A Novel Pathway to Down-Regulate ErbB Signaling in Mammary Epithelial Cells
Abstract
Activation of tyrosine kinases plays a key role in cell proliferation, and ErbB receptor tyrosine kinases are specifically implicated in breast cancer. Biochemical studies have recently identified the proto-oncogene product Cbl as a negative regulator of EGF receptor and ErbB2. The Cbl-dependent negative regulation of ErbB receptors was associated with their ubiquitin modification and down-regulation from the cell surface. Based on these observations, this proposal is investigating the role of Cbl-mediated ubiquitination as a signal for targeting activated ErbB receptors to lysosomes where they undergo degradation. The work reported here has demonstrated that ubiquitin modification of EGFR is essential for its down-regulation. Furthermore, this modification is shown to be essential for EGFR trafficking between early and late endosome, while being dispensable for initial endocytosis. Further studies aim to establish a causal role of Cbl in this process, using Cbl non-binding EGFR mutants that have been engineered and Cbl-deficient cell lines expressing EGFR or ErbB2 that have been generated. The present studies, thus, aim to understand the molecular basis of a novel pathway that controls the down-regulation of proliferative signals in breast cancer cells. Elucidation of this pathway is likely to reveal novel targets to develop rational therapeutic agents for breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2002
- Accession Number
- ADA405502
Entities
People
- Hamid Band
- Lei Duan
Organizations
- Brigham and Women's Hospital