Mechanisms of ErbB2/HER2/Neu Activation

University Of Pennsylvania, Philadelphia PA

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Abstract

[unreadable] DESCRIPTION (Provided by applicant): Growth factor receptors from the epidermal growth factor (EGF) receptor, or erbB/Her/Neu family can be activated in two ways. In the first, growth factor binding stabilizes a receptor homodimer in which the intracellular tyrosine kinase domains are activated. This is exemplified by EGF activation of its receptor (erbB1). The second mode involves 'transmodulation', for which the mechanism is not at all clear. Transmodulation was first reported for erbB2 activation by EGF, which it does not bind. EGF-dependent erbB2 activation requires the presence of erbB1 (the EGF receptor), which activates erbB2 in trans through a mechanism that involves formation of erbB1/erbB2 hetero-oligomers. For erbB2, which has no known ligand, such transmodulation offers the only route for normal activation. Since erbB2 is so important in breast and other cancers, understanding the mechanism of its transmodulation is an important aim, and is the focus of this proposal. If we can understand how erbB2 is activated, it should ultimately be possible to design approaches to reverse activation when it happens inappropriately and leads to cancer. In previous in vitro studies, we found that ligand-induced erbB receptor homodimerization, but not hetero-oligomer formation, can be reproduced with isolated receptor extracellular domains (ECD's). This finding argues that homodimerization and the hetero-oligomerization required for transmodulation differ in how they are driven. Specifically, the finding argues that regions other than the ECD's are important for hetero-oligomerization. To resolve the mechanistic differences, and to determine which regions of erbB receptors drive their hetero-oligomerization, we propose a systematic study of ligand-induced erbB receptor homo- and hetero-oligomerization in vivo, to address the following mechanistic questions: 1. To test the hypothesis that normal erbB2 activation involves its homodimerization by 'proxy', induced by a ligand-stabilized erbB1 or erbB4 dimer. 2. To determine which pairwise erbB receptor combinations occur in oligomers induced by different erbB ligands in vivo. 3. To determine which portions of erbB receptors are required for interactions that cause transmodulation.