Regulation of ErbB Signaling in Breast Cancer Epithelial Cells by Cbl Proto-Oncogene Product

摘要

Our laboratory investigates the mechanism of action of Cbl, a protein that is inducibly recruited to activated EGF receptors (EGF-R) and enhances receptor ubiguitination, downregulation, and degradation. Understanding the molecular basis for EGF-R regulation is an important goal in breast cancer research: the receptor is deregulated in up to 48% of all breast cancers. By defining the mechanisms used by Cbl to attenuate EGF-R signaling, we may identify interventions for the treatment of breast cancers. We have proposed to determine whether the recruitment of Cbl to EGF-R is ligand-selective and critical for the termination of signaling by the receptor. In linked studies of receptor signaling and subcellular localization, we will determine whether different EGF-R ligands that elicit distinct biological responses do so because of their differential recruitment of Cbl to EGF-R. In the 8.5 months since the award was reactivated, we have established the experimental parameters necessary to complete Tasks 1, 5, and 6. A key finding of this work is that Cbl is recruited equally well to EGF-R activated by EGF or TGF-alpha, and Cbl ubiquitinates the differently activated receptors identically. This indicates that the recruitment of Cbl to EGF-R is not sufficient to target the protein for degradation.