been observed in vivo. These findings argue that erbB receptor homo- and hetero-oligomerization occur though different mechanisms. Subsequently, using a variety of approaches for analyzing erbB receptor transmodulation in living cells, we have generated data that support a homodimer-nucleated heterotetramer model. In this case, an activated erbB 1 homodimer is the effective ligand for erbB2, and activates it. This view, although preliminary, provides new ideas for developing approaches to reverse aberrant erbB2 activation in breast cancer.