Recycling of HER/ErbB Receptor: Rescue from Apoptosis and Targets for Immunotherapy
Abstract
Signals to multiply, migrate and outgrow blood vessels are mediated by growth factors of the EGF/neuregulin family. Concentrating on the EGF-receptor, our first task was to resolve mechanisms that normally restrain signalin. These efforts have led to the realization that activated growth factor receptors are modified by mono-ubiquitins rather than by poly-ubicuitylation. Receptor ubiquitylation is mediated by the c-Cbl E3 ligase, and we identified a Cbl-binding protein, called Grb2, as an enhancer of Cbl's action on active receptors. Our Task 2 relates to a putative particle that modulates recycling of ErbBs, and we identified c-Src as a major player in recycling: c-Src phopshorylates c-Cbl and leads to its proteasomal destruction. Consequently, tumor cells overexpressing c-Src are unable to down-regulate ErbB proteins. In addition, we identified the Hgs adaptor and the Nedd4 ubiquitin ligase as regulators of receptor recycling. In an effort to translate our findings to clinical protocols, our Task 3 involved in vitro studies and as says in animals testing combinations of monoclonal antibodies to ErbBs, inhibitors of their intrinsic tyrosine kinase activity, and blockers of c-Src. Unlike the results of the first two tasks, which have been published, the results of the latter part are currently assembled for publication.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA417034
Entities
People
- Yosef Yarden
Organizations
- Weizmann Institute of Science