Development of Strategies to Manipulate ErbB Receptor Heterodimerization from a Quantitative Analysis of Receptor/Ligand Relationships
Abstract
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 erbB1 (the EGF receptor) by directly inducing its homodimerization, the same growth factor activates erbB2 by inducing the formation of hetero-oligomeric complexes between erbB1 and erbB2. We have shown that the isolated extracellular domain of erbB1 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. Using a variety of approaches for directly visualizing erbB receptor homo- and hetero- oligomerization in living cells, we are now investigating the origin of this mechanistic difference, and defining the regions of the receptors that participate. Answers to these questions will likely suggest new avenues for pharmacological intervention when erbB receptors are inappropriately activated.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADB266202
Entities
People
- Mark A. Lemmon
Organizations
- University of Pennsylvania