A Novel Pathway to Down-Regulate ErbB Signaling in Mammary Epithelial
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 downregulation 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 focused on characterization of a series of mutant forms of Cbl that are unable to mediate ubiquitination of EGFR. The analyses of these mutants support the role of ubiquitination in Cbl-mediated cell surface regulation of EGFR. Further studies will establish the intracellular targeting of downregulated ErbB receptors to lysosomes, and utilize a number of biological systems to directly explore if ubiquitination is an essential mechanism for sorting ErbB receptors to lysosomes. The present studies, thus, aim to define novel strategies to downregulate proliferative signals in breast cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2001
- Accession Number
- ADA391078
Entities
People
- Hamid Band
- Lei Duan
Organizations
- Brigham and Women's Hospital